The 100 most-cited articles in Alzheimer s & Dementia, 2020

This article describes the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality and morbidity, use and costs of care, and the overall impact on caregivers and society. The Special Report discusses the future challenges of meeting care demands for the growing number of people living with Alzheimer's dementia in the United States with a particular emphasis on primary care. By mid-century, the number of Americans age 65 and older with Alzheimer's dementia may grow to 13.8 million. This represents a steep increase from the estimated 5.8 million Americans age 65 and older who have Alzheimer's dementia today. Official death certificates recorded 122,019 deaths from AD in 2018, the latest year for which data are available, making Alzheimer's the sixth leading cause of death in the United States and the fifth leading cause of death among Americans age 65 and older. Between 2000 and 2018, deaths resulting from stroke, HIV and heart disease decreased, whereas reported deaths from Alzheimer's increased 146.2%. In 2019, more than 16 million family…

Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to…

Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzheimer's disease. The sponsor claimed that subsets of participants receiving sufficiently high doses of aducanumab demonstrated benefits in both trials. In contrast, we identified alternative accounts for the apparent drug benefits in post hoc subgroups that are unrelated to dose effects. Biomarker data were consistent with target engagement, but no evidence was presented to correlate biomarker changes to cognitive benefits. Our analysis supports the conduct of a third, phase III trial with high-dose aducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes.

The etiology of the common, sporadic form of Alzheimer's disease (sAD) is unknown. We hypothesize that tau pathology within select projection neurons with susceptible microenvironments can initiate sAD. This postulate rests on extensive data demonstrating that in human brains tau pathology appears about a decade before the formation of Aβ plaques (Aβps), especially targeting glutamate projection neurons in the association cortex. Data from aging rhesus monkeys show abnormal tau phosphorylation within vulnerable neurons, associated with calcium dysregulation. Abnormally phosphorylated tau (pTau) on microtubules traps APP-containing endosomes, which can increase Aβ production. As Aβ oligomers increase abnormal phosphorylation of tau, this would drive vicious cycles leading to sAD pathology over a long lifespan, with genetic and environmental factors that may accelerate pathological events. This hypothesis could be testable in the aged monkey association cortex that naturally expresses characteristics capable of promoting and sustaining abnormal tau phosphorylation and Aβ production.

Abstract Introduction Synaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density. Methods We measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using [ 11 C]UCB‐J PET and a cerebellar reference region for calculation of the distribution volume ratio. Results We observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume. Conclusion We were able to measure widespread synaptic loss due to AD using [ 11 C]UCB‐J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring potential therapies.

Abstract Introduction Exosomes are an emerging candidate for biomarkers of Alzheimer's disease (AD). This study investigated whether exosomal synaptic proteins can predict AD at the asymptomatic stage. Methods We conducted a two‐stage‐sectional study (discovery stage: AD, 28; amnestic mild cognitive impairment [aMCI], 25; controls, 29; validation stage: AD, 73; aMCI, 71; controls, 72), a study including preclinical AD (160) and controls (160), and a confirmation study in familial AD (mutation carriers: 59; non‐mutation carriers: 62). Results The concentrations of growth associated protein 43 (GAP43), neurogranin, synaptosome associated protein 25 (SNAP25), and synaptotagmin 1 were lower in AD than in controls (P < .001). Exosomal biomarker levels were correlated with those in cerebrospinal fluid (R2 = 0.54–0.70). The combination of exosomal biomarkers detected AD 5 to 7 years before cognitive impairment (area under the curve = 0.87–0.89). Discussion This study revealed that exosomal GAP43, neurogranin, SNAP25, and synaptotagmin 1 act as effective biomarkers for prediction of AD 5 to…

Since 1989, four Canadian Consensus Conferences on the Diagnosis and Treatment of Dementia (CCCDTD) have provided evidence-based dementia guidelines for Canadian clinicians and researchers. We present the results of the 5th CCCDTD, which convened in October 2019, to address topics chosen by the steering committee to reflect advances in the field, and build on previous guidelines. Topics included: (1) utility of the National Institute on Aging research framework for clinical Alzheimer's disease (AD) diagnosis; (2) updating diagnostic criteria for vascular cognitive impairment, and its management; (3) dementia case finding and detection; (4) neuroimaging and fluid biomarkers in diagnosis; (5) use of non-cognitive markers of dementia for better dementia detection; (6) risk reduction/prevention; (7) psychosocial and non-pharmacological interventions; and (8) deprescription of medications used to treat dementia. We hope the guidelines are useful for clinicians, researchers, policy makers, and the lay public, to inform a current and evidence-based approach to dementia.

