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Current and Future Treatments in Alzheimer Disease: An Update

Konstantina g yiannopoulou.

1 Memory Center, Neurological Department, Henry Dunant Hospital Center, Athens, Greece

Sokratis G Papageorgiou

2 Cognitive Disorders/Dementia Unit, 2nd Neurological Department, National and Kapodistrian University of Athens, Attikon General University Hospital, Athens, Greece

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

Introduction

Alzheimer disease (AD) is one of the greatest medical care challenges of our century and is the main cause of dementia. In total, 40 million people are estimated to suffer from dementia throughout the world, and this number is supposed to become twice as much every 20 years, until approximately 2050. 1

Because dementia occurs mostly in people older than 60 years, the growing expansion of lifespan, leading to a rapidly increasing number of patients with dementia, 2 mainly AD, has led to an intensive growth in research focused on the treatment of the disease. However, despite all arduous research efforts, at the moment, there are no effective treatment options for the disease. 3 , 4

The basic pathophysiology and neuropathology of AD that drives the current research suggests that the primary histopathologic lesions of AD are the extracellular amyloid plaques and the intracellular Tau neurofibrillary tangles (NFTs). 5 The amyloid or senile plaques (SPs) are constituted chiefly of highly insoluble and proteolysis-resistant peptide fibrils produced by β-amyloid (Aβ) cleavage. Aβ peptides with Aβ38, Aβ40, and Aβ42 as the most common variants are produced after the sequential cleavage of the large precursor protein amyloid precursor protein (APP) by the 2 enzymes, β-secretase (BACE1) and γ-secretase. Nevertheless, Aβ is not formed if APP is first acted on and cleaved by the enzyme α-secretase instead of β-secretase. 6 According to the “amyloid hypothesis” Aβ production in the brain initiates a cascade of events leading to the clinical syndrome of AD. It is the forming of amyloid oligomers to which neurotoxicity is mainly attributed and initiates the amyloid cascade. The elements of the cascade include local inflammation, oxidation, excitoxicity (excessive glutamate), and tau hyperphosphorylation. 5 Tau protein is a microtubule-associated protein which binds microtubules in cells to facilitate the neuronal transport system. Microtubules also stabilize growing axons necessary for neuronal development and function. Abnormally hyperphosphorylated tau forms insoluble fibrils and folds into intraneuronic tangles. Consequently, it uncouples from microtubules, inhibits transport, and results in microtubule disassembly. 6 Although in the amyloid hypothesis, tau hyperphosphorylation was thought to be a downstream event of Aβ deposition, it is equally probable that tau and Aβ act in parallel pathways causing AD and enhancing each other’s toxic effects. 3 Progressive neuronal destruction leads to shortage and imbalance between various neurotransmitters (eg, acetylcholine, dopamine, serotonin) and to the cognitive deficiencies seen in AD. 5

All of the already established treatments that are used today try to counterbalance the neurotransmitter imbalance of the disease. The acetylocholinesterase inhibitors (AChEIs) which are approved for the treatment of AD are donepezil, galantamine, and rivastigmine. 4 , 5 Their development was based in the cholinergic hypothesis which suggests that the progressive loss of limbic and neocortical cholinergic innervation in AD is critically important for memory, learning, attention, and other higher brain functions decline. Furthermore, neurofibrillary degeneration in the basal forebrain is probably the primary cause for the dysfunction and death of cholinergic neurons in this region, giving rise to a widespread presynaptic cholinergic denervation. The AChEIs increase the availability of acetylcholine at synapses and have been proven clinically useful in delaying the cognitive decline in AD. 7

A further therapeutic agent approved for moderate to severe AD is the low-to-moderate affinity, noncompetitive N -methyl- d -aspartate (NMDA) receptor antagonist memantine. 4 , 5 Memantine binds preferentially to open NMDA receptor–operated calcium channels blocking NMDA-mediated ion flux and ameliorating the dangerous effects of pathologically elevated glutamate levels that lead to neuronal dysfunction. 8

In clinical trials, both Aβ and tau are prime targets for disease-modifying treatments (DMTs) in AD. From this point of view, AD could be prevented or effectively treated by decreasing the production of Aβ and tau; preventing aggregation or misfolding of these proteins; neutralizing or removing the toxic aggregate or misfolded forms of these proteins; or a combination of these modalities. 7

A number of additional pathogenic mechanisms have been described, possibly overlapping with Aβ plaques and NFT formation or induced by them, including inflammation, oxidative damage, iron deregulation, and cholesterol metabolism blood-brain barrier (BBB) dysfunction or α-synuclein toxicity. 9 - 13

This article will review current nonpharmacological and pharmacological management of the cognitive and behavioral symptoms of AD, with a focus on the medications that are currently FDA (Food and Drug Administration)–approved for the treatment of the cognitive and functional deficits of AD. 10 Pharmacological agents under research in phase 1, 2, and 3 clinical trials in AD will be summarized. 11 - 13

Current management of AD

A multifactorial tailored management of AD is attempted nowadays based in the following components:

• Open physician, caregiver, and patient communication: a sincere and successful conveying of information and feelings between them will offer opportune identifying of symptoms, exact evaluation and diagnosis, and suitable guidance.
• - Consistency and simplification of environment 10 ;
• - Established routines 10 ;
• - Communicative strategies such as calm interactions, providing pleasurable activities, using simple language and “saying no” only when safety is concerned 10 ;
• - Timely planning for legal and medical decisions and needs 10 ;
• - Cognitive behavioral therapy 14 , 15 ;
• - Exercise therapy, light therapy, music therapy. 14 , 15
• - Planned short rest periods for the caregiver;
• - Psychoeducation including preparing for effects of dementia on cognition, function and behaviors, expectations, avoiding situations that can worsen the symptoms or increasing the dangers for safety and well-being
• - Encouraging the development of support networks for the caregivers. 10
• Pharmacological interventions.

FDA-approved AD medications

The AChEIs donepezil, galantamine, rivastigmine, and the NMDA antagonist memantine are the only FDA-approved AD medications. 10

AChEIs attempt at reducing the breakdown of acetylcholine levels in the brain of the patients with AD by inhibiting the responsible enzyme acetylcholinesterase in the synaptic cleft. 5 Thus, AChEIs enhance central cholinergic neurotransmission and finally tend to mitigate decline in cognition at least during the first year of treatment. Further decline occurs, but even temporary discontinuation of these drugs results in rapid decline and is associated with greater risk of nursing home placement. 16

Initiation of AChEI treatment as soon as possible after the diagnosis is preferred as patients who started the AChEI 6 months later showed more rapid cognitive decline than those who started the drug immediately. 17 All 3 AChEIs have proved their treatment benefits in delaying decline, stabilizing, or even improving cognition and activities of daily living in randomized placebo-controlled trials up to 52 weeks duration. 10 , 18 Longer term open-label extension studies support also longer term treatment benefits. 10

Significant efficacy differences among the AChEIs have not been reported. Donepezil and rivastigmine have been approved by FDA for mild, moderate, and severe AD, whereas galantamine for mild and moderate AD. 18

The most common adverse effects are triggered by the cholinomimetic action of the AChEIs on the gastrointestinal tract and often include diarrhea, nausea, and vomiting. Rapid eye movement sleep behavior disorder has been also remarked in some individuals. Administration of the drug after a meal in the morning can minimize all of these adverse effects. The transdermal patch of rivastigmine can induce rash at the site of application. Adverse effects affect usually a 5% to 20% of patients but are mostly transient and mild. The AChEIs may also trigger bradycardia and increase the risk of syncope. Thus, AChEIs are contraindicated in conditions including severe cardiac arrhythmias, especially bradycardia or syncope. They are also contraindicated in active peptic ulcer or gastrointestinal bleeding history and uncontrolled seizures. Slow titration over months to years to a maximal tolerated of the indicated dose is important for the safety of the patients. 17 , 18

Pharmacokinetic characteristics differ among AChEIs: the primary route of elimination for donepezil and galantamine is hepatic metabolism, whereas for rivastigmine is liver and intestine metabolism. Donepezil and galantamine inhibit selectively and reversibly the acetylcholinesterase, whereas rivastigmine is a “pseudo-irreversible” inhibitor of acetylcholinesterase and butyrylcholinesterase. Donepezil has a long elimination half-life of 70 hours and galantamine of 6 to 8 hours. The elimination half-life of rivastigmine is very short (1-2 hours for oral and 3-4 hours for transdermal administration), but the duration of action is longer as acetylcholinesterase and butyrylcholinesterase are blocked for around 8.5 and 3.5 hours, respectively. 10 , 17 , 18

Memantine is a noncompetitive low-affinity NMDA-receptor open-channel blocker and affects glutamatergic transmission. 5 Its main elimination route is unchanged via the kidneys with a half-life of 70 hours. It has been approved by FDA for moderate and severe AD either as monotherapy or in combination with an AChEI. 3 Memantine monotherapy has demonstrated short- and long-term benefits for patients with moderate to severe AD as assessed by different scales evaluating activities of daily living, cognition, and behavioral and psychological symptoms of dementia (BPSD). 19

Memantine can be administered in combination with an AChEI, as they have complementary mechanisms of action. Their combination benefits patients with usually additive effects, without any increase in adverse effects. 14 , 15

Duration and persistence of monotherapy or combination treatment with higher doses in moderate or even in advanced dementia are associated with better global function and outcomes. 20

Medications for BPSD

Antipsychotics and antidepressants remain the main medications for BPSD. Selective serotonin reuptake inhibitors are preferred for treating depression and anxiety. Drugs with low anticholinergic effects and an acceptable tolerability, such as sertraline, citalopram, and escitalopram, are more appropriate. Antipsychotics should be administered only when a significant safety risk for the patient or for the caregivers by aggressive behaviors makes them necessary. Controversial and limited evidence cannot adequately support the use of benzodiazepines, anticonvulsants stimulants, or dextromethorphan/quinidine. Pharmacological approaches to managing BPSD are highly individualized and changeable, depending on patient’s comorbidities, stage of the disease, and symptoms’ severity. 21

Removal of superfluous and deleterious medications

Polypharmacy in older patients with dementia is usual (with a prevalence of 25%-98%). 22 Anticholinergics and sedatives are commonly used inappropriate medications. These drugs are prescribed despite strong evidence (Beers Criteria) that they should be avoided in cognitively vulnerable older persons because of their potential adverse cognitive effects. 23 Estrogen is another commonly prescribed potentially inappropriate medication despite evidence that its use is associated with increased cognitive decline in postmenopausal women. 24

Specific examples of usually prescribed potentially harmful medications in the elderly are diphenhydramine, often taken with acetaminophen for insomnia and pain, benzodiazepines for anxiety, anticholinergics (tolderodine, oxybutynin, tamsulosin) for urinary incontinence, biperiden, and pramipexole for extrapyramidal tremor 25 and sedative/hypnotics for sleep disorders. 26

Treating underlying medical conditions

Careful management of vascular risk factors (hyperlipidemia, diabetes, hypertension) is of paramount importance for patients with AD. Hydration, sleep, and nutrition status should also be closely monitored. Disorders in thyroid function or electrolytes, deficiencies in vitamin B 12 , folate, vitamin D, or systemic conditions and diseases that can affect cognition (infections, eg, urinary tract infection, pain, constipation) should be treated. 27

Current Landscape in Treatment Research for AD

No new drug has been approved by FDA for AD since 2003 and there are no approved DMTs for AD, despite many long and expensive trials. 22 , 28 As a matter of fact, more than 200 research projects in the last decade have failed or have been abandoned. 10 Nevertheless, drug pipeline for AD is still full of agents with mechanisms of action (MOA) that target either disease modification or symptoms. 4 , 10 Some of the recent failures of anti-amyloid agents in phase 3 clinical trials in patients with early-stage, mild, or mild-to-moderate stage AD were semagacestat, 29 bapineuzumab, 30 solanezumab 31 and in similar trials of β-secretase inhibitors (BACE) lanabecestat, 32 verubecestat, 33 and atabecestat. 34

The most popular and broadly accepted explanations for the multiple failures of clinical trials of DMT agents for AD include the too late starting of therapies in disease development, the inappropriate drug doses, the wrong main target of the treatment, and mainly an inadequate understanding of the pathophysiology of AD. 35 A novel approach to the problem seems more technical and mathematical than biological and suggests that the selected trials’ clinical endpoint may be extremely premature, and additionally, the variability in diagnostic markers and end points may result in inaccurate diagnosis of patients’ disease state and is finally a definite source of errors. 28 Given the fact that longer trial durations increase the probability of detecting a significant effect but at the same time increase tremendously the costs, the proposed solution seems to be the use of clinical trial simulators. 28 These simulators are constructed with mathematical, computational, and statistical tools and can predict the likelihood that a strategy and clinical end point selection of a given trial are proper or not, before the initiation of the trial. 36 They can also help in the perfecting of the design of the study; hence, they may augment the probability of success of estimated new drugs or save invaluable time and resources, by indicating earlier the forthcoming failure of any inappropriate therapy. 37 Although the use of clinical trial simulators is not frequent in recent research, 38 should this practice be abandoned, especially when potential treatments for diseases with slow progression and long duration, such as AD, are evaluated. 37

At the same time, current research remains focused on the development of therapeutic approaches to slow or stop the disease progression, taking into consideration every new aspect in the biology of the disease, the diagnostic markers, and the precise diagnosis of disease state of every individual and the design of clinical trials. Furthermore, drug development research for AD has become more complicated as preclinical and prodromal AD populations are potentially included in current trials, as well as traditionally included populations of all the clinical stages of AD dementia. 38 Consequently, current guidance provided by the FDA for AD clinical trials further includes use of fluid or neuroradiological biomarkers in disease staging for preclinical and prodromal AD trials and of a single primary outcome in prodromal AD trials. In addition, the use of clinical trial simulators, Bayesian statistics, and modifiable trial designs is strongly suggested. 4

The National Institute on Aging and the Alzheimer’s Association (NIA-AA) proposed a new framework for research, 39 which requires the application of amyloid, tau, and neurodegeneration biomarkers to clinical trials, succeeds in precise classification of patients in AD stages, and can be used to assist clinical trials design.

Tau positron emission tomography (tau PET), neurofilament light, and neurogranin are the new biomarkers that are increasingly used by clinical trials. 40

The above-mentioned biological and statistical advances that are recently integrated in clinical trials may comprise the final assets for succeeding in drug development. The current clinical trials in AD in phases 1, 2, and 3 4 , 11 - 13 are briefly discussed. The tested agents in these trials are classified either as potentially modifying the disease or as symptomatic for the cognitive enhancement, and for the relief of neuropsychiatric symptoms. The new directions in AD clinical trials, such as agents with novel MOA, advanced immunotherapies, the involvement of biomarkers in drug development, and repurposed agents, are highlighted.

A search for phases 1, 2, and 3 “recruiting” or “active but not recruiting” clinical trials for AD in clinicaltrials.gov (accessed August 19, 2019) showed 165 outcomes. The last annual review of the drug development pipeline for AD examined clinicaltrials.gov in February, 2019 (132 agents in 156 trials) and provides information and conclusions available at that time: 28 drugs in 42 clinical trials in phase 3 trials, 74 drugs in 83 phase 2 trials, and 30 drugs in 31 phase 1 trials. 4 The tested agents are classified as DMTs (73%), symptomatic cognitive enhancers (13%), and symptomatic for the treatment of BPSDs (11%). 4 The DMT agents were further separated into small molecules or biologics (monoclonal antibodies [mAbs] and other immunotherapies). The DMT agents were also classified according to their potential MOA as amyloid targeting, as tau-related targeting, and as having other MOA such as anti-inflammatory or metabolic protection, neuroprotection, and growth factor support. 4 The DMTs are suggested to be effective to delay or halt disease progression that would be expressed clinically with long-lasting benefits in cognition over many months to years. Symptomatic agents are supposed to show symptomatic benefits over weeks to many months in cognition improvement or BPSD elimination. 10

In this review, agents currently studied as potential DMTs will be discussed. Furthermore, an approach to a future “precision medicine” multifactorial therapeutic model based on biomarkers profile, genetic analysis, neuropsychologic evaluation, and neuroimaging accomplished with risk factors restriction will be attempted. 2 , 3

Currently studied DMTs for AD

Amyloid-related mechanisms—dmts.

The crucial step in AD pathogenesis is the production of amyloid (Aβ), which forms SPs (insoluble and proteolysis-resistant fibrils). The Aβ derives from a protein overexpressed in AD, APP through sequential proteolysis by β-secretase (BACE1) in the extracellular domain and γ-secretase in the transmembrane region. Full-length APP is first cleaved by α-secretase or β-secretase. The APP cleavage by α-secretase leads to nonamyloidogenic pathway, whereas APP cleavage by β-secretase (BACE1) leads to amyloidogenic pathway. Sequential cleavage of APP by BACE1 in the extracellular and γ-secretase in the transmembrane area results in the Aβ production. Major sites of γ-secretase cleavage usually occur in positions 40 and 42 of Aβ, thus Aβ40 and Aβ42 oligomers are the main products of the sequential APP cleavage, as the amyloidogenic pathway is favored in neurons because of the greater plentifulness of BACE1. On the contrary, the nonamyloidogenic processing is more favored in other cells without BACE1 predominance. 5

“Amyloid hypothesis” suggests that Aβ production in the brain triggers a cascade of pathophysiologic events leading to the clinical expression of AD. Aβ is a protein consisting of 3 main isoforms: Aβ38, Aβ40, and Aβ42. Aβ42 is the most aggregation-prone form and has the tendency to cluster into oligomers. Oligomers can form Aβ-fibrils that will eventually form amyloid plaques. Aβ40 is somewhat aggregation-prone and it is mostly found in the cerebral vasculature as a main component of “cerebral amyloid angiopathy.” Aβ40 usually constitutes more than 50% of total detected Aβ. Aβ38 is soluble, present in the vasculature of patients with sporadic and familial AD. Neurotoxicity is mainly attributed to the forming of amyloid oligomers, which finally initiates the amyloid cascade. 5

Oxidation, inflammation, excessive glutamate, and tau hyperphosphorylation are supposed to be the main pathophysiologic pillars of the cascade. Tau protein binds microtubules in cells to facilitate the neuronal transport system. Microtubules also stabilize growing axons. Hyperphosphorylated tau forms insoluble fibrils and folds into intraneuronic NFTs. Consequently, it inhibits neuronal transport and microtubule function. 2 Although in the initial amyloid hypothesis, tau hyperphosphorylation was thought to be a downstream event of Aβ deposition, it is now equally probable that tau and Aβ act in parallel pathways causing AD and enhancing each other’s toxic effects. 2 The result of massive neuronal destruction is the shortage and imbalance between neurotransmitters, such as acetylcholine, dopamine, serotonin, and to the cognitive and behavioral symptoms of AD. 5

Consequently, anti-amyloid DMTs have focused on 3 major MOAs: (1) reduction of Aβ42 production (γ-secretase inhibitors, β-secretase inhibitors, α-secretase potentiation), (2) reduction of Aβ-plaque burden (aggregation inhibitors, drugs interfering with metals), and (3) promotion of Aβ clearance (active or passive immunotherapy). 10

Reduction of Aβ42 production

γ-secretase inhibitors.

According to the amyloid hypothesis, amyloidogenic pathway is promoted after the sequential cleavage of APP by BACE1 and γ-secretase. Consequently, the inhibition of these enzymes has been considered as a major therapeutic target. Unluckily, concerning γ-secretase, in addition to APP, this particular enzyme acts on many other substances and cleaves different transmembrane proteins. Notch receptor 1, which is essential for control of normal cell differentiation and communication, is among them. 5 This fact is probably responsible for recent failures in clinical trials with γ-secretase inhibitors: semagacestat 29 was associated with worsening of activities in daily leaving and increased rates of infections and skin cancer, avagacestat 41 was associated with higher rate of cognitive decline and adverse dose-limiting effects (skin cancer) and tarenflurbil which showed low brain penetration. 42 Serious safety concerns for γ-secretase inhibitors remove γ-secretase from the role of appropriate target for the treatment of AD 43 until in depth studies on this key enzyme could help to therapeutically target γ-secretase in a safe way. 44 No γ-secretase modulators are currently studied in phase 1-3 clinical trials. 4

BACE inhibitors

Two BACE inhibitors are still elaborated: elenbecestat (E2609) in phase 2 and umibecestat (CNP520) in phase 3. 4 The later agent is studied in asymptomatic individuals at risk of developing AD (APOE4 homozygotes or APOE4 heterozygotes with elevated amyloid, detected by cerebrospinal fluid [CSF] biomarkers or amyloid PET). 45

Fluid and neuroimaging biomarkers indicative of AD pathology or neurodegeneration are integrated in this study.

However, the clinical trials with the BACE inhibitors lanabecestat, 32 verubecestat, 33 and atabecestat 34 have been recently discontinued due to unexpected difficulties. The phase 3 lanabecestat trial was discontinued due to lack of efficacy, whereas verubecestat and atabecestat trials were ceased due to ineffectiveness, as well as safety reasons (rash, falls, liver toxicity, and neuropsychiatric symptoms). 10 , 32 - 34 All agents showed significant and dose-dependent result of reducing CSF Aβ42, but without cognitive or functional benefit while many of them were poorly tolerated and some of them failed in subjects with prodromal AD. These results might support the suggestion that blocking the process of forming of Aβ may be not capable of halting the disease progression. 46

α-secretase modulators

According to the amyloid hypothesis, nonamyloidogenic pathway is promoted after the cleavage of APP by α-secretase. Consequently, the modulation of the enzyme has been considered as a major therapeutic target. However, little is known of the main signaling pathways that could stimulate cleavage of APP by α-secretase. Restricted, nowadays, knowledge assumes that α-secretase activation is promoted through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and may be through γ-aminobutyric acid (GABA) receptor signaling; thus, agents that activate the PI3K/Akt pathway or act as selective GABA receptor modulators are suggested as potential therapeutic drugs for AD. 47 , 48

Etazolate (EHT0202) stimulates the nonamyloidogenic α-secretase pathway acting as a selective modulator of GABA receptors. A previous, phase 2 trial has showed that the agent was safe and well tolerated in patients with mild to moderate AD. However, further evaluation of etazolate in phase 3 trials has not progressed. 48 Etazolate is currently evaluated in animal studies for its preventive effect in post-traumatic stress disorder. 49

Two α-secretase modulators that activate the PI3K/Akt pathway are studied in phase 2 clinical studies: APH-1105 and ID1201. APH-1105 is delivered intranasally and is assessed in mild to moderate AD. 4 ID1201 is a fruit extract of melia toosendan and also induces α-secretase activation. It is evaluated in mild AD. 47

Reduction of Aβ-plaque burden

Aggregation inhibitors (anti-amyloid aggregation agents).

Aggregation inhibitors interact directly with the Aβ peptide to inhibit Aβ42 fiber formation, thus they are considered potential therapeutic for AD.

The last Aβ42 aggregation inhibitor which was tested in humans was the oral agent scyllo-inositol (ELND005). A phase 2 clinical trial in patients with AD did not provide evidence to support a clinical benefit of ELND005 while severe toxicity issues (infections) forced the cessation of the study. Further development of the agent at a lower dose has not progressed in the last 8 years. 50

Nowadays, specific agents in the form of peptidomimetics that inhibit and partially reverse the aggregation of Aβ 42 are tested in transmission electron microscopic studies. KLVFF is a peptide sequence that resembles the hydrophobic central part of the Aβ and gradually replaces natural polypeptides. The KLVFF compound that mainly prevents the aggregation of Aβ 42 and can also dissolve the oligomerics to a limited extend is the final compound 18, which is resilient in proteolytic decomposition. 51

Another newly developed class of peptidomimetics are the “γ-AApeptides.” 52 One of them, compound γ-AA26, seems almost 100-fold as efficient as the compound 18 of the KLVFF in the inhibition of the aggregation of Aβ 42 . 52

In vivo animal studies will be developed to manifest the biological potential of peptidomimetics.

Reduction of Aβ-plaque burden via drugs interfering with metals

Abnormal accumulation or dyshomeostasis of metal ions such as iron, copper, and zinc has been associated with the pathophysiology of AD. 5

Deferiprone is an iron chelating agent which is studied in phase 2 trials in participants with mild and prodromal AD. 4 , 53

A metal protein–attenuating compound, PBT2, has recently progressed in phase 2 AD treatment trials, as it demonstrated promising efficacy data in preclinical studies. 54 In a 3-month phase 2 study, PBT2 succeeded in a 13% reduction of CSF Aβ and an executive function improvement in a dose-related pattern in patients with early AD. 55

Promotion of Aβ clearance (active or passive immunotherapy)

The 2 main immunotherapeutic approaches that intend to promote Aβ clearance and are currently tested in clinical and preclinical studies are active and passive immunization: 56

• Active immunization.

Aβ, phosphorylated tau (ptau) peptides, or specific artificial peptides such as polymerized British amyloidosis (ABri)-related peptide (pBri) 57 are used as immunogens. ABri is a rare hereditary amyloidosis associated with a mutation that results in the production of a highly amyloidogenic protein with a unique carboxyl terminus that has no homology to any other human protein. The pBri peptide corresponds to this terminus and induces an immune response that recognizes Aβ and ptau.

Antigen-presenting cells present the immunogens to B cells. Use of Ab or ptau peptides will produce antibodies to Ab or ptau epitopes, respectively. Use of pBri will produce antibodies to both Aβ and ptau epitopes. 56

• Passive immunization.

Monoclonal Abs to Ab, ptau, or b sheet epitopes are systemically and adequately for BBB penetration infused. As antibodies cross the BBB, they act to clear, degrade, or alternatively disaggregate or neutralize their targets. 56

• Stimulation of innate immunity either by active or passive immunization also ameliorates the pathology of the disease by promoting microglia and macrophage function. 56

Overall, Aβ-targeted strategies seem promising if used very early in the progression of the disease, before the presence of any symptoms; thus, they are developed in current trials in preclinical AD. Strategies that target tau pathology, although promising, bear the risk of toxicity at the moment. Nevertheless, it is hypothesized that, in sporadic late onset AD, ptau and Aβ pathologies could be evolved by separate pathways that can affect each other synergistically. 58 Consequently, it is possible that effective AD immunotherapies must be able to simultaneously target both ptau and Aβ pathologies. 56

Immunotherapeutic approaches have dominated in the past 15 years with negative results until now. However, lessons from these fails have altered the current immunotherapy development research for AD. 56

Active Aβ immunotherapy

Six active immunotherapy agents are currently studied in phase 1, 2, and 3 clinical trials:

CAD106 is an active Aβ immunotherapeutic agent, is studied in preclinical AD under the umbrella of the Alzheimer prevention initiative generation program, which comprises 2 phase 3 studies that evaluate simultaneously the safety and efficacy of CAD106 and umibecestat in asymptomatic individuals at risk of developing AD (60-75 years of age, APOE4 homozygotes, or APOE4 heterozygotes with elevated amyloid in CSF or in amyloid PET). 45

Subjects will be registered in generation study 1 (cohort 1: CAD106 or placebo, cohort 2: umibecestat or placebo) or generation study 2 (umibecestat 50 and 15 mg, or placebo). 45

ABvac40 is evaluated in a phase 2 study, as the first active vaccine against the C-terminal end of Aβ 40 . A phase 1 study was conducted with patients with mild to moderate AD aged 50 to 85 years. Neither incident vasogenic edema nor microhemorrhages were identified. Specific anti-Aβ 40 antibodies were developed in the 92% of the individuals receiving injections of ABvac40. 59

GV1001 peptide (tertomotide) was previously studied as a vaccine against various cancers, whereas now it is evaluated in a phase 2 study for AD. 60

ACC-001 (vanutide cridificar), an Aβ vaccine, was studied in phase 2a extension studies in subjects with mild to moderate AD. It was administered with QS-21 adjuvant. Long-term therapy with this combination was very well tolerated and produced the highest anti-Aβ IgG titers compared with other regimens. 61

UB-311, a synthetic peptide used as Aβ vaccine, has been advanced into an ongoing phase 2 study in patients with mild and moderate AD. In phase 1, it induced a 100% responder rate in patients with AD. The usual adverse effects were swelling in the injection site and agitation. A slower cognitive decline rate was observed in patients with mild AD. 62

Lu AF20513 epitope vaccine is estimated in a phase 1 study in mild AD. 63

The occurrence of encephalitis in previous studies (AN-1792) 64 led to the development of improved anti-Aβ active immunotherapy agents, more specific to Aβ sites less probable to activate T cells, currently studied in clinical trials. 5 , 6

Passive Aβ immunotherapy—via mAbs

Passive Ab immunotherapy via mAbs is the most active and promising class. Cerebral microhemorrhages and vasogenic edema are the main drawbacks in this group of agents. 5 Valuable learning gained from previous failed phase 3 trials of the first agents of this class, bapineuzumab 65 and solanezumab, 66 enlightened the mAbs’ research. Strict inclusion criteria were applied, such as biomarker proof of “amyloid positivity” and enrollment of individuals with preclinical stages of the disease. Furthermore, the design of the studies became more specific and targeted: the characteristics of amyloid-related imaging abnormalities were associated with the dose of antibodies and APOε4 genotyping, higher dosing necessity was recognized, and accurate measures for specific targets, such as reduction of Aβ plaque burden on amyloid PET, were required. 10

Many ongoing mAbs trials are in phase 3, including aducanumab, 67 gantenerumab, 68 and BAN2401 69 in prodromal and very mild AD, and crenezumab, 70 gantenerumab, and solanezumab 71 in studies for preclinical or at-risk populations. First results from aducanumab and BAN2401 trials suggested, at first, a treatment-related result of reducing in cerebral amyloid burden in agreement to deceleration of cognitive decline in patients with prodromal and very mild AD. 71 , 72 On the contrary, the initial trial of gantenerumab in prodromal AD was prematurely stopped for lack of efficacy, but exploratory analyses suggest that higher dosing of gantenerumab may be needed for clinical efficacy and an open-label extension for participating patients with mild AD is continued, simultaneously with a double-blind, placebo-controlled study in patients with mild AD. 4 , 68 Similarly, until now, solanezumab did not delay rates of brain atrophy. 73

Intravenous doses of LY3002813 (donanemab) and LY3372993 are studied in participants with mild cognitive impairment (MCI) and mild to moderate AD in separate phase 1 clinical studies. 4

Passive Aβ immunotherapy—via immunoglobulins

Anti-Aβ antibodies are included in naturally occurring autoantibodies. In contrast to mAbs, blood-derived human anti-Aβ immunoglobulin G (IgG) Abs are polyclonal, with lower avidity for single Aβ molecules, and higher for a broader range of epitopes, especially in Aβ oligomers and fibrils. The natural presence of antibodies against Aβ has been reported in intravenous immunoglobulin (IVIg); thus, IVIg has been considered as a possible AD treatment. Intravenous immunoglobulin is obtained from plasma of healthy donors and is made up of human Abs mainly of the IgG-type. 5 , 74

Nevertheless, the first completed phase 3 trial of IVIg as a treatment for AD demonstrated good tolerability but lack of efficacy of the agent on clinical stability or delay of cognitive or functional decline of participants with mild and moderate AD. 74

Another strategy directed at diminishing the accumulation of Aβ in the brain is based in altering the transportation of Aβ through the BBB. A recent therapeutic method performs plasma exchange (PE) with albumin replacement, inducing the shifting of the existing dynamic equilibrium between plasma and brain Aβ. This therapeutic method is based in the following considerations: (1) high levels of Aβ aggregation in the brain are accompanied by low levels of Aβ in CSF in AD, (2) albumin is the main protein transporter in humans, (3) albumin binds around the 90% of the circulating Aβ, and (4) albumin has proved Aβ-binding ability. Consequently, it is suggested that PE-mediated possession of albumin-bound Aβ would increase the shift of free Aβ from CSF to plasma to correct the imbalance between brain and blood Aβ levels. 75

A phase 3 trial called Alzheimer’s Management by Albumin Replacement (AMBAR) in mild and moderate AD assesses PE with several replacement volumes of albumin, with or without intravenous immunoglobulin. 76

Furthermore, an ongoing phase 2 study evaluates IVIg Octagram 10% in mild and moderate AD. 4

A novel immunotherapeutic strategy that targets simultaneously Aβ and tau is represented by the NPT088 agent. NPT088 is a mixture of the capsid protein of bacteriophage M13 (g3p) and human-IgG 1 -Fc. NPT088 reduced Aβ and ptau aggregates and improved cognition in aged Tg2576 mice. The agent is currently assessed in a phase 1 clinical study. 77

Tau-related mechanisms—DMTs

Anti-phospho-tau approaches consist a major potential treatment strategy, even if there are yet no agents with this specific MOA advanced in phase 3 studies.

Only 1 agent with tau-related mechanism is evaluated in phase 2/3, whereas 10 agents that target tau as one of their mechanisms are evaluated in phase 2, and 5 more agents with tau-related mechanism are assessed in phase 1 studies. 4

Prevention of ptau formation

The hyperphosphorylation of tau is induced by kinases. 78 Thus, kinase inhibitors are examined as potential therapeutic approaches targeting tau. Glycogen synthase kinase 3 (GSK3β) has become prominent as a possible therapeutic target. The most studied GSK3 inhibitor is lithium chloride, a therapeutic agent for affective disorders, which seems to prevent phosphorylation of tau in mouse models. Lithium is currently reassessed within the novel framework for drug research. 79

Another GSK-3 inhibitor, tideglusib, did not meet phase 2 clinical endpoints in patients with mild and moderate AD. 80

ANAVEX 2-73 is evaluated in a phase 2 trial, for eligible subjects AD MCI or mild AD. 81 ANAVEX 2-73 is also a GSK-3b inhibitor but additionally it is a high affinity sigma 1 receptor agonist and a low-affinity muscarinic agonist. 4 Results presented at 2019 Alzheimer’s Association International Conference (AAIC) revealed that patients treated with ANAVEX 2-73 had high levels of 2 gut microbiota families, Ruminococcaceae and Porphyromonadaceae, which were associated with improved activities of daily living. The effect might potentially be reversal of the microbiota imbalances and might have a homeostatic effect on the brain-gut-microbiota axis. 81

Inhibitors of tau aggregation

Methylene blue (MB), a known phenothiazine, is evaluated in AD studies as a potential tau aggregation inhibitor. The problem with this drug is that urine is colored blue, resulting in a lack of blinding. A monotherapy trial with MB on mild and moderate AD ( {"type":"clinical-trial","attrs":{"text":"NCT00515333","term_id":"NCT00515333"}} NCT00515333 ) has demonstrated some clinical benefit in moderate, but not mild AD. 82 However, the methodology of the study, as blinding is impossible, has been highly criticized. 83

Methylene blue’s derivative TRx0237 (LMTX) which was studied in phase 3 failed finally to show efficacy, and based on the analysis of the results, a new phase 2/3 study named LUCIDITY was started 1 year ago in subjects with mild AD with a lower dose of the agent. 84

Microtubule stabilizers

The microtubule-stabilizing agent davunetide was studied in a phase 2 trial but it did not meet the clinical end points. 85

TPI-287 (abeotaxane), a small molecule derived from taxol, is a microtubule protein modulator. It was administered intravenously to patients with mild to moderate AD in a phase 1/2 study ( {"type":"clinical-trial","attrs":{"text":"NCT01966666","term_id":"NCT01966666"}} NCT01966666 ). First results presented report that the agent was not well tolerated by the participants. 84

IONIS MAPTRx (BIIB080), a microtubule-associated protein tau RNA inhibitor, an antisense oligonucleotide, is assessed in a phase 2 clinical study that is still in the recruiting process of patients with mild AD ( {"type":"clinical-trial","attrs":{"text":"NCT02623699","term_id":"NCT02623699"}} NCT02623699 ). 86

Targeting posttranslational modifications of Tau

Another tau modification that promotes aggregation besides phosphorylation is posttranslational modification by lysine acetylation. Thus, the use of inhibitors of tau acetylation is proposed as a possible therapeutic approach for AD.

Nilotinib is a c-Abl tyrosine kinase inhibitor which is used in patients with leukemia. It also appears to trigger intraneuronal autophagy to clear tau. It is now studied in a phase 2 trial in individuals with mild to moderate AD ( {"type":"clinical-trial","attrs":{"text":"NCT02947893","term_id":"NCT02947893"}} NCT02947893 ). 4 , 83

Promotion of Tau clearance—immunotherapy

Recently emerged evidence in various animal models strongly suggests that targeting ptau epitopes is a practical approach to induce antibody responses that are able to promote tau clearance. 81 Hence, a number of active and passive immunotherapy projects have reached clinical trials for AD treatment. 83

Active immunotherapy

AADvac1 contains a synthetic tau peptide and is currently studied in a phase 2 clinical study in mild to moderate AD ( {"type":"clinical-trial","attrs":{"text":"NCT02579252","term_id":"NCT02579252"}} NCT02579252 ). 4 , 10 , 83

Passive immunotherapy

ABBV-8E12 is a humanized anti-tau MAb assessed in a phase 2 clinical study in patients with early AD ( {"type":"clinical-trial","attrs":{"text":"NCT02880956","term_id":"NCT02880956"}} NCT02880956 ). 87

BIIB092 is a humanized IgG4 MAb against tau fragments derived from the stem cells of a patient with familial AD. 84 A phase 2 clinical trial assesses the safety and efficacy of the agent in participants with AD MCI and mild AD. 4

RO7105705 (MTAU9937 A) is an anti-tau MAb which is assessed in a phase 2 study in individuals with prodromal and mild AD ( {"type":"clinical-trial","attrs":{"text":"NCT03289143","term_id":"NCT03289143"}} NCT03289143 ). 83 , 88

Three other anti-tau mAbs (BIIB076, JNJ-63733657, and LY3303560) are currently assessed in phase 1 clinical trials. 4

DMTs with other mechanisms

Neuroprotection.

AGB101 (low-dose extended-release levetiracetam) is an SV2A modulator that is assessed in a phase 3 clinical trial as a repurposed agent (approved for use in another indication, not epilepsy but MCI due to AD). It is supposed to reduce neuronal hyperactivity induced by Aβ ( {"type":"clinical-trial","attrs":{"text":"NCT03486938","term_id":"NCT03486938"}} NCT03486938 ) ( Diagram 1 ). 4

DMTs with other mechanisms. DMTs indicate disease-modifying therapies; hMSCs, human mesenchymal stem cells.

BHV4157 (troriluzole) is a glutamate modulator that reduces synaptic levels of glutamate and is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03605667","term_id":"NCT03605667"}} NCT03605667 ). 4

Icosapent ethyl is the eicosapentaenoic acid (EPA) omega-3 fatty acid in a purified form. It is supposed to protect neurons from disease pathology and is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02719327","term_id":"NCT02719327"}} NCT02719327 ). 4

There are also 2 biologics and 24 small molecules with neuroprotection as one of their mechanisms 4 assessed in phase 2 clinical studies and 8 small molecules in phase 1 clinical trials. 4

Anti-inflammatory effects

Although neuroinflammation has been proposed as a possible mechanism for the pathogenesis of AD more than 30 years ago, only recently research is spurred into neuroiflammation probably due to 2 enlightening discoveries: first, there is evidence that activated glial cells are involved in the formation of the brain lesions in AD and second, epidemiological studies revealed that patients with rheumatoid arthritis, who are treated with anti-inflammatory drugs for decades, are spared from AD. 89 Further exploration of the inflammatory mechanisms in the disease showed that activation of glial cells, microglia, and astrocytes induces the production of inflammatory cytokines, mainly interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α). More specifically, TNF-α signaling has been proved to exacerbate both Aβ aggregation and tau phosphorylation in vivo, 90 whereas its levels have been found elevated in brain and plasma of patients with AD. 91

According to the previously mentioned neuroinflammatory mechanisms, it is established by multiple biomarker and epidemiological studies of Aβ levels in the CSF and the brain that nonsteroidal anti-inflammatory drugs, complement activation blockers, and other anti-inflammatory agents could postpone the clinical onset of AD if they are timely and for a long time applied, such as in rheumatoid arthritis. 89

Furthermore, the already existing TNF-α inhibitors (TNFIs), which are FDA-approved biologic drugs (mAbs) for the treatment of rheumatoid arthritis, Crohn disease, psoriatic arthritis, and other peripheral inflammatory diseases, are studied as a potential therapeutic strategy for AD. The TNF-α–specific mAbs are the agents infliximab, adalimumab, golimumab, and certolizumab, whereas etanercept is a recombinant fusion protein, which is also a TNFI. 91 The limited BBB penetration of these agents is the main drawback for their development. Peripheral targeting of TNF-α activity is the one proposed method for the tackling of the problem and reengineering of the TNFIs to enable BBB penetration is the other. 91 To sum up, large-scale randomized controlled trials assessing the safety and the effectiveness of TNFIs on patients with AD are warranted.

The following are the anti-inflammatory agents currently assessed in phase 3 clinical trials:

• ALZT-OP1a plus ALZT-OP1b (cromolyn plus ibuprofen) is a combination of a mast cell stabilizer and an anti-inflammatory agent, respectively, assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02547818","term_id":"NCT02547818"}} NCT02547818 ). 4
• COR388 targets a periodontal pathogen acting as bacterial protease inhibitor that reduces neuroinflammation and consequently hippocampal degeneration and is currently assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03823404","term_id":"NCT03823404"}} NCT03823404 ). 4
• Masitinib acts on mast cells as a selective tyrosine kinase inhibitor and a modulator of neuroinflammation. It is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT01872598","term_id":"NCT01872598"}} NCT01872598 ). 4

The following are the anti-inflammatory agents studied in phase 2:

• Elderberry Juice improves the mitochondrial function acting as powerful antioxidant rich in anthocyanins ( {"type":"clinical-trial","attrs":{"text":"NCT02414607","term_id":"NCT02414607"}} NCT02414607 ) and GRF6019, a human plasma protein fraction administered with infusions, based on the hypothesis that brain neuroinflammation can be counteracted by young blood parabiosis ( {"type":"clinical-trial","attrs":{"text":"NCT03520998","term_id":"NCT03520998"}} NCT03520998 , {"type":"clinical-trial","attrs":{"text":"NCT03765762","term_id":"NCT03765762"}} NCT03765762 ). 4
• Anti-inflammatory agents studied in phase 1 are the mAbs AL002, AL003 ( {"type":"clinical-trial","attrs":{"text":"NCT03635047","term_id":"NCT03635047"}} NCT03635047 , {"type":"clinical-trial","attrs":{"text":"NCT03822208","term_id":"NCT03822208"}} NCT03822208 ). 4

Growth factor promotion

NDX-1017 is an hepatocyte growth factor with the role to regenerate neurons, which is studied in a phase 1 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT03298672","term_id":"NCT03298672"}} NCT03298672 ). 4

Metabolic effects

Losartan plus amlodipine plus atorvastatin plus exercise is a combination repurposed agent suggested to succeed significant reduction of the vascular risk capable of preserving cognitive function. It is assessed in a phase 3 clinical trial ( {"type":"clinical-trial","attrs":{"text":"NCT02913664","term_id":"NCT02913664"}} NCT02913664 ). 4

Candesartan, an angiotensin receptor blocker; formoterol, a β 2 adrenergic receptor agonist; and intranasal insulin glulisine, which rises brain insulin signaling, are currently studied in phase 2 clinical trials ( {"type":"clinical-trial","attrs":{"text":"NCT02646982","term_id":"NCT02646982"}} NCT02646982 , {"type":"clinical-trial","attrs":{"text":"NCT02500784","term_id":"NCT02500784"}} NCT02500784 , {"type":"clinical-trial","attrs":{"text":"NCT02503501","term_id":"NCT02503501"}} NCT02503501 , respectively), whereas intranasal insulin aspart is assessed in a phase 1 clinical study. 4

Stem cell therapies

AstroStem is a stem-cell-based treatment administered 10 times intravenously, which consists of stem cells derived from autologous adipose tissue. AstroStem is currently assessed in a phase 2 study ( {"type":"clinical-trial","attrs":{"text":"NCT03117738","term_id":"NCT03117738"}} NCT03117738 ), whereas hMSCs (human mesenchymal stem cells) treatment is assessed in a phase 1 study ( {"type":"clinical-trial","attrs":{"text":"NCT02600130","term_id":"NCT02600130"}} NCT02600130 ). 4

Symptomatic agents

Symptomatic treatments are agents that target and improve the clinical symptoms of the disease, either cognitive or BPSD, without modifying the pathological steps leading to AD or acting on the evolution of the disease, as DMTs are supposed to do.

Overall, there are 33 symptomatic agents in current trials: 19 agents aim to improve cognition and 14 target BPSD.

Eleven of them are studied in phase 3: 3 cognitive intensifiers and 8 acting on BPSD.

Twenty symptomatic agents are in phase 2: 14 cognitive intensifiers and 6 acting on BPSD.

There are also 2 cognitive intensifiers being studied in phase 1. 4

Arduous research efforts persist to develop effective DMTs for AD, as well as symptomatic therapeutics. A plethora of continuing phase 1, 2, and 3 human studies are focused on various treatment targets in AD. Given the recent experience of a high proportion of lack of success in AD clinical trials on therapeutic agents, more recent trials appear robustly empowered by the integration of developments in biomarkers of AD, of the targeting of a single primary outcome, especially in prodromal AD studies, of the enrollment of earlier populations and the innovative trial designs. 91 - 93

At the same time, innovative research targets the development of more sophisticated diagnostic tools (neuroimaging, fluid, proteomic, and genomic AD biomarkers), whereas prevention studies for the disease are also ongoing. 10

If all these research efforts come to fruition, an effective “precision medicine” context could be applied in every patient with AD in the near future: risk factor elimination, comorbid disease treatment, and personalized advice for lifestyle modification will be provided. An AD biomarkers and neuropsychological evaluation profile will be outlined. Afterward, the patient may start a combination of DMTs tailored to meet his genetic, neuroimaging, biochemical, and neuropsychological requirements. 3 , 94

Furthermore and beyond any DMT perspective, clinicians should always maintain a patient/caregiver-targeted dealing with AD. Establishing a strong therapeutic alliance with the patient and his or her caregivers with a holistic and realistic approach involving psychoeducation, behavioral, and environmental techniques; advanced planning for future care needs; and appropriate pharmaceutical treatment is not only an efficient but also an ethical care in AD.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author Contributions: SGP conceptualized the study, developed the proposal and coordinated the project. KGY completed initial data entry and analysis, and wrote the report. Both authors read and approved the final manuscript.

Dementia risk factors identified in new global report are all preventable – addressing them could reduce dementia rates by 45%

Affiliate Professor of Medicine, UW School of Medicine, University of Washington

Dean Emerita and Distinguished Professor of Nursing and Health, Drexel University

Disclosure statement

Eric B. Larson receives funding from National Institutes of Health, National Institute on Aging and UpToDate royalties for chapters that he writes and updates.

Laura N. Gitlin receives funding from the National Institute on Aging, Veterans Administration and also royalties from various books. She also is the creator of several online courses to train health providers in evidence-based care programs that she and her teams have tested and shown to be efficacious for which she and her university affiliations are entitled to training fees.

University of Washington and Drexel University provide funding as members of The Conversation US.

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Nearly half of all dementia cases could be delayed or prevented altogether by addressing 14 possible risk factors, including vision loss and high cholesterol.

That is the key finding of a new study that we and our colleagues published in the journal The Lancet.

Dementia , a rapidly increasing global challenge, affects an estimated 57 million worldwide, and this number is expected to increase to 153 million by 2050 worldwide . Although the prevalence of dementia is on the decline in high-income countries, it continues to increase in low- and middle-income countries .

This third updated report of the Lancet Commission on Dementia offers good news and a strong message: Policymakers, clinicians, individuals and families can be ambitious about prevention and reduce dementia risk; and for those living with dementia and their caregivers, support their quality of life using evidence-based approaches.

The new report confirms 12 previously identified potentially modifiable risk factors from two previous reports, published in 2017 and 2020 . It also offers new evidence supporting two additional modifiable risk factors: vision loss and high levels of low-density lipoprotein (LDL) cholesterol , often called “bad” cholesterol.

Our study of published evidence found that collectively, addressing 14 modifiable risk factors could potentially reduce the prevalence of dementia by 45% worldwide. Even greater risk reductions could be possible in low- and middle-income countries and for people with low income in higher-income countries given the higher prevalence of dementia , health disparities and risk factors in these populations.

The report further indicates that reducing these 14 risks can increase the number of healthy years of life and reduce the length of time with poor health in people with dementia.

Additionally, the report cites clinical trials showing that nonpharmacological approaches, such as using activities tailored to interests and abilities, can reduce dementia-related symptoms and improve quality of life .

We are a general internist and an applied sociologist and intervention scientist , and our work focuses on memory and wellness in older adults. Together with 25 other internationally recognized dementia experts under the leadership of psychiatry professor Dr. Gill Livingston , we carefully reviewed the evidence to derive recommendations for prevention, intervention and care.

Why it matters

The rapid growth of aging populations worldwide is a triumph of better public and personal health throughout the entire life span. Yet, given the lack of a dementia cure, this report highlights the importance of prevention as well as supporting quality of life for those with a dementia diagnosis.

In the new report, our team proposed an ambitious program for preventing dementia that could be implemented at the individual, community and policy levels and across the life span from early life through mid and late life. The key points include:

• In early life, improving general education.
• In midlife, addressing hearing loss, high LDL cholesterol, depression, traumatic brain injury, physical inactivity, diabetes, smoking, hypertension, obesity and excessive alcohol.
• In later life, reducing social isolation, air pollution and vision loss.

Together, these add up to the Lancet Commission on Dementia’s estimate that 45% of dementia risk can be reduced. And an abundance of new research shows that when risk factors are addressed, such as exposure to air pollution, they are linked with improved cognition and likely reduction of dementia risk .

New evidence supports the notion that in high-income countries, reducing dementia risk can translate to more healthy years, years free of dementia and a shorter duration of ill health for people who develop dementia.

What still isn’t known

The 45% reduction in dementia risk across the world’s population is based on a calculation that assumes that risk factors are causal and can be eliminated. It shows how dementia prevention is critical and the impact it would have on individuals and families.

The commission emphasized the need for more research to identify additional risk factors, test risk factor changes in clinical trials, provide guidance for public health efforts, and identify and evaluate strategies for implementing and scaling evidence-based programs that support people with dementia and caregivers.

The updated report has worldwide public health and research impact and is being widely disseminated. It serves as a guideline to clinicians and policymakers and outlines new research directions.

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Nearly Half of Dementia Cases Can Be Prevented or Delayed

Science suggests 14 ways to forestall cognitive decline..

Posted August 26, 2024 | Reviewed by Hara Estroff Marano

• What Is Dementia?
• Take our Memory Test
• Find counselling to help with dementia
• The vast majority of adults worry about cognitive decline.
• Vision loss and high cholesterol levels are newly added to the list of modifiable risk factors for dementia.
• Fourteen health modifications can prevent or delay 45% of all dementia cases.
• Education, exercise, social ties—all are key to protecting brain health from an early age.

Three-quarters of adults age 40 and older are concerned about their brain health declining in the future, according to an AARP survey of 1,563 adults.

Many older adults try strategies like doing crossword puzzles and taking supplements to stave off dementia , but do such approaches actually work?

Research shows that potentially 45% of dementia cases can be prevented or delayed through a series of personal and societal changes.

A new report in the journal Lancet , dated July 31, 2024, highlights two new modifiable risk factors for dementia, bringing the known total to 14.

14 Evidence-Based Modifiable Risk Factors for Dementia

According to the 2024 report, by the Lancet Commission on dementia, highlighling prevention, intervention, and care, there are 14 evidence-based modifiable risk factors for dementia. They include:

• Less education
• Head injury
• Physical inactivity
• Excessive alcohol consumption
• Hypertension
• Hearing loss
• Infrequent social contact
• Air pollution
• Vision loss (new)
• High cholesterol (new)

Modifying all 14 risk factors would potentially delay or prevent a remarkable 45% of all dementia cases whether or not a person has the APOE gene (the Alzheimer's gene).

​Now that we know the modifiable risk factors for preventing or delaying dementia, here's what the Lancet Commission recommends that you do to prevent or delay dementia.

Specific Recommendations to Prevent or Delay Dementia

• Ensure that good-quality education is available for all, and encourage cognitively stimulating activities in midlife to protect cognition .
• Make hearing aids accessible to people with hearing loss, and decrease harmful noise exposure to reduce hearing loss.
• Treat depression effectively.
• Encourage use of helmets and head protection in contact sports and on bicycles.
• Encourage exercise, because people who participate in sport and exercise are less likely to develop dementia.
• Reduce cigarette smoking through education, price control, and preventing smoking in public places, and make smoking cessation advice accessible.
• Prevent or reduce hypertension and maintain systolic blood pressure of 130 mm Hg or less from age 40 on.
• Detect and treat high LDL cholesterol from midlife.
• Maintain a healthy weight and treat obesity as early as possible, which also helps to prevent diabetes.
• Reduce high alcohol consumption through price control and increased awareness of levels and risks of overconsumption.
• Prioritize age-friendly and supportive community environments and housing, and reduce social isolation by facilitating participation in activities and living with others.
• Make screening and treatment for vision loss accessible for all.
• Reduce exposure to air pollution.

The Lancet Commission also recommends being ambitious about prevention starting early in life and continuing throughout life.

Did You Notice Something Missing from the List?

Sleep. Anxiety . PTSD . Severe mental illness. Diet . Infection. Menopause .

​The Lancet Commission cites these domains as potential risk factors as well, noting that each is correlated with dementia as well. However, at present, there is not enough research to prove that they are causal of dementia.

That still leaves many opportunities for action by mental health providers, senior care providers, friends, family, and individuals.​

Take the Challenge

Review the list of recommendations above and choose one domain to begin to make changes with in your own life. Then share this list with others so that older adults will get the mental health care they need.

Livingston, G., Huntley, J., Liu, K. Y., Costafreda, S. G., Selbæk, G., Alladi, S., Ames, D., Banerjee, S., Burns, A., Brayne, C., Fox, N. C., Ferri, C. P., Gitlin, L. N., Howard, R., Kales, H. C., Kivimäki, M., Larson, E. B., Nakasujja, N., Rockwood, K., Samus, Q., … Mukadam, N. (2024). Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet (London, England) , 404 (10452), 572–628. https://doi.org/10.1016/S0140-6736(24)01296-0

Skufca, Laura. 2015 Survey on Brain Health. Washington, DC: AARP Research, October 2015. https://doi.org/10.26419/res.00114.001

Regina Koepp, PsyD, ABPP , is a clinical geropsychologist and the founder of the Center for Mental Health & Aging.

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Recent breakthroughs in Alzheimer’s research provide hope for patients

While there is no cure, researchers say a newly approved drug, advanced testing, and increasing knowledge about the disease may improve patients’ lives..

A few years ago, Lori Weiss, a high school math and engineering teacher, noticed it was taking her longer to do her lesson plans and grading. She also repeatedly needed to ask for help using spreadsheets she’d once mastered and she struggled to answer her students’ questions.

The symptoms were all too familiar to Weiss. Not only had she cared for her grandfather with Alzheimer’s disease when she was a teenager, she’d also watched her mother slowly lose her memory to the disease for nearly two decades. She had aunts, uncles, and a cousin as well who were diagnosed with the neurological disorder, which gradually steals a person’s memory and cognitive abilities.

“It’s rampant in my family,” Weiss says.

Weiss decided to speak with her primary care physician, who referred her to a neurologist for testing. In 2020, at the age of 62, Weiss was diagnosed with mild cognitive impairment. Two years after that, a PET scan revealed amyloid plaques, a buildup of toxic proteins in the brain that disrupt neural function and are a hallmark of Alzheimer’s disease.

Soon, Weiss began to lose her sense of direction, which prompted fears that she might be forced into a full-time care facility at a young age.

“Losing my freedom was just more than I could handle,” she says. Around that time, a friend saw a TV advertisement for a clinical trial for a drug that would attempt to slow progression of the disease using manmade monoclonal antibodies to attack and remove the amyloid plaques in the brain.

“I don’t even think that I thought twice about” enrolling in the trial, says Weiss, who has been receiving monthly infusions of the drug, called donanemab , near her home in Portland, Oregon, for about a year. “I just said, ‘Yeah, sign me up!’”

Although donanemab is not approved by the Food and Drug Administration (FDA), it uses a similar approach to the drug lecanemab, which received accelerated FDA approval on Jan. 6, and which showed biological and clinical benefits for patients in trials. In November, drugmaker Eli Lilly and Company announced promising results for donanemab, but last week, the FDA denied the company’s request for accelerated approval, saying it needed more data for participants receiving the drug for at least 12 months.

Nonetheless, this recent progress has given people like Weiss hope that previous generations have not had.

“Alzheimer’s research is getting to a place where cancer research was maybe 30, 40 years ago.” Anton Porsteinsson, MD, University of Rochester Medical Center in New York

Participating in the clinical trial “has had a huge impact,” Weiss says. “It’s given me the drive to do things while I can; it’s given me the desire to talk to more people about getting treatment, getting diagnosed early, and getting in drug trials.”

Weiss says that since she’s begun taking donanemab, she’s regained her sense of direction and has not noticed significant cognitive decline. For her, even the hope that the trial has given her has made all the difference.

“For my husband and I, it’s totally changed our lives. Instead of living in fear … we treat each day like it’s Valentine’s Day,” Weiss says. Getting diagnosed early has “given me so much more life. [I thought] getting the disease was a death sentence for me, but I’m taking a water painting class, I’m in a walking group and a music group. I thrive on my relationships with my Alzheimer’s friends and other friends, and I’m connected with my family. I feel like I’m living my life. It’s so much better than I imagined.”

And while Alzheimer’s researchers are careful to emphasize that they are still a long way from a cure, many say the hope is not a false one. The field has had several breakthroughs in recent years, from identifying easier and cheaper ways to diagnose the disease early to better understanding how individuals with the disease might require a variety of interventions.

“Alzheimer’s research is getting to a place where cancer research was maybe 30, 40 years ago,” says Anton Porsteinsson, MD, director of the Alzheimer’s Disease Care, Research and Education Program at the University of Rochester Medical Center in New York. “I think we’re at a point where we’re going to see a logarithmic increase in discovery.”

Fighting a complex disease

Alzheimer’s disease, which was discovered in 1906 and is now the seventh leading cause of death in the United States, has long boggled the scientific community. Though research over the decades has identified characteristics of the disease — such as the presence of amyloid plaques between neurons and the buildup, known as tangles, of another toxic protein, tau, inside neurons — questions remain about what causes the disease and how best to treat it in a clinically meaningful way.

“It’s a complex disease. It’s not just a single molecule that’s gone awry. It’s not an infection that has a viral particle,” says Ronald C. Petersen, MD, PhD, director of the Mayo Clinic Alzheimer’s Disease Research Center in Rochester, Minnesota. “We’ve defined it by the presence of amyloid , neuritic plaques , and neurofibrillary tangles , but that’s just the tip of the iceberg.”

Many researchers now believe that the precursors to developing Alzheimer’s begin to accumulate in the brain 10 or more years before symptoms begin to show.

Alzheimer’s disease progression affects the brain much like a forest fire, with many factors affecting how it spreads, says Rudolph E. Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital in Boston.

Amyloid plaques and tau tangles can build up over years, at some point triggering an inflammatory response that can quickly destroy brain cells. These conditions can be influenced by a range of factors, from genetic predisposition to environmental exposures to lifestyle, he explains.

That’s why the solution to treating — or ideally, preventing — Alzheimer’s disease will likely require a combination of interventions, Petersen says.

One important part of the puzzle — and a part that has been the focus of much pharmaceutical development — is targeting the amyloid plaques.

This approach has been controversial. In 2021, the FDA granted accelerated approval to the anti-amyloid drug aducanumab, sold as Aduhelm, despite objections from an advisory committee and outcry from the scientific community that the lack of clinical benefit made the drug’s high cost, initially set at $56,000 a year and later reduced to $28,000 a year, unjustifiable. A Congressional investigation found numerous flaws and irregularities in the process the FDA used when approving the drug.

Lecanemab, on the other hand, has been met with more optimism in the Alzheimer’s research community because its clinical trials demonstrated an actual clinical benefit to patients early in the disease progression.

“The field is feeling that, finally, we have a drug that didn’t have the controversy aducanumab had,” Petersen says. “It looks like it does what it’s supposed to do biologically [and] this looks like it could be meaningful for patients.”

In clinical trials , lecanemab showed a modest but tangible decrease in cognitive decline (of 27%) over 18 months in Alzheimer’s patients who were early in the disease’s progression, compared with patients who were given a placebo. Though it’s far from a cure, experts say it could give patients months of retaining memory and cognition that they might otherwise lose, a prospect that could be meaningful for patients and their families who have no other options.

But this drug, too, has stirred some controversy because of its high price tag and potentially deadly side effects, including swelling and bleeding in the brain. The pharmaceutical company Eisai has priced lecanemab, sold as Leqembi, at $26,000 a year, and the Centers for Medicare and Medicaid Services has yet to decide if it will cover the drug.

“It’s very expensive,” Tanzi says, explaining that patients who take the drug will also need several MRIs to check for brain bleeds on top of the cost of the infusions. “There is a health care disparity this could create; those who want to remove amyloid can pay out of pocket [but] the average person can’t afford that. The wealthy can protect themselves.”

Equity starting in research

The high costs of treatment could also exacerbate existing racial disparities when it comes to Alzheimer’s outcomes. Although Black Americans are about twice as likely as White Americans to have Alzheimer’s, and Hispanics are about 1.5 times as likely to have it, White people make up a disproportionate majority of clinical trial participants and non-White people report greater barriers to diagnosis and access to care, according to the Alzheimer’s Association .

“Most of the research operations are either based at large academic institutions or private professional research sites,” Porsteinsson explains about pharmaceutical company trials. “The temptation [for researchers] is to go where the treatment is ‘easiest’; where you’ve recruited before.”

In its clinical trial recruitment for lecanemab, the University of Rochester succeeded in increasing the representation of Hispanic participants, but struggled to include a representative number of Black patients.

“We can’t just wait until the brain deteriorates.” Rudolph E. Tanzi, PhD, Massachusetts General Hospital in Boston

“If we want to go after historically underrepresented groups in research, first we need to recognize they’re underrepresented for a reason,” Porsteinsson says. “There might have been a poor experience with researchers coming [into their community], doing a study [the researchers] needed, and then basically leaving. There isn’t an ongoing commitment.”

He says that if Alzheimer’s treatments are going to be meaningful to all people affected by the disease, it will take a concerted effort to include more diversity in clinical trial participants, not only in race and ethnicity, but in health status and inclusion of people with comorbidities. Often, trials tend to select for the healthiest patients possible, he explains.

“[We must] secure making our research more representative of the American population,” Porsteinsson says. “It’s going to take an investment in infrastructure and it’s going to take an investment of time.”

A stage set for discovery

Alzheimer’s disease already affects more than six million people living in the United States, and that number is projected to grow to 13 million by 2050. It’s also an incredibly financially costly disease, with an economic impact of $321 billion in health care costs in 2022, expected to rise to $1 trillion by 2050, according to the Alzheimer’s Association. That prospect prompted the U.S. Congress to approve an additional $226 million to the National Institutes of Health for Alzheimer’s research in December, bringing the annual federal funding outlay to more than $3.7 billion .

Experts say it is not in vain. Research efforts, particularly those at teaching hospitals, have helped unlock mysteries about the genetic underpinnings of the disease, ways to identify biomarkers in the blood that can more easily diagnose the disease in its earliest states, and complex treatment approaches that use lifestyle interventions and a combination of drug therapies.

Tanzi believes that the future of Alzheimer’s treatment and prevention will be similar to current management of heart disease and diabetes. It could mean more regular screenings and early interventions, such as taking anti-amyloid drugs and incorporating lifestyle and diet changes before the disease gets out of control. And for those already diagnosed, it means using a combination of therapies that target different aspects of the disease, such as neuroinflammation and plaque buildup.

“We can’t just wait until the brain deteriorates,” he says.

With the current momentum, Porsteinsson hopes that young and aspiring physician-scientists will be inspired to join the field and continue the research for generations to come.

“What many medical students and young doctors have historically been hesitant about is that dementia is very nebulous, there is a lot of gray there. … They felt things were pretty bleak, too uncertain, and there was too little you could offer,” he says. “Now, I think we are at the dawn of a very different era.”

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Research on Alzheimer’s Disease and Related Dementias

Alzheimer’s disease and related dementias are a series of complex brain disorders that affect millions of Americans and many more people worldwide. These disorders have an enormous impact on individuals and their families, long-term care facilities, health care providers, health care systems and infrastructure, and the communities in which we all live. As the economic, social, and personal costs of these diseases climb, the research community is working to discover solutions that will improve the lives of those with dementia, their caregivers, and their communities.

The federal government’s Alzheimer’s and related dementias research strategy focuses on engaging a cross-disciplinary team of geneticists, epidemiologists, gerontologists, behavioral scientists, disease and structural biologists, pharmacologists, clinical researchers, and others to bring the greatest and most diverse expertise to the field. This includes training new generations of researchers and clinician-scientists and engaging in innovative partnerships with private industry, nonprofit groups, and more to foster collaboration and broaden access to research resources and data.

Critically, the government’s research strategy includes the search to find treatment and prevention strategies, as well as interventions, services, and supports to improve quality of life for those already living with these diseases and their families.

Who Funds Alzheimer’s and Related Dementias Research?

The National Institutes of Health (NIH) is made up of Institutes, Centers, and Offices that conduct and fund research into all aspects of human health. The National Institute on Aging (NIA) leads NIH’s efforts in clinical, behavioral, and social research in Alzheimer’s and related dementias through efforts aimed at finding ways to treat and ultimately prevent the disorder. NIA collaborates closely with the National Institute of Neurological Disorders and Stroke (NINDS), which manages a research portfolio targeting Alzheimer’s-related dementias. While some of this research takes place in NIH laboratories, the vast majority of NIH support is provided through a competitive grants process to institutions and small businesses across the country. Other federal agencies support a range of activities focused on public health and community programs.

Advances in Alzheimer's and Related Dementias Research

As the nation’s biomedical research agency, NIH supports research ranging from basic biology to drug development and from clinical studies to evaluating public health outcomes. Within the past several decades, researchers have made great strides toward better understanding what causes Alzheimer’s and related dementias and discovering approaches that may prevent, diagnose, and treat them. Some highlights of these efforts include:

• Drug discovery and drug repurposing. Thanks to the substantial investment in Alzheimer’s and related dementias research over the past decade, NIH has increased drug discovery significantly. Of the many compounds in NIH-supported drug development programs for Alzheimer’s and related dementias, 18 new dementia drug candidates have now matured through the pipeline, from discovery in the lab all the way through preclinical development, to reach the stage of human testing. NIA currently supports more than 60 clinical trials testing drug candidates that target many different aspects of the disease. Several of these drug candidates are intended to stop or slow the disease process rather than only treat symptoms. For example, some target amyloid plaques and tau tangles in new ways. Researchers are also exploring multiple ways to repurpose drugs for the potential treatment of dementia, including FDA-approved drugs used to treat epilepsy and diabetes.
• Early detection and diagnosis. Researchers have made significant progress in developing, testing, and validating biomarkers that detect signs of the disease process. For example, in addition to PET scans that detect abnormal beta-amyloid plaques and tau tangles in the brain, NIH-supported scientists have developed the first commercial blood test for Alzheimer’s. This test and others in development can not only help support diagnosis but also be used to screen volunteers for research studies. Other discoveries are leading to the development of potential biomarkers for other dementias. These include the detection of abnormal TDP-43 protein, found in frontotemporal dementias, and a cerebrospinal fluid test to help diagnose Lewy body dementia and Parkinson’s disease. Researchers are also studying behavioral and social indicators, including problems with paying bills and a combined decline in memory and walking speed, that may be early signs of these diseases. Other early markers are also under study.
• Risks factors, genetics, and disease pathways. NIH’s research investments to identify the biological mechanisms that lead to Alzheimer’s and related dementias are fundamental for the discovery of potential drugs that target them. There are many biological pathways that scientists can target with investigational drugs. For example, several recent studies have further revealed how components of the immune system, brain inflammation, vascular disease, and possibly viruses and bacteria — including the many tiny organisms that live in the digestive system, known as the gut microbiome — contribute to the development of these diseases. Scientists are also exploring genetic variations that may contribute to or prevent disease. Recent research has revealed that the genetic risk for Alzheimer’s differs between ethnic and racial groups, highlighting the need for more diversity in genetic research studies. Scientists are also discovering genetic variants that may help protect against Alzheimer’s. Other studies are identifying the genetic underpinnings of related dementias, including new gene variants linked to the development of Lewy body dementia.
• Population studies and precision medicine. By studying large, diverse groups of people, researchers are identifying which genes, behaviors, and lifestyle choices are linked with dementia. Population studies have shown that sedentary behavior, low socioeconomic status, low level of education, and living in a poor neighborhood may increase the risk of developing dementia. These observational discoveries, along with knowledge of genetic and other factors, can be used to advance the development of methods for diagnosis, prevention, and treatment at an individualized level.
• Health disparities and dementia risk. NIH-funded researchers are examining the biological, social, and environmental factors that contribute to the higher prevalence of dementia in Hispanic Americans and Black Americans compared with other White Americans. Since dementia is also underdiagnosed in these populations, researchers are studying approaches to improve diagnoses in underserved communities. NIH is also investing in strategies to increase diversity in research study participants.
• Lifestyle interventions. Researchers are investigating interventions around exercise, healthy eating, cognitive training, preventive health care, and management of chronic conditions, such as high blood pressure, that — if made early in life — may be able to prevent or delay disease symptoms. Emerging areas of study include interventions to enhance cognitive reserve — the mind’s ability to cope with the effects of aging — and interventions to potentially compensate for premature cognitive decline and dementia linked to adverse exposures in early life, such as abuse and malnutrition. NIA currently supports more than 150 trials testing behavioral and lifestyle interventions.
• Dementia care and caregiver support. NIH has significantly expanded research on how to improve dementia care and support for care partners. Researchers are investigating new dementia care models and strategies to equip family caregivers with tools and knowledge to manage the challenges of caring for a loved one with dementia. Studies are also underway to examine ways to improve quality of life for people with dementia and their caregivers. Other studies aim to understand the costs and challenges of dementia, including lost wages and paying for long-term care. NIA currently supports more than 200 studies on dementia care and caregiving.
• Infrastructure development. NIH is continually investing in research infrastructure to advance Alzheimer’s and related dementias research. Efforts in this area include launching a consortium for Alzheimer’s clinical trials, a collaboratory to test interventions to improve care of people with dementia in real-world settings, research efforts to validate cognitive tests in a primary care setting, and centralized data-sharing platforms and other technologies.

Challenges for the Alzheimer’s Research Community

Even with the progress that we’ve made, there’s still a lot of work to do before we can find treatment and prevention strategies for the millions of people affected by Alzheimer’s and related dementias. These devastating diseases are highly complex conditions caused by an interplay of genetic, lifestyle, and environmental factors. They usually develop gradually — changes in the brain take place over years and even decades, long before the first symptoms appear. This complexity presents challenges to the discovery and development of new drugs and other prevention and treatment approaches.

Researchers believe Alzheimer’s and related dementias will likely require multiple treatments customized to individuals. We also know that as the older population continues to grow — aging remains the most important risk factor for dementia — we will see increased numbers of people living with these diseases. That’s why thousands of researchers around the country are working on this issue.

Setting the Federal Research Agenda

NIH takes a collaborative, methodical approach to reviewing progress, identifying gaps, and setting the future agenda for research into Alzheimer’s and related dementias. NIH funding in this area is guided by gaps and opportunities identified in research summits , which alternate yearly to focus on Alzheimer’s, Alzheimer’s-related dementias, or dementia care and services. Smaller, focused workshops are held more frequently on specific aspects of this research.

NIH outlines its Alzheimer’s research efforts in the NIH AD/ADRD Research Implementation Milestones , a research framework detailing specific steps and success criteria toward achieving the goals of the National Plan to Address Alzheimer’s Disease . The milestones also showcase funding initiatives, accomplishments, and highlights of progress toward accomplishing the National Plan goals.

NIH’s research progress is highlighted in the annual Alzheimer’s and related dementias professional judgment budget , which is submitted to Congress each year.

What Is a Professional Judgment Budget?

Each year NIH submits a professional judgment budget that estimates the additional funding needed to advance NIH-supported research into the treatment and prevention of Alzheimer’s and related dementias. The report also summarizes progress and promising research opportunities. Only two other areas of biomedical research — cancer and HIV/AIDS — follow a similar process designed to accelerate research discovery. This approach is often referred to as a “bypass budget” because of its direct transmission to the President and then to Congress without modification through the traditional federal budget process.

Clinical Research Into Alzheimer’s and Related Dementias

No major advance in Alzheimer’s and related dementias treatment, prevention, or care will be possible without robust clinical research. Clinical research includes studies that involve people so scientists can learn more about disease progression, how behavior and lifestyle factors may affect health, and the safety and effectiveness of an intervention. Advances made through clinical research rely on the volunteers who participate in these types of studies. NIA is working on multiple initiatives to enhance recruitment and retention of diverse populations in clinical research. View some of those resources below.

NIA-funded clinical research includes both observational studies through which researchers gather important information, and clinical trials in which researchers test interventions to treat or prevent disease, improve care and caregiver support, and enhance quality of life for people living with dementia. NIA is currently funding more than 400 active clinical trials .

NIA also funds more than 30 Alzheimer’s Disease Research Centers across the country. Scientists at these centers conduct clinical research to improve diagnosis and care for people with dementia and their families, and to find a treatment or increase prevention.

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Find More Resources on Alzheimer’s Research

Explore the resources on this website and linked below to find more information from federal government agencies.

View professional judgment budgets for Alzheimer’s and related dementias from NIH, including yearly updates on research progress.

Browse this database to learn more about research implementation plans and progress toward the goal of treating or preventing Alzheimer’s and related dementias.

Search this repository of resources to support the recruitment and retention of participants into clinical trials and studies on Alzheimer’s disease and related dementias.

Learn about the data sharing policies, considerations, resources, and guidance available to support researchers in safely and efficiently sharing data from their studies.

Visit IADRP to search a database of categorized research across public and private sources.

Learn about NIA's efforts toward the National Plan and NIH annual summits that shape research priorities.

View a list of all active NIA-funded clinical trials, including drug trials, intervention studies, and care and caregiver interventions.

Search for NIA-supported clinical research tools, datasets, samples, visualization tools, and more for Alzheimer’s and related dementias research.

Read the National Strategy for Recruitment and Participation in Alzheimer’s and Related Dementias Research and get resources to support study recruitment.

Read about the National Institute of Neurological Disorders and Stroke’s research into Alzheimer’s disease-related dementias.

Search NIH-funded research in Alzheimer’s and related dementias.

Other Articles in This Section

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Questions? Contact the ADEAR Center

The Alzheimer’s & related Dementias Education & Referral (ADEAR) Center is a service of the National Institute on Aging at the National Institutes of Health. Call 800-438-4380 or email [email protected] to talk with an information specialist.

Last updated: July 9, 2024

This content is provided by the National Institute on Aging (NIA), part of the National Institutes of Health. NIA scientists and other experts review this content to ensure it is accurate and up to date.

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Alzheimer's drug may slow down cognitive decline in dementia with Lewy bodies

by Karolinska Institutet

Dementia with Lewy bodies is a type of dementia that is similar to both Alzheimer's disease and Parkinson's disease, but studies on long-term treatments are lacking. A new study from Karolinska Institutet in Sweden, published in Alzheimer's & Dementia , highlights the potential cognitive benefits of cholinesterase inhibitor treatment.

Lewy body disease, which includes dementia with Lewy bodies (DLB) and Parkinson's disease with and without dementia, is the second most common neurodegenerative disorder, following Alzheimer's disease. DLB accounts for approximately 10–15% of dementia cases and is characterized by changes in sleep, behavior, cognition, movement, and regulation of automatic bodily functions.

"There are currently no approved treatments for DLB, so doctors often use drugs for Alzheimer's disease, such as cholinesterase inhibitors and memantine, for symptom relief," says Hong Xu, assistant professor at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and first author of the paper. "However, the effectiveness of these treatments remains uncertain due to inconsistent trial results and limited long-term data."

In the current study, researchers have examined the long-term effects of cholinesterase inhibitors (ChEIs) and memantine compared with no treatment for up to ten years in 1,095 patients with DLB. They found that ChEIs may slow down cognitive decline over five years compared to memantine or no treatment. ChEIs were also associated with a reduced risk of death in the first year after diagnosis.

"Our results highlight the potential benefits of ChEIs for patients with DLB and support updating treatment guidelines," says Maria Eriksdotter, professor at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and last author of the paper.

Due to the study's observational nature, no conclusions can be drawn about causality. The researchers did not have data on patient lifestyle habits, frailty, blood pressure, and Alzheimer's disease co-pathology, which may have influenced the findings. Another limitation of the study is that it remains challenging to diagnose DLB accurately.

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• Open access
• Published: 21 August 2024

Burden and satisfaction with social support in families with a history of problematic substance use or dementia – a comparison

• Renate Soellner 1 &
• Christine Hofheinz 1  

BMC Psychology volume  12 , Article number:  448 ( 2024 ) Cite this article

164 Accesses

Metrics details

Living in a family with a history of problematic substance use or dementia is a major stressful experience for family members and results often in an impaired health condition. Seeking and receiving social support has been emphasized as a major resource while coping with this stress. However, especially family members of people with problematic substance use often refrain from help-seeking. This paper examines whether (1) family members of problematic substance users are more physically and psychologically distressed than caregivers of people with dementia, and (2) whether and to what extent differences are mediated by satisfaction with perceived professional and private social support.

Two samples of family members of people with a chronic disease (problematic substance use ( n  = 221), dementia ( n  = 322)) completed self-administered questionnaires on burden, quality of life and social support. Physical distress was assessed using the Giessen Subjective Complaints List, psychological distress using the Center for Epidemiological Studies Depression Scale and anxiety symptoms using the Hospital Anxiety and Depression Scale. Quality of life was measured using the WHOQOL-BREF, and satisfaction with professional and private social support was assessed using a visual analog scale. Multivariate analyses of variance were performed to compare the two groups on the means of (1) burden ratings and (2) QoL dimensions and followed up by discriminant analyses to explore meaningful variables according to group differences. Parallel mediation analyses were performed to test the mediators private and professional support.

Family members of problematic substance users score higher on the burden indicators, while they score lower with regard to the quality of life dimensions than caregivers of people with dementia. The difference in burden is mainly explained by the higher scores for exhaustion, stomach discomfort and depression of family members of problematic substance users. Caregivers of people with dementia reported greater satisfaction with perceived social support, either private or professional. Satisfaction with private support was shown to be more important in mediating the impact of stress.

Conclusions

Family members of people with problematic substance use are in great need of tailored support programs and should be explicitly targeted.

Peer Review reports

Family members of persons with a chronic disease, often requiring intensive care, generally have poorer health [ 1 ]. For example, caregivers of people with dementia report an increased prevalence of anxiety and depressive symptoms, as well as poorer physical health and quality of life [ 2 , 3 ]. Impaired caregiver health has also been reported after stroke and for people with family members with mental disease [ 4 , 5 ]. Among these, relatives of people with substance use problems (SUP) are a special group. Living together with someone who misuses alcohol or drugs places a heavy burden on family members or friends [ 6 , 7 , 8 ]. Family members describe ongoing insecure living conditions, conflicts over money and personal possessions, and a relationship with the substance-using person that becomes uncomfortable and sometimes aggressive [ 9 ]. They show increased symptoms of depression, anxiety and stress [ 10 ], reduced quality of life, and higher levels of physical (exhaustion, gastrointestinal disorders) and psychological (somatization, uncertainty in social contacts) distress compared to the general population [ 8 ].

In order to better describe and understand the situation faced by family members of substance users Orford and colleagues have developed a stress-strain-coping support model [ 11 ]. They emphasize the role of the quality of social support, which is not simply measured by the number of people available, but by how well the support works to adequately address the problem. According to this model, for family members of problematic substance users, social support (e.g. emotional, informational or practical) is particularly important for coping, but often fails [ 9 ]. Because seeking and receiving social support plays an important role in coping with stress, this is a major health risk factor [ 12 , 13 ]. Referring to the concept of social support, it has been repeatedly suggested that perceived and received social support, which were found to be only moderately correlated, should be distinguished [ 13 , 14 ]. Perceived social support refers to how persons rate how accessible and valuable their potential support is, while received support refers to the amount of support they actually receive. Perceived social support was found to be more predictive of mental health, such as depression [ 15 ], while received support was only marginally predictive [ 16 ]. Among caregivers of people with dementia or older adults, at least two studies have found that social support mediates the relationship between resilience and stress [ 17 , 18 ]. A meta-analysis of caregivers of adults and older adults found a moderate, negative association of perceived social support with subjective distress while the negative association of received support with subjective distress was only small [ 19 ]. Social support through professional or private help promotes mental as well as physical health [ 20 , 21 ]. In particular, informal social support was found to be more important than professional support [ 22 ]. For example, in a meta-analysis of 148 studies, Holt-Lundstad and colleagues [ 23 ] showed that both social integration and social support, in the form of perceived support from others, were associated with reduced mortality, even exceeding the effects of behavioral factors such as physical activity or excessive drinking.

Family members of people with SUP often refrain from seeking professional services in the first place. For example, 58% of the interviewed relatives of substance misusers in Brazil waited an average of 2.6 years before actively seeking professional help [ 24 ]. Most of them thought that substance misuse was a temporary problem (40.6%) or did not know what kind of help they needed (29.7%). About 10% reported that they had tried to hide the problem. In addition, family members often believe that the problem should be dealt with within the family [ 6 ].Specifically, they perceive professionals as lacking in knowledge, awareness or empathy and feel excluded from treatment.

One possible explanation for this lack of social support for family members lies in the stigma experienced by people with SUP [ 25 , 26 , 27 ]. In a study on the factor structure of public stigma of substance use disorders (SUD), 337 participants rated how they think the public would believe certain statements on “addicts”. A four-factor solution was found for stereotypes including themes like reckless (unpredictable, uncontrollable), unreliable (weak, hopeless, selfishly), inadequate (worthless, lazy, to blame for their own problems), and threat (they are seen as cheaters and liars) [ 28 ]. Furthermore, people were expected to form prejudices, covering emotional reactions like anger (leading to hate and resentment), pity (because they do not know how to help), and dread (being afraid or wary of people with SUP) [ 28 ]. The process of being stigmatized has been widely reported for people with mental illness in general [ 29 , 30 ]. In a representative sample in the USA, people with various mental disorders were assessed for help-seeking behavior [ 31 ]. People with SUPs were found to be less likely to seek help than people with mood disorders in general. The topic is still relevant today, especially in the light of the alarmingly rising rates of overdoses and opioid and stimulant consumption within the last years in the United States. Krendl and Perry [ 26 ] recently provided a comprehensive overview on research on stigma on SUD and non-substance related mental illness. They conclude, that people with SUD are generally viewed as more dangerous than people with mental illness and that stigma is a barrier not only to seeking treatment but also predicts negative attitudes toward treatment seeking.

Stigma has been shown to affect not only the person with mental illness but also their families [ 32 , 33 ], the so called ‘courtesy stigma’ [ 34 ]. This is also evident, for caregivers of people with dementia, who report feeling stigmatized [ 35 ]. As a consequence, caregivers and other family members refrain from seeking help due to fear of being stigmatized [ 9 , 36 , 37 ] or self-stigmatize. Self-stigma, in turn, is defined as endorsing negative stereotypes about oneself [ 38 ]. Family caregivers of people with dementia, for example, self-stigmatize ‘being a neglectful caregiver’ or ‘receiving a punishment from God’ which results in isolation and not seeking help [ 39 ]. However, as dementia and its consequences have received increasing attention in policy and public discourse over the past two decades, dementia has been somewhat de-tabooized. Support for people with dementia and their families, such as Alzheimer’s Society family groups and tailored interventions such as TeleTAnDem [ 40 ], has increased, and caregivers of people with dementia are more likely to receive and actively seek formal or informal social support.

While help-seeking per se is stigmatized and leads to reduced help-seeking behavior [ 41 ], Clement and colleagues [ 42 ] found a median association between stigma and help-seeking of d=-0.27 in a systematic review of the impact of mental health stigma on the formal service use, which equals a small effect size [ 43 ]. Increasing stigmatization is therefore accompanied by less help-seeking behavior. Self-stigmatization and anticipated discrimination when seeking help were most frequently associated with reduced help-seeking.

In summary, literature on stigma and mental illness suggests that family members of people with SUP are particularly affected by both public stigma and internalized self-stigma, resulting in less help-seeking behavior and, hence, less social support. However, the quality of social support, particularly informal perceived social support, is very important in reducing the burden of the family situation. Given these differences in stigma for family members of people with SUP on the one and caregivers of people with dementia on the other hand, we expect greater burden and poorer mental and physical health condition for family members of people with SUP. Furthermore, we expect, that caregivers for people with dementia will be more satisfied with the social support they perceive compared to family members of people with SUP, which mediates this complex relationship.

In this paper we will examine whether (1) family members of problematic substance users are more physically and psychologically distressed than caregivers of people with dementia, and (2) whether and to what extent differences in physical and psychological distress are mediated by satisfaction with perceived professional and private social support.

Participants and procedure

The sample for this paper is taken from two research projects with family members of people with a chronic disease: (1) a participatory research project with relatives of people with SUP ( n  = 221) in 2015-2017 [ 7 ] and (2) a controlled cognitive behavioral intervention study with caregivers of people with dementia ( n  = 322) taking place in the years 2013–2015 [ 44 ]. Both samples were convenience samples and were gathered via newspaper advertisements, self-help groups or e.g. the Alzheimer Society. In this paper the baseline measures of both samples are compared. Thus, we do not assume any interaction of the answering behavior with the treatment (two-arm controlled intervention study versus participatory approach). Family members of persons with SUP (FM group) were mainly interviewed online from January to 2016 to August 2016, while the questionnaires for caregivers of people with dementia (CG group) were collected by paper and pencil between September 2012 to November 2013. Recruitment for both projects used a variety of publicity relations methods: printed information materials available at cooperation partners (clinics, practices, home support services), editorial articles in regional and national newspapers, television and radio interviews, project websites, online newsletters and postings in online groups. To be included, participants in the FM group had to identify themselves as relatives of a problematic substance user. A medical diagnosis of an addiction was not required and there were no exclusion criteria. Inclusion criteria for the CG group were somewhat stricter: Participants had to be the main person responsible for the care of the person with dementia, and the person with dementia must had to have at least low-grade dementia according to medical diagnosis. Exclusion criteria were that the caregiver was receiving ongoing psychotherapeutic treatment, had a serious physical illness or medically diagnosed psychiatric disorder, and that the person with dementia was institutionalized or planned to be institutionalized in the next 6 months.

Both research projects were approved by the Ethics Committee of the respective Universities (University of Hildesheim, Friedrich-Schiller‐University Jena (3453‐05/12)). All participants provided written informed consent.

Physical distress was assessed using the exhaustion and stomach discomfort subscales of the short version of the Giessen Subjective Complaints List ( Gießener Beschwerdebogen , GBB-24 ) [ 45 ]. Participants had to indicate how much each of the six complaints per subscale bothered them (0 = not at all, 4 = strongly). Cronbach’s alpha was 0.90 for exhaustion and 0.74 for stomach discomfort for the caregivers and 0.87 for exhaustion and 0.83 for stomach discomfort for the family members of people with SUP. Psychological distress was assessed by measuring symptoms of depression and anxiety. Depressive symptoms were assessed using the German version of Center for Epidemiological Studies - Depression Scale ( Allgemeine Depressionsskala , ADS )) [ 46 ]. The ADS measures how often 20 symptoms applied to the participant in the past week (0 = rarely/less than 1 day, 3 = mostly/5–7 days). Cronbach’s alpha was 0.89 for the caregivers [ 3 ] and 0.91 for family members of persons with SUP. Anxiety symptoms were derived from the anxiety subscale of the Hospital Anxiety and Depression Scale ( HADS ) [ 47 ] (German version [ 48 ]). Participants were asked to rate how often they had experienced seven symptoms in the past week. Cronbach’s alpha was 0.81 for the caregivers and 0.82 for family members.

Quality of Life (QoL)

QoL was measured using the WHOQOL-BREF (WHO, 1996; German version: [ 49 ]) with the four domains physical (seven items), psychological (six items), environmental (eight items), and social relationships QoL (three items). Participants rated their satisfaction with the quality in each domain over the last 2 weeks on a 4-point Likert scale. Internal consistency, as measured by Cronbach’s Alpha, ranged from 0.58 (social relationships), 0.72 (environment), 0.81 (psychological health) to 0.83 (physical health) for the caregivers [ 50 ]. A similar pattern emerged for the family members of people with SUP, again with internal consistency worst for social relationships (0.57), but in the good range for physical health (0.79), environment (0.81) and psychological health (0.87). Raw data for each domain were transformed into summed scores ranging from 0 = not at all satisfied to 100 = very satisfied.

Satisfaction with social support

Satisfaction with professional, personal and emotional social support was measured using a one-item visual analog scale for each facet. Participants had to indicate their satisfaction with each type of support (from 0 = not at all satisfied to 100 = very satisfied). These scales were developed in study 2 along with several other one-point item measures relating to burden of care and emotional wellbeing [ 44 ]. For this paper the personal and emotional support facets were aggregated into a new variable “satisfaction with private support”, with the higher value of the two original variables.

Statistical analysis

Chi-square and t-tests in SPSS 27 were used to assess differences between the FM and the CG groups on socio-demographic characteristics. Two multivariate analyses of variance (MANOVA) were performed to compare the two groups on the means of (1) the four burden assessments and (2) the four QoL domains. MANOVA assumptions regarding multivariate normality and homogeneity of variance covariance matrices were tested using the BOX-M-Test. Given different sample sizes, with larger variances and covariances of the smaller sample size, a significant Box-M-Test may be too liberal and should be treated with caution [ 51 ]. However, if the assumption of multivariate normality is met, the assumption of homogeneity of variances can be safely assumed [ 52 ]. Therefore, to check for multivariate normality, the Mahalanobis distance was additionally plotted against the Chi-square [ 53 ]. The MANOVAs were followed up by discriminant analyses to explore meaningful variables according to group differences. Mediation analyses were conducted by using the PROCESS macro for SPSS [ 54 ]. Variables that were found to be significantly different between the two groups in the discriminant analyses ( r  > .5) were included as outcomes in the mediation models. Satisfaction with professional and private support were included as mediators in a parallel mediation analysis.

Sample characteristics

Sociodemographic characteristics are shown in Table  1 . Participants in both groups were predominantly female (FM = 91.2%; CG = 80.1%). Caregivers of people with dementia were significantly older than family members of persons with SUP ( t (537) = -17.85, p  < .001). While the gender ratio among the ill relatives in the CG group is relatively balanced (51.2% female), in the FM group it is predominantly men who are affected by the substance use problem (19.6% female). Regarding the most common substance used in the FM group was alcohol (71.9%), followed by cannabis (30.3%) and other illicit drugs (26.2%). The most common type of dementia in the CG group was Alzheimer’s disease (44.4%), followed by vascular dementia (10.3%).

Differences in Burden and QoL

Using Pillai’s trace the two MANOVAs on four indicators of burden and four dimensions of QoL showed both significant differences between the two groups of relatives ( V  = 0.077, F (4,514) = 10.65, p  < .001; V  = 0.034, F (4,507) = 4.04, p =  .002; Table  2 ). Family members of problematic substance users score higher in the indicators of burden while they score lower with regard to the QoL dimensions than caregivers of people with dementia.

Following up the MANOVA results with a discriminant analysis for the indicators of burden one significant discriminant function emerged ( Λ  = 0.92, χ 2 (4) = 41.02, p  < .001, canonical R 2 = 0.076). The correlation between the independent variables and the discriminant function showed that exhaustion loaded the highest ( r  = .894), stomach discomfort and depression loaded in a middle range ( r  = .636, r  = .524,), and that anxiety was less discriminant ( r  = .325). Hence, the difference in burden between both groups is predominantly explained by the higher exhaustion, stomach discomfort, and depression values of the family members of problematic substance users. Also, the discriminant analysis for the QoL dimensions turned out into one significant discriminant function ( Λ  = 0.97, χ 2 (4)17.35, p  = .002, canonical R 2  = 0.033). Here, only psychological QoL discriminated strongly between family members of substance users and caregivers of people with dementia ( r  = .935), while all other dimensions correlated with the discriminant function less than 0.5. Again, family members of people with SUP show a poorer psychological health condition compared to caregivers of people with dementia.

Mediation analysis

Parallel mediation analyses were conducted for the four outcomes that correlated at least 0.5 with the discriminant function: exhaustion, stomach discomfort, depression and psychological QoL. The results for each path are displayed in Table  3 . Total, direct and indirect effects are shown in Table  4 . Graphs of the various effects are provided in Figs.  1 – 4 .

Parallel mediation model: exhaustion

Parallel mediation model: stomach discomfort

Parallel mediation model: depression

Parallel mediation model: psychological QoL

In general, caregivers of people with dementia reported being more satisfied with perceived social support regarding both, private and professional support, than family members of people with SUP, while this difference was obviously more pronounced for professional support than for private support (e.g. exhaustion: b = 32,41 vs. b = 10,25). The direct effects of the mediators on the outcome variables were mixed. Satisfaction with private support was negatively associated with exhaustion and stomach discomfort, and positively associated with psychological QoL. Satisfaction with professional support only predicted psychological QoL positively. There was no direct significant association between any of the satisfaction with social support measures and depression.

However, both mediators show specific indirect effects for depression (private support: -1,2857, [CI: -2,1754 - -,5182]; professional support: -1,3924, [CI: -2,8111 - -,0821]) and psychological QoL (private support: 1,8270, [CI: ,6584-3,2417]; professional support: 3,8787, [CI: 1,4299–6,3860]). Caregivers of people with dementia are less depressed and report a higher QoL, which is mediated by satisfaction with private and professional social support. With regard to stomach discomfort and exhaustion, only satisfaction with private social support significantly mediated the effect of group membership (stomach discomfort: -,1573, [CI: -,3740 - -,0026]; exhaustion: -,3866, [CI: -,7118 - -,1354]). The FM group shows higher levels of exhaustion and stomach discomfort than the CG group, which are both mediated by satisfaction with private social support.

Living in a family with a history of problematic substance use or dementia is a major stressful experience for family members and results often in an impaired health condition. Within this study family members of persons with either substance use problems or dementia were compared concerning their level of burden. It is further argued, that poorer health may be mediated by reduced help-seeking behavior and thus lower satisfaction with social support.

Caregivers of people with dementia showed less stress than family members of people with problematic substance use. In fact, the latter suffered from higher burden on all variables, while exhaustion, followed by stomach discomfort and depression, being the most distinctive. As caregivers of people with dementia have been repeatedly described as highly exhausted due to the physical and psychological demands of caring for a person with dementia [ 3 , 55 ], this finding underlines the even higher burden faced by family members of people with a history of substance abuse. This is supported by recent research describing mothers of children with substance use disorders as having higher levels of burnout and depression than mothers of patients suffering from schizophrenia [ 56 ]. However, other studies report that the burden of caregivers respectively family members of these two mental illnesses is high but equivalent [ 57 ].

Regarding our second research question, we found that perceived social support did mediate the differences in psychological and physical distress but the results depended on the type of support. While satisfaction with private support mediated all group differences, satisfaction with professional support was relevant only for depression and psychological quality of life. This finding is in line with previous research, showing that people generally rely more on informal sources such as family and friends and seek less professional support, while seeking professional support is highest among those suffering from more severe conditions [ 58 ]. Again, in a qualitative study with caregivers of dementia, emotional support was identified as one of the most important aspects of caregivers’ health needs [ 59 ].

As family members of persons with SUP were less satisfied with both, private and professional social support, their mental health outcomes were worse. Given the higher level of stigmatizing experienced by people with SUP, their family members appear to be equally affected. Living with, or being close to, a problematic substance user presents specific challenges. Amongst them are uncomfortable relationships, sometimes aggressive behavior, constant worry and fear of public embarrassment, and repeatedly dashed hopes that the loved one will be abstinent [ 11 , 57 ]. They lead to a range of negative emotions, such as anger, fear, guilt, shame, and hopelessness which are associated with increased levels of stress, depression and anxiety [ 10 , 60 ]. These stressors as well as the high level of self-stigmatizing of family members of people with SUP [ 56 ], may have an additionally negative impact on the mental and physical health status of this group.

One possible explanation may be that family members of people with SUP are reluctant to proactively seeking help for fear of shame and guilt. Less satisfaction with existing support structures for families with a history of problematic substance use could also be seen as a consequence of the reduced help-seeking behavior of families with people with SUP. In general, while support structures for caregivers of people with dementia have been developed and become more accessible over the last decade, family members of people with SUP are still rarely specifically addressed in the support system. This is also true in the private sector, where support for dementia seemed to be much more accessible and affordable than for a family member of people with problematic substance use. In other words, doing the shopping or looking after a person with dementia seems easier and less embarrassing for the supporting person than dealing with a person who is behaving aggressively under the influence of alcohol.

However, although social factors contribute about as much to explaining life expectancy as well-known behavioral risk factors such as smoking, high alcohol consumption and physical inactivity, the importance of social factors for health is still underestimated by the public [ 61 ]. It is a societal responsibility to disseminate this knowledge and promote the development of tailored support structures for family members of people with problematic substance use. Moreover, the structural discrimination against people experiencing substance-related problems and their families finally need to be broadly addressed to change the game [ 62 ]. This includes adequate media coverage, using person-first language, i.e. speaking from persons with substance use instead of substance users [ 26 ], risk-factor reduction as well as treatment access and humanizing narratives [ 63 ].

Strengths and limitations

This is the first paper to compare the two groups of family members, those of people with problematic substance use and those of people with dementia. Given the high and rising prevalence of these diseases, research on this topic is particularly important. The results therefore affect a large number of people. From a clinical perspective, they indicate that although both groups suffer from psychological and physiological distress, family members of people with SUP may be in particular need of more appropriate professional and private support. This means that those working in the help system should automatically think about the relatives of people with problematic substance use. Whenever a person enters the help system because of substance use problems, the relatives should also be immediately considered and provided with specific services.

There are also some limitations to note. As our sample consists of family members of people with chronic diseases, our data only represent the views of family members and not the patients themselves. We measured satisfaction with social support as a proxy for help-seeking behavior on the one hand and stigma on the other. We expected differences in distress variables to be mediated by satisfaction with perceived social support, but cannot show whether they are mediated by stigma. Future research should pick up that issue and investigate stigma and help-seeking behavior directly. However, since the results support our expectations of different levels of stress and perceived social support, our expectation of different levels of stigmatization associated with these diseases are at least plausible and not rejected.

Importantly, measurement took place mostly online for the FM group and paper and pencil with telephone support for the CG group. Therefore, we cannot rule out the possibility that the lower burden within the CG group was also due to the fact that the telephone support made the survey less anonymous when completed. The telephone support was provided by other members of the research group and the authors of this study and the respective therapists in the intervention project were not involved. Nevertheless, it is possible that some CGs found it more difficult to express their true distress in telephone contact. Although both samples were recruited differently, both were convenience samples. Therefore, the issue of specific representativeness needs to be considered. A major limitation is the age difference between the two groups, as family members of people with SUP were considerably younger than those caring for people with dementia. In addition, people with problematic substance use were predominantly male, whereas the people with dementia were equally divided between men and women. However, as problematic substance use tends to occur earlier in life than dementia, we believe that these samples are representative of the specific condition. We deliberately chose not to use matching techniques such as propensity score matching, as this would have resulted in both samples being truncated on one side of the distribution, resulting in a superficial sample. Rather, we believe that the age of the family members and the gender of those affected seem to be inherent characteristics of the sample of question. Although the data are from before the pandemic, we do not expect any changes in the interplay between stigma, satisfaction with social support and health outcomes. Furthermore, there is no evidence that the structures of support systems and attitudes towards mental illness, particularly substance use problems, have changed. Lastly, based on cross-sectional data, mediation analyses do not necessarily imply causality. It is thus also possible, that a higher burden could lead to lower satisfaction with social support.

People with problematic substance use and their family members should be addressed at a societal level. In addition to educational programs broad structural measures are needed to initiate social change and to reduce structural discrimination. It is long overdue that people with SUP and their families are assessed and treated in the same way as people with other mental and non-mental diseases. More tailored programs need to be developed to support family members of people with a history of substance abuse. Emphasis should be placed on overcoming self-stigma, coupled with proactively seeking and accepting social support. Access to the support system should be broadened according to their specific situation. This can be one component in a necessary package of measures towards a more inclusive and solidary society, where everyone has their place.

Data availability

The datasets generated and/or analysed during the current study are not publicly available due to the Ethics approval and the data contract for both projects.

Abbreviations

Substance use problem

Substance use disorders

Quality of life

Family Members

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Acknowledgements

The studies on which this work is based were conducted in collaboration with Gabriele Wilz, Friedrich-Schiller-University Jena, and Wolfgang Schröer, University of Hildesheim.

Open Access funding enabled and organized by Projekt DEAL. This work was supported by the German Federal Ministry of Health [Grant number Project 1: ZMVI1-2515DSM217; Grant number Project 2: IIA5-2512FSB555].

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Soellner, R., Hofheinz, C. Burden and satisfaction with social support in families with a history of problematic substance use or dementia – a comparison. BMC Psychol 12 , 448 (2024). https://doi.org/10.1186/s40359-024-01940-1

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• Published: 15 February 2023

Dementia research needs a global approach

Nature Medicine volume  29 ,  page 279 ( 2023 ) Cite this article

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The international community needs to prioritize research on interventions and preventative measures for dementia that are likely to produce the greatest global impact.

Dementia is the seventh leading cause of death worldwide, and the number of people living with this disorder is expected to triple by 2050 . The burden of dementia is not equal across all countries, with around two thirds of people with dementia living in low- and middle-income countries (LMICs), where increases are predicted to occur more rapidly than in higher-income countries (HICs). Women are disproportionately affected by dementia, with greater prevalence rates than men in all age groups and a higher proportion of deaths. Women are also responsible for providing roughly 70% of informal care hours globally, with the highest proportions being in LMICs.

Although progress has been made, research into dementia remains fragmented and siloed to areas unlikely to generate the greatest global impact. Even the recent approval of lecanemab by the US Food and Drug Administration is tempered by the fact that the cost and infrastructure requirements of this treatment are likely to be prohibitive for LMICs — where most people with dementia reside. The World Health Organization (WHO) global status report on the public health response to dementia in 2017–2025 highlights the need for increased efforts globally to reach the dementia targets set for 2025 by Member States. The report’s bottom line is unequivocal: it is time for the international community to prioritize research on interventions and preventative measures that are likely to benefit all people at risk of dementia.

On 4 October 2022, the WHO released a dementia research blueprint to support implementation of the Global action plan on the public health response to dementia in 2017–2025, representing a first-of-its-kind publication in the context of non-infectious diseases. Leveraging key lessons learned from previous WHO efforts to prioritize and coordinate research into infectious diseases, the blueprint emphasizes key objectives across the entire dementia research spectrum that will have the greatest impact on the global burden of this devastating disorder. For example, a better understanding of the prevalence and incidence of dementia, the costs of illness and the prevalence and impact of risk factors is needed in LMICs and other ethnic and regional groups. Research into the mechanisms of dementia, such as biomarkers and genetic and epigenetic markers, should include and account for differences in these groups. This may require improved engagement and collaboration with communities that may be less willing or unable to participate in these types of studies.

Studies in HICs have reported a decrease in the prevalence of dementia, linked to modifiable dementia risk factors. These exciting findings suggest that modification of risk factors could slow cognitive decline and delay the onset of dementia, or prevent it altogether. Given the costs of dementia care, primary prevention is likely to be the cheapest and easiest way to reduce the projected global impact of dementia. Yet there are little data available on modifiable risk factors in LMICs or in culturally, ethnically and sexually diverse sub-populations in both HICs and LMICs. Furthermore, the data used to calculate these risk factors are from HICs, despite studies showing that some risk factors are more prevalent than others in LMICs and account for more cases of dementia there than in the rest of the world . Differing environmental and social exposures also influence dementia risk. This includes exposure to air pollution and pesticides, which is associated with an increased dementia risk, whereas proximity to green spaces is linked to positive cognitive outcomes.

There are also few robust studies on sex-specific risk factors such as early menopause and complications during pregnancy and on the differential effect of risk factors in men and women, as recently shown for cardiovascular events. It is now generally accepted that longevity alone is not responsible for sex differences seen in dementia, and studies are increasingly highlighting a biological component. Men and women with Alzheimer’s disease (AD) exhibit different cognitive and psychiatric symptoms, and women show faster cognitive decline after a diagnosis of mild cognitive impairment or AD dementia. Epidemiological studies demonstrate that the allele encoding apolipoprotein E confers different AD risk profiles on the basis of sex, with women who have the allele encoding apolipoprotein E-ε4 being at greater risk for developing AD than age-matched men are. Despite these findings, little to no data are available on sex differences in the efficacy and safety of drugs used in recently completed phase 3 clinical trials for mild to moderate AD. Furthermore, women remain under-represented in clinical trials for AD . Systematic studying and reporting of sex differences in disease symptomatology, biomarkers, progression, risk factors and treatment responses will be crucial for efforts to reduce the global impact of dementia.

Funding is obviously the key driver of research. Data for 2019 indicate that although funding for dementia has increased, it is directed mainly toward research in HICs. Of the 50 organizations and institutions that received the most grants for dementia research in 2019, 41 were in the United States, 6 were in the United Kingdom and 3 were in Canada. Furthermore, the vast majority of funding is directed toward research into AD, despite the fact that dementia is caused by several diseases. Although increased funding for dementia research is a step in the right direction, this needs to happen in a more structured and equitable fashion.

Dementia is highly complex, and the challenge of tackling the global burden of this disorder cannot be overcome by people working in silos. Considerable research gaps exist in the understanding of this disorder, particularly in areas in which its burden is greatest. Closing these gaps requires implementation of a harmonized global research plan with equitable inclusion and research capacity-building in under-resourced settings. Only such a level of global research prioritization can ensure that ongoing research efforts deliver the greatest impact possible.

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Dementia research needs a global approach. Nat Med 29 , 279 (2023). https://doi.org/10.1038/s41591-023-02249-z

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