Burden Of Alzheimer's Disease Research Articles

Current and evolving treatment strategies for the Alzheimer disease continuum.

The burden of Alzheimer disease (AD) on the US healthcare system is substantial and increasing. AD progresses along a continuum from preclinical disease characterized by normal cognition and abnormal brain biomarkers to mild cognitive impairment and then clinically apparent dementia. Diagnosis early in the AD continuum has benefits for patients and caregivers and appears cost-effective, but often, the clinical diagnosis of AD may be delayed. Currently available biomarkers include β-amyloid positron emission tomography and cerebrospinal fluid tests. Collectively, they are expensive, may lead to adverse effects, are not widely available, and are not suited for primary care. Currently available treatment options, cholinesterase inhibitors and memantine, do not alter disease progression, but can help with some symptoms. Benefits of currently available treatments on cognition are difficult to quantify and are offset by a burden of adverse effects that often go unrecognized. More accurate diagnostic biomarkers and disease-modifying drug therapies are critical unmet needs of patients with AD despite decades of clinical research. Because many phase 3 clinical trials that enrolled patients with symptomatic AD have failed, researchers believe that disease-modifying treatment is more likely to demonstrate benefit when utilized early in the disease continuum. Within the past few years, significant achievements that will advance clinical trials in early AD include the Research Framework to define and stage the AD continuum, FDA guidance on study design in early AD, and development of scales to measure cognition that are suitable for early AD. In October 2019, the AD community was re-invigorated by unexpected news that a Biologics License Application will be submitted for aducanumab to treat AD. This article explores the current state of biomarker-driven drug development across the AD continuum and reviews investigational drugs in phase 2/3 clinical development for AD.

Pharmaceutical Treatment for Alzheimer's Disease and Related Dementias: Utilization and Disparities.

Four prescription drugs (donepezil, galantamine, memantine, and rivastigmine) are approved by the US FDA to treat symptoms of Alzheimer's disease (AD). Even modest effectiveness could potentially reduce the population-level burden of AD and related dementias (ADRD), especially for women and racial/ethnic minorities who have higher incidence of ADRD. Describe the prevalence of antidementia drug use and timing of initiation relative to ADRD diagnosis among a nationally representative group of older Americans, and if there are disparities in prevalence and timing by sex and race/ethnicity. Descriptive analyses and logistic regressions of Medicare claims (2008-2016) for beneficiaries who had an ADRD or dementia-related symptom diagnosis, or use of an FDA approved drug for AD. We investigate prevalence of use and timing of treatment initiation relative to ADRD diagnosis across time and beneficiary characteristics (age, sex, race/ethnicity, socioeconomic status, comorbidities). Among persons diagnosed with ADRD or related symptoms, 33.3% used an approved drug over the study period. Odds of use was higher among Whites than non-Whites. Among ADRD drug users, 40% initiated use within 6 months of the initial ADRD or related symptoms diagnosis, and 16% initiated prior to a diagnosis. We observed disparities by race/ethnicity: 28% of Asians, 24% of Hispanics, 16% of Blacks, and 15% of Whites initiated prior to diagnosis. The use of antidementia drugs is relatively low and varies widely by race/ethnicity. Heterogeneity in timing of initiation and use may affect health and cost outcomes, but these effects merit further study.

Marine bacterial extracts as a new rich source of drugs against Alzheimer's disease.

Alzheimer's disease (AD) is a prevalent, progressive and irreversible, neurodegenerative disease with no disease modifying treatment yet available. The projected burden of AD on our healthcare system is immense and thus there is an immediate need for new drugs that prevent or attenuate AD symptoms. While most efforts in the field are directed at treatments that reduce amyloid or tau burden in the brain, we have taken an alternate approach - a model based on reducing AD-associated neuronal cell cycle events. Using this model, we have screened a largely unexplored source of compounds with therapeutic potential - the natural products created by diverse strains of marine bacteria. Two hundred and twenty-five bacterial extracts from different strains were tested for both toxicity and neuroprotective properties by crystal violet and In-cell Western -first in HT22 cells andthen in mouse primary neuronal cultures. Based on these screens, we have identified several promising leads, and here we focus on the most promising of these. We found that we could directly assay even a crude bacterial extract in our E16 mouse cortical neuronal cultures and screen for activities that prevent cell cycle reentry and preserve synaptic structure. Preliminary tests in 1-month-old animals from a mouse model of Ataxia telangiectasia, showed that blockage of cell cycle-related neuronal death could also be successful in vivo. This adds an important extension to our in vitro studies. These findings showcase a new effective and efficient assay system and validate the use of marine natural compounds as a novel source for new drugs to fight Alzheimer's disease. Cover Image for this issue: doi: 10.1111/jnc.14733.

Associated Factors of Total Costs of Alzheimer's Disease: A Cluster-Randomized Observational Study in China.

Alzheimer's disease (AD) exerts a heavy burden on China. Substantial factors are found associated with high expenditure of AD in high-income countries. To date, few studies have been conducted in China. This study aimed to analyze the associated factors of the total annual costs of AD in China. Data were drawn from a multi-center, cross-sectional, socioeconomic study on the costs of AD conducted in China from October 2015 to March 2016. Generalized linear model (GLM) using gamma distribution with a log-link function was employed to examine the associated factors of the total cost. Univariate analysis showed that the demographic and clinical characteristics of AD patients and their caregivers had a substantial impact on the total cost. In GLM analysis, age, monthly household income, AD severity, number of comorbidities, and treatment with memantine were associated with higher expenditure, while the use of a nursing home/care facility was associated with lower expenditure. The mean annual costs for patients with severe dementia were almost twice as high as those for patients with mild dementia (US$ 25,601 versus US$ 13,387, p < 0.001). The mean total cost of AD patients with at least five comorbidities (US$ 38,348) was almost three times than those with no comorbidities (US$ 13,744). In China, AD severity and comorbidities were the most critical factors impacting the total cost. Optimizing care patterns, delaying disease progression, and managing comorbidities comprehensively could decrease the heavy burden of AD.

Nature and implications of sex differences in AD pathology.

A new study has identified key differences between women and men with regard to the nature and burden of Alzheimer disease (AD) pathology in the brain. In addition to highlighting possible sex differences in AD pathophysiology, the findings could have important implications for the diagnosis and management of this condition.

Iron and Alzheimer's Disease: An Update on Emerging Mechanisms.

Iron is a crucial transition metal for life and is the most abundant transition metal in the brain. However, iron's biological utility as an effective redox cycling metal also endows it with the potential to catalyze production of noxious free radicals. This "Janus-faced" nature of iron demands a tight regulation of cellular its metabolism. This regulation is crucial in the CNS, where iron plays myriad keystone roles in CNS processes, including mitochondrial energy transduction, enzyme catalysis, mitochondrial function, myelination, neurotransmitter anabolism and catabolism. Aberrations in brain iron homeostasis can elevate levels of this redox-active metal, leading to mislocalization of the metal and catastrophic oxidative damage to sensitive cellular and subcellular structures. Iron dyshomeostasis has been strongly linked to the pathogenesis of Alzheimer's disease (AD), as well as other major neurodegenerative diseases. Despite the growing societal burden of AD, no disease-modifying therapy exists, necessitating continued investment into both drug-development and the fundamental science investigating the disease-causing mechanisms. Targeting iron dyshomeostasis in the brain represents a rational approach to treat the underlying disease. Here we provide an update on known and emerging iron-associated mechanisms involved in AD. We conclude with an overview of evidence suggesting that, in addition to apoptosis, neuronal loss in AD involves "ferroptosis", a newly discovered iron- and lipid-peroxidation-dependent form of regulated necrosis. The ferroptosis field is rapidly progressing and may provide key insights for future drug-development with disease-modifying potential in AD.

Epidemiology, associated burden, and current clinical practice for the diagnosis and management of Alzheimer's disease in Japan.

The burden of dementia in Japan is large and growing. With the world’s fastest aging population, it is estimated that one in five elderly people will be living with dementia in Japan by 2025. The most common form of dementia is Alzheimer’s disease (AD), accounting for around two-thirds of dementia cases. A systematic review was conducted to examine the epidemiology and associated burden of AD in Japan and to identify how AD is diagnosed and managed in Japan. English and Japanese language databases were searched for articles published between January 2000 and November 2015. Relevant Japanese sources, clinical practice guideline registers, and reference lists were also searched. Systematic reviews and cohort and case–control studies were eligible for inclusion, with a total of 60 studies included. The most recent national survey conducted in six regions of Japan reported the mean prevalence of dementia in people aged ≥65 years to be 15.75% (95% CI: 12.4, 22.2%), which is much higher than the previous estimated rate of 10% in 2010. AD was confirmed as the predominant type of dementia, accounting for 65.8% of all cases. Advancing age and low education were the most consistently reported risk factors for AD dementia. Japanese guidelines for the management of dementia were released in 2010 providing specific guidance for AD about clinical signs, image findings, biochemical markers, and treatment approaches. Pharmacotherapies and non-pharmacotherapies to relieve cognitive symptoms were introduced, as were recommendations to achieve better patient care. No studies reporting treatment patterns were identified. Due to population aging and growing awareness of AD in Japan, health care expenditure and associated burden are expected to soar. This review highlights the importance of early detection, diagnosis, and treatment of AD as strategies to minimize the impact of AD on society in Japan.

Alcohol and Alzheimer's Disease-Does Alcohol Dependence Contribute to Beta-Amyloid Deposition, Neuroinflammation and Neurodegeneration in Alzheimer's Disease?

To investigate the underlying neurobiology between alcohol use, misuse and dependence and cognitive impairment, particularly Alzheimer's disease (AD). Review of the literature using searches of Medline, Pubmed, EMBASE, PsycInfo, and meeting abstracts and presentations. The role of alcohol as a risk factor and contributor for cognitive decline associated withAD has received little attention. This is despite the high prevalence of alcohol use, the potential reversibility of a degree of cognitive impairment and the global burden of AD. Until now the focus has largely been on the toxic effects of alcohol, neuronal loss and the role of thiamine. We propose alcohol adds to the cognitive burden seen in dementia through additional mechanisms to neurodegenerative processes or may contribute at various mechanistic points in the genesis and sustenance of AD pathology via neuroinflammation. We describe the common underlying neurobiology in alcohol and AD, and examine ways alcohol likely contributes to neuroinflammation directly via stimulation of Toll-like receptors and indirectly from small bowel changes, hepatic changes, withdrawal and traumatic brain injury to the pathogenesis of AD. Alcohol use, misuse and dependence cause cognitive impairment. We propose alcohol adds to the cognitive burden seen in dementia through additional mechanisms to neurodegenerative processes or may contribute at various mechanistic points in the genesis and sustenance ofAD pathology via neuroinflammation.

Alzheimer's and Parkinson's Diseases: Expected Economic Impact on Europe-A Call for a Uniform European Strategy.

The purpose of this study is to analyze the economic burden of persons with Alzheimer's disease (AD) and Parkinson's disease (PD) in Europe. On the basis of available data about the number of persons with dementia, their prevalence, and treatment and care costs, a mean cost burden is estimated for the year of 2030 and for the year of 2050 in Europe. The method of retrospective analysis of available sources was used; furthermore, analysis of database data such as WHO and Eurostat, which provide information about the number of older people and people with dementia; and specification of direct and indirect medical and nonmedical costs of patients with AD and PD from current studies was also used. The findings of this study confirm that the number of patients affected with AD and PD, as well as annual costs of the treatment and care of these patients, in the selected European countries are rapidly growing. The cost burden of both AD and PD in the selected European countries rises year by year, and by 2050, the cost burden of both diseases in fact will be almost two times higher in comparison with the year of 2010. In 2050, the overall mean cost burden is estimated to reach 357 billion Euros. The European Union calls for a joint initiative in the development of a uniformed strategic plan in the fight against dementia.

Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila

Alzheimer's disease (AD) is the most prevalent of a large group of related proteinopathies for which there is currently no cure. Here, we used Drosophila to explore a strategy to block Aβ42 neurotoxicity through engineering of the Heat shock protein 70 (Hsp70), a chaperone that has demonstrated neuroprotective activity against several intracellular amyloids. To target its protective activity against extracellular Aβ42, we added a signal peptide to Hsp70. This secreted form of Hsp70 (secHsp70) suppresses Aβ42 neurotoxicity in adult eyes, reduces cell death, protects the structural integrity of adult neurons, alleviates locomotor dysfunction, and extends lifespan. SecHsp70 binding to Aβ42 through its holdase domain is neuroprotective, but its ATPase activity is not required in the extracellular space. Thus, the holdase activity of secHsp70 masks Aβ42 neurotoxicity by promoting the accumulation of nontoxic aggregates. Combined with other approaches, this strategy may contribute to reduce the burden of AD and other extracellular proteinopathies.

Gender Differences: A Lifetime Analysis of the Economic Burden of Alzheimer's Disease

BackgroundGender is one of the best-established differences in risk for Alzheimer's disease (AD) and other forms of dementia, with women being at greater risk. However, the financial implications are unknown. This study aims at understanding the economic burden of AD by gender. MethodThis study takes a life-time perspective to investigate the burden of AD over the course of the disease. Nationally representative Medicare Current Beneficiary Survey data were used to estimate the course of illness of AD from age 65 to death and the incremental costs of AD on Medicare and Medicaid. Published data on the use and costs of assisted living facilities, home health care, and informal care were imputed into the course of illness to calculate the lifetime costs of these services. ResultsFemales and males have distinctively different patterns of course of illness of AD. Women face higher risks of having AD (15.5% vs. 13.1%) and of serving as informal caregivers for AD patients (6.8% vs. 4.0%) before death. Medicare and Medicaid account for major payers of AD care for both genders, but the greatest economic challenge of AD to women is the cost of the informal care they deliver, resulting in women bearing six times the cost of men. ConclusionPublic policy interventions that aim at curing or slowing the progress of AD will greatly benefit the welfare and economic status of women.

Melatonin Attenuates Memory Impairment, Amyloid-β Accumulation, and Neurodegeneration in a Rat Model of Sporadic Alzheimer's Disease.

Melatonin is a multifunctional molecule and plays a crucial role in the regulation of circadian rhythms. The role of melatonin in the protection of the central nervous system is well documented. Therefore, melatonin was proposed as a possible therapeutic agent for reducing the severity of Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by cognitive decline and memory dysfunction. Recently, we showed beneficial neuroprotective effects of prophylactic supplementation with melatonin in a suitable model of sporadic AD: OXYS rats, which exhibit disturbances in melatonin secretion. In the present study, we demonstrated that melatonin administration, when started at the age of active progression of AD-like pathology, decreased the amyloid-β1 - 42 and amyloid-β1 - 40 levels in the hippocampus and amyloid-β1 - 42 levels in the frontal cortex of OXYS rats. Furthermore, oral administration of melatonin slowed down degenerative alterations in hippocampal neurons of OXYS rats. The most noticeable improvement was observed in the CA1 region of the hippocampus. Melatonin administration prevented the decrease in the mitochondria-occupied portion of the neuronal volume and improved the ultrastructure of mitochondria in the neurons of the CA1 region. Additionally, melatonin treatment of OXYS rats slowed down an increase in anxiety and deterioration of reference memory. Thus, melatonin administration could alleviate the burden of AD and may be considered a promising pharmaceutical treatment of the disease.

Biomarkers, assays, and therapies for Alzheimer disease.

Alzheimer disease (AD) is a devastating neurodegenerative disorder characterized by a progressive decline in cognitive function. In 2010, an estimated 36 million people worldwide had AD or a related dementia, with this number projected to double by 2030. The social and economic burden of AD is well documented and will be amplified by this increase in prevalence. The initial pathophysiologic changes of AD are found in the hippocampus region of the brain, disrupting memory and the ability to learn. AD progression is linked to nerve cell dysfunction and cell death due to the accumulation of 2 protein aggregates: β-amyloid (Aβ)5 and tau. In the cerebrospinal fluid (CSF), these proteins are biomarkers for AD. Cleavage of the amyloid precursor protein (APP) generates varying lengths of Aβ peptides (38–43 amino acids) that accumulate in the extracellular space. Of these monomers, Aβ-42 is the major form associated with AD. In addition, tau entanglement is also associated with AD and consists of insoluble hyperphosphorylated tau protein in the intracellular space. Both total tau (t-tau) and phosphorylated tau (p-tau) proteins are measured and associated with AD. Currently, clinical trials are testing therapies that target these proteins in hopes to delay or halt the cognitive decline in AD patients. In this Q&A, we discuss the current state and future direction of biomarkers, assays, and therapies for AD with 3 experts. Established Alzheimer biomarkers include β-amyloid and tau protein in CSF, as well as imaging techniques that involve MRI and positron emission tomography (PET). What are the limitations of these biomarkers that restrict them mostly to research purposes? Erik Portelius: In the recently updated diagnostic criteria for AD (the International Working Group-2 criteria), the CSF AD biomarkers (Aβ-42, t-tau, and p-tau) and neuroimaging with Pittsburgh compound B (PiB)-PET were included. Although MRI may mirror the disease …

The economic impact of moderate stage Alzheimer's disease in Italy: evidence from the UP-TECH randomized trial.

There is consensus that dementia is the most burdensome disease for modern societies. Few cost-of-illness studies examined the complexity of Alzheimer's disease (AD) burden, considering at the same time health and social care, cash allowances, informal care, and out-of-pocket expenditure by families. This is a comprehensive cost-of-illness study based on the baseline data from a randomized controlled trial (UP-TECH) enrolling 438 patients with moderate AD and their primary caregiver living in the community. The societal burden of AD, composed of public, patient, and informal care costs, was about €20,000/yr. Out of this, the cost borne by the public sector was €4,534/yr. The main driver of public cost was the national cash-for-care allowance (€2,324/yr), followed by drug prescriptions (€1,402/yr). Out-of-pocket expenditure predominantly concerned the cost of private care workers. The value of informal care peaked at €13,590/yr. Socioeconomic factors do not influence AD public cost, but do affect the level of out-of-pocket expenditure. The burden of AD reflects the structure of Italian welfare. The families predominantly manage AD patients. The public expenditure is mostly for drugs and cash-for-care benefits. From a State perspective in the short term, the advantage of these care arrangements is clear, compared to the cost of residential care. However, if caregivers are not adequately supported, savings may be soon offset by higher risk of caregiver morbidity and mortality produced by high burden and stress. The study has been registered on the website www.clinicaltrials.org ( NCT01700556).

Recent Advances from the Bench Toward the Bedside in Alzheimer's Disease

Recent Advances from the Bench Toward the Bedside in Alzheimer's Disease

Epidemiological and Economic Burden of Alzheimer's Disease: A Systematic Literature Review of Data across Europe and the United States of America

Alzheimer's disease (AD) weighs heavily on health expenditure and is strongly associated with increasing age. Due to population aging, increasing global prevalence of AD will pose huge challenges to public health and elderly care systems in all countries across the world. This study aimed to better understand the burden of AD from a healthcare perspective. A systematic literature review of journal articles published between January 2002 and December 2012 was performed for studies conducted in France, Germany, Italy, The Netherlands, Spain, the United Kingdom (UK), and the United States of America (USA), using Medline, Embase, and the NHS Economic Evaluation Database. 3,288 references were initially retrieved, and 39 epidemiological and 66 economic publications were selected for data extraction. AD incidence rates greatly varied between countries; however, prevalence was more consistent across all included countries, ranging between 3-7%. Overall, medical costs were lower in France compared to other included countries and increased with AD severity, e.g., direct medical costs per year for mild AD ranged from 5,476 int$ in France to 27,380 int$ in Spain. Limitations, such as heterogeneous methodology and missing data, prevented the comparison of results across studies between countries or the conclusion of any trend over time. This review corroborates previous understanding that AD burden is high for both society and healthcare providers. Limitations regarding study heterogeneity restricted conclusions; further research is required. Stakeholders could benefit from new healthcare strategies addressing both epidemiological and economic aspects of AD.

Identification and characterization of Aβ peptide interactors in Alzheimer’s disease by structural approaches

Currently, there are very limited pharmaceutical interventions for Alzheimer’s disease (AD) to alleviate the amyloid burden implicated in the pathophysiology of the disease. Alzheimer’s disease is characterized immunohistologically by the accumulation of senile plaques in the brain with afflicted patients progressively losing short-term memory and, ultimately, cognition. Although significant improvements in clinical diagnosis and care for AD patients have been made, effective treatments for this devastating disease remain elusive. A key component of the amyloid burden of AD comes from accumulation of the amyloid-beta (Aβ) peptide which comes from processing of the amyloid precursor protein (APP) by enzymes termed secretases, leading to production of these toxic Aβ peptides of 40–42 amino acids. New therapeutic approaches for reducing Aβ are warranted after the most logical avenues of inhibiting secretase activity appear less than optimal in ameliorating the progression of AD.Novel therapeutics may be gleaned from proteomics biomarker initiatives to yield detailed molecular interactions of enzymes and their potential substrates. Explicating the APPome by deciphering protein complexes forming in cells is a complementary approach to unveil novel molecular interactions with the amyloidogenic peptide precursor to both understand the biology and develop potential upstream drug targets. Utilizing these strategies we have identified EC 3.4.24.15 (EP24.15), a zinc metalloprotease related to neprilysin (NEP), with the ability to catabolize Aβ 1–42 by examining first potential in silico docking and then verification by mass spectrometry. In addition, a hormone carrier protein, transthyreitin (TTR), was identified and with its abundance in cerebrospinal fluid (CSF), found to clear Aβ by inhibiting formation of oligomeric forms of Aβ peptide. The confluence of complementary strategies may allow new therapeutic avenues as well as biomarkers for AD that will aid in diagnosis, prognosis and treatment.

Analysis of burden in caregivers of people with Alzheimer's disease using self-report and supervision hours.

This study aimed to describe the baseline characteristics of informal carers of community-living Alzheimer's disease (AD) patients by AD severity group and to identify factors associated with two measures of caregiver burden. GERAS is a prospective observational study in France, Germany, and the UK, designed to assess costs and resource use associated with AD, for patients and their caregivers, stratified by disease severity. 1497 community-dwelling AD patients and their primary caregivers. Subjective caregiver burden assessed using the Zarit Burden Interview [ZBI] and time spent supervising patients (an objective measure of burden recorded using the Resource Utilization in Dementia instrument) during the month before the baseline visit were recorded. Separate multiple linear regression analyses using ZBI total score and caregiver supervision time as dependent variables were performed to identify patient and caregiver factors independently associated with caregiver burden. Increasing AD severity was associated with both subjective caregiver burden (ZBI total score) and overall caregiver time, which includes supervision time (both p<0.001, ANOVA). Better patient functioning (on instrumental activities of daily living) was independently associated with both a lower ZBI total score and less supervision time, whereas higher levels of caregiver distress due to patient behavior were associated with greater caregiver burden. Other factors independently associated with an increased ZBI total score included younger caregiver age, caregiver self-reported depression, caring for a male patient, and longer time since AD diagnosis. Caregivers living with the patient, being a male caregiver, patient living in a rural location, higher patient behavioral problem subdomain scores for apathy and psychosis, more patient emergency room visits, not receiving food delivery and receiving financial support for caregiving were all associated with greater caregiver supervision time. Our results show that subjective caregiver burden and caregiver time are influenced by different factors, reinforcing the need to consider both aspects of caregiving when trying to minimize the burden of AD. However, interventions that minimize caregiver distress and improve patient functioning may impact on both subjective and objective burden.

Is there a link between gynecologic surgeries and Alzheimer disease?

In 2001, an Institute of Medicine report concluded that “being male or female is an important fundamental variable that should be considered when designing and analyzing basic and clinical research.”1 The extent to which gender- and sex-specific factors influence the risk of Alzheimer disease (AD) is a matter of profound importance.2 Sex refers to biological characteristics of men and women such as chromosomal differences (e.g., XX vs XY chromosomes), hormonal differences (e.g., effects of estrogen), or reproductive differences (e.g., pregnancy or breastfeeding). By contrast, gender refers to social, political, and cultural differences (e.g., access to education or to certain jobs). The burden of AD is particularly great in women, and gender-associated differences in educational attainment may explain part of the differences in AD risk. In addition, exposures to gonadal steroids are linked to differences in Alzheimer-related pathology in animal models, although implications for human disease remain controversial.3

Modification of the Relationship of the Apolipoprotein E ε4 Allele to the Risk of Alzheimer Disease and Neurofibrillary Tangle Density by Sleep

The apolipoprotein E (APOE [GenBank, 348; OMIM, 107741]) ε4 allele is a common and well-established genetic risk factor for Alzheimer disease (AD). Sleep consolidation is also associated with AD risk, and previous work suggests that APOE genotype and sleep may interact to influence cognitive function. To determine whether better sleep consolidation attenuates the relationship of the APOE genotype to the risk of incident AD and the burden of AD pathology. A prospective longitudinal cohort study with up to 6 years of follow-up was conducted. Participants included 698 community-dwelling older adults without dementia (mean age, 81.7 years; 77% women) in the Rush Memory and Aging Project. We used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation and ascertained APOE genotype. Participants underwent annual evaluation for AD during a follow-up period of up to 6 years. Autopsies were performed on 201 participants who died, and β-amyloid (Aβ) and neurofibrillary tangles were identified by immunohistochemistry and quantified. During the follow-up period, 98 individuals developed AD. In a series of Cox proportional hazards regression models, better sleep consolidation attenuated the effect of the ε4 allele on the risk of incident AD (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .04 per allele per 1-SD increase in sleep consolidation). In a series of linear mixed-effect models, better sleep consolidation also attenuated the effect of the ε4 allele on the annual rate of cognitive decline. In individuals who died, better sleep consolidation attenuated the effect of the ε4 allele on neurofibrillary tangle density (interaction estimate, -0.42; SE = 0.17; P = .02), which accounted for the effect of sleep consolidation on the association between APOE genotype and cognition proximate to death. Better sleep consolidation attenuates the effect of APOE genotype on incident AD and development of neurofibrillary tangle pathology. Assessment of sleep consolidation may identify APOE+ individuals at high risk for incident AD, and interventions to enhance sleep consolidation should be studied as potentially useful means to reduce the risk of AD and development of neurofibrillary tangles in APOE ε4+ individuals.