INTRODUCTION: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood. METHODS: immunoassays to measure cerebrospinal fluid (CSF) amyloid-β (Aβ)42, Aβ40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum. RESULTS: CSF t-tau, p-tau, and neurogranin increase throughout aging only in Aβ-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p-tau and p-tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers. DISCUSSION: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum.

Vascular contributions to cognitive impairment and dementia (VCID) are characterized by the aging neurovascular unit being confronted with and failing to cope with biological insults due to systemic and cerebral vascular disease, proteinopathy including Alzheimer's biology, metabolic disease, or immune response, resulting in cognitive decline. This report summarizes the discussion and recommendations from a working group convened by the National Heart, Lung, and Blood Institute and the National Institute of Neurological Disorders and Stroke to evaluate the state of the field in VCID research, identify research priorities, and foster collaborations. As discussed in this report, advances in understanding the biological mechanisms of VCID across the wide spectrum of pathologies, chronic systemic comorbidities, and other risk factors may lead to potential prevention and new treatment strategies to decrease the burden of dementia. Better understanding of the social determinants of health that affect risks for both vascular disease and VCID could provide insight into strategies to reduce…

OBJECTIVE: To propose a new hypothesis that GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease (AD). BACKGROUND: Synaptic dysfunction and E/I imbalance emerge decades before the appearance of cognitive decline in AD patients, which contribute to neurodegeneration. Initially, E/I imbalance was thought to occur first, due to dysfunction of the glutamatergic and cholinergic systems. However, new evidence has demonstrated that the GABAergic system, the counterpart of E/I balance and the major inhibitory neurotransmitter system in the central nervous system, is altered enormously and that this contributes to E/I imbalance and further AD pathogenesis. NEW HYPOTHESIS: Alterations to the GABAergic system, induced by multiple AD pathogenic or risk factors, contribute to E/I imbalance and AD pathogenesis. MAJOR CHALLENGES FOR THE HYPOTHESIS: This GABAergic hypothesis accounts for many critical questions and common challenges confronting a new hypothesis of AD pathogenesis. More specifically, it explains why amyloid beta (Aβ),…

Abstract Background Cognitive impairment is a key clinical feature of cerebral small vessel disease (SVD), but the full range of SVD-related cognitive impairments is unclear, and little is known about how they might vary across clinical and non-clinical manifestations of SVD. Methods In systematic searches of OVID MEDLINE, Embase, and PsychINFO from 1 st January 1985 to 6 th October 2019, we identified studies reporting cognitive test results for study participants with SVD and control participants without SVD. Using standardised group-level cognitive test data, we performed random effects meta-analyses in seven cognitive domains to test whether cognitive test scores differed between SVD and control groups. We conducted meta-regression analyses to test whether differences in age, education, or vascular risk factors between SVD and control groups, or whether different clinical manifestations of SVD (e.g. stroke, cognitive impairment, or non-clinical presentations) accounted for cognitive effect sizes. Findings Of 8562 studies identified, we included 69 studies from six continents,…

We have provided an overview on the profound impact of COVID-19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health-care settings, including hospital, out-patient, care homes, and the community during the COVID-19 pandemic. We have also proposed a conceptual framework and practical suggestions for health-care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health-care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD-19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term.

INTRODUCTION: We evaluated the clinical profile of the orexin receptor antagonist suvorexant for treating insomnia in patients with mild-to-moderate probable Alzheimer's disease (AD) dementia. METHODS: Randomized, double-blind, 4-week trial of suvorexant 10 mg (could be increased to 20 mg based on clinical response) or placebo in patients who met clinical diagnostic criteria for both probable AD dementia and insomnia. Sleep was assessed by overnight polysomnography in a sleep laboratory. The primary endpoint was change-from-baseline in polysomnography-derived total sleep time (TST) at week 4. RESULTS: Of 285 participants randomized (suvorexant, N = 142; placebo, N = 143), 277 (97%) completed the trial (suvorexant, N = 136; placebo, N = 141). At week 4, the model-based least squares mean improvement-from-baseline in TST was 73 minutes for suvorexant and 45 minutes for placebo; (difference = 28 minutes [95% confidence interval 11-45], p < 0.01). Somnolence was reported in 4.2% of suvorexant-treated patients and 1.4% of placebo-treated patients. DISCUSSION: Suvorexant improved TST in…

INTRODUCTION: Counteracting impaired brain glucose metabolism with ketones may improve cognition in mild cognitive impairment (MCI). METHODS: Cognition, plasma ketone response, and metabolic profile were assessed before and 6 months after supplementation with a ketogenic drink containing medium chain triglyceride (ketogenic medium chain triglyceride [kMCT]; 15 g twice/day; n = 39) or placebo (n = 44). RESULTS: Free and cued recall (Trial 1; P = .047), verbal fluency (categories; P = .024), Boston Naming Test (total correct answers; P = .033), and the Trail-Making Test (total errors; P = .017) improved significantly in the kMCT group compared to placebo (analysis of covariance; pre-intervention score, sex, age, education, and apolipoprotein E4 as covariates). Some cognitive outcomes also correlated positively with plasma ketones. Plasma metabolic profile and ketone response were unchanged. CONCLUSIONS: This kMCT drink improved cognitive outcomes in MCI, at least in part by increasing blood ketone level. These data support further assessment of MCI progression to Alzheimer's disease.

In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain…

INTRODUCTION: Extracellular vesicles (EVs) from human Alzheimer's disease (AD) biospecimens contain amyloid beta (Aβ) peptide and tau. While AD EVs are known to affect brain disease pathobiology, their biochemical and molecular characterizations remain ill defined. METHODS: EVs were isolated from the cortical gray matter of 20 AD and 18 control brains. Tau and Aβ levels were measured by immunoassay. Differentially expressed EV proteins were assessed by quantitative proteomics and machine learning. RESULTS: Levels of pS396 tau and Aβ1-42 were significantly elevated in AD EVs. High levels of neuron- and glia-specific factors are detected in control and AD EVs, respectively. Machine learning identified ANXA5, VGF, GPM6A, and ACTZ in AD EV compared to controls. They distinguished AD EVs from controls in the test sets with 88% accuracy. DISCUSSION: In addition to Aβ and tau, ANXA5, VGF, GPM6A, and ACTZ are new signature proteins in AD EVs.

Abstract Background In 2019 Alzheimer’s Disease International (ADI) undertook the biggest global survey on attitudes to dementia, with 70,000 people across 54 countries participating. Alongside expert essays, case studies and programmes to tackle stigma, the survey results formed the core of the 2019 World Alzheimer Report Method ADI commissioned London School of Economics & Political Science to create and design a global survey engaging 4 distinct audiences: people living with dementia, carers, healthcare professionals and the general public. The survey was distributed online, through the ADI network, with an offline/supported option for assisted completion. Result Headlines. 95% of respondents think they will develop dementia in their lifetimes. 78% are concerned. 2 in 3 people think dementia is a normal part of ageing. 62% of healthcare practitioners that resounded believe dementia is a normal part of ageing. 1 in 4 believes there is nothing you can do about it. 82% would take a genetic test. 54% believe lifestyle factors play a part in developing dementia. Conclusion Three years…

INTRODUCTION: Relationships between brain atrophy patterns of typical aging and Alzheimer's disease (AD), white matter disease, cognition, and AD neuropathology were investigated via machine learning in a large harmonized magnetic resonance imaging database (11 studies; 10,216 subjects). METHODS: Three brain signatures were calculated: Brain-age, AD-like neurodegeneration, and white matter hyperintensities (WMHs). Brain Charts measured and displayed the relationships of these signatures to cognition and molecular biomarkers of AD. RESULTS: WMHs were associated with advanced brain aging, AD-like atrophy, poorer cognition, and AD neuropathology in mild cognitive impairment (MCI)/AD and cognitively normal (CN) subjects. High WMH volume was associated with brain aging and cognitive decline occurring in an ≈10-year period in CN subjects. WMHs were associated with doubling the likelihood of amyloid beta (Aβ) positivity after age 65. Brain aging, AD-like atrophy, and WMHs were better predictors of cognition than chronological age in MCI/AD. DISCUSSION: A Brain Chart quantifying brain-aging…

Abstract Introduction Mild behavioral impairment (MBI) is characterized by the emergence of neuropsychiatric symptoms in elderly persons. Here, we examine the associations between MBI and Alzheimer's disease (AD) biomarkers in asymptomatic elderly individuals. Methods Ninety‐six cognitively normal elderly individuals underwent MRI, [ 18 F]AZD4694 β‐amyloid‐PET, and [ 18 F]MK6240 tau‐PET. MBI was assessed using the MBI Checklist (MBI‐C). Pearson's correlations and voxel‐based regressions were used to evaluate the relationship between MBI‐C score and [ 18 F]AZD4694 retention, [ 18 F]MK6240 retention, and gray matter (GM) volume. Results Pearson correlations revealed a positive relationship between MBI‐C score and global and striatal [ 18 F]AZD4694 standardized uptake value ratios (SUVRs). Voxel‐based regression analyses revealed a positive correlation between MBI‐C score and [ 18 F]AZD4694 retention. No significant correlations were found between MBI‐C score and [ 18 F]MK6240 retention or GM volume. Conclusion We demonstrate for the first time a link between MBI and early AD pathology…

INTRODUCTION: plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD. METHODS: The CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants. RESULTS: The CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non-fluent/agrammatic variant primary progressive aphasia participants. DISCUSSION: The global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation…

INTRODUCTION: Non-pharmacological treatments (NPTs) have the potential to improve meaningful outcomes for older people at risk of, or living with dementia, but research often lacks methodological rigor and continues to produce mixed results. METHODS: In the current position paper, experts in NPT research have specified treatment targets, aims, and ingredients using an umbrella framework, the Rehabilitation Treatment Specification System. RESULTS: Experts provided a snapshot and an authoritative summary of the evidence for different NPTs based on the best synthesis efforts, identified main gaps in knowledge and relevant barriers, and provided directions for future research. Experts in trial methodology provide best practice principles and recommendations for those working in this area, underscoring the importance of prespecified protocols. DISCUSSION: We conclude that the evidence strongly supports various NPTs in relation to their primary targets, and discuss opportunities and challenges associated with a unifying theoretical framework to guide future efforts in this area.

INTRODUCTION: Numerous results suggest the implication of infectious agents in the onset of Alzheimer's disease (AD). METHODS: In the Bordeaux-3C prospective cohort, we assessed the impact of herpes simplex virus type 1 (HSV-1) infection on the incidence of AD according to apolipoprotein E (APOE) status, a genetic susceptibility factor. Cox models were performed to estimate the 10-year risk of AD associated with anti-HSV antibodies in 1037 participants according to APOE4 status. RESULTS: Among APOE4 carriers, subjects for whom the frequency of HSV-1 reactivation is supposed to be high, that is, immunoglobulin M (IgM) positive or elevated levels of IgG, had an increased risk of AD with adjusted hazard ratios (HRs) of 3.68 (1.08-12.55) and 3.28 (1.19-9.03), respectively. No significant association was found in APOE4-negative subjects. DISCUSSION: These results, in accordance with a solid pathophysiological rationale, suggest a role for HSV-1 in AD development among subjects with a genetic susceptibility factor, the APOE4 allele.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the…

INTRODUCTION: Phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) is an established Alzheimer's disease (AD) biomarker. Novel immunoassays targeting N-terminal and mid-region p-tau181 and p-tau217 fragments are available, but head-to-head comparison in clinical settings is lacking. METHODS: N-terminal-directed p-tau217 (N-p-tau217), N-terminal-directed p-tau181 (N-p-tau181), and standard mid-region p-tau181 (Mid-p-tau181) biomarkers in CSF were evaluated in three cohorts (n = 503) to assess diagnostic performance, concordance, and associations with amyloid beta (Aβ). RESULTS: CSF N-p-tau217 and N-p-tau181 had better concordance (88.2%) than either with Mid-p-tau181 (79.7%-82.7%). N-p-tau217 and N-p-tau181 were significantly increased in early mild cognitive impairment (MCI)-AD (A+T-N-) without changes in Mid-p-tau181 until AD-dementia. N-p-tau217 and N-p-tau181 identified Aβ pathophysiology (area under the curve [AUC] = 94.8%-97.1%) and distinguished MCI-AD from non-AD MCI (AUC = 82.6%-90.5%) signficantly better than Mid-p-tau181 (AUC = 91.2% and 70.6%, respectively). P-tau…

INTRODUCTION: This phase 2b/3 trial examined the effects of plasma exchange (PE) in patients with mild-to-moderate Alzheimer's disease (AD). METHODS: Three hundred forty-seven patients (496 screened) were randomized (1:1:1:1) into three PE treatment arms with different doses of albumin and intravenous immunoglobulin replacement (6-week period of weekly conventional PE followed by a 12-month period of monthly low-volume PE), and placebo (sham). RESULTS: PE-treated patients performed significantly better than placebo for the co-primary endpoints: change from baseline of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; P = .03; 52% less decline) with a trend for Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; P = .06; 66% less decline) scores at month 14. Moderate-AD patients (baseline Mini-Mental State Examination [MMSE] 18-21) scored better on ADCS-ADL (P = .002) and ADAS-Cog (P = .05), 61% less decline both. There were no changes in mild-AD patients (MMSE 22-26). PE-treated patients scored better on the Clinical Dementia Rating Sum of…

Abstract Introduction This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared biomarkers across groups defined by clinical diagnosis and pTau181/Aβ42 status (+/−) and explored their value in predicting cognition. Methods CSF biomarkers amyloid beta (Aβ)42, pTau181, tTau, Aβ40, neurogranin, neurofilament light (NfL), α‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), S100 calcium binding protein B (S100B), and interleukin 6 (IL6), were measured with the NeuroToolKit (NTK) for 720 adults ages 40 to 93 years (mean age = 63.9 years, standard deviation [SD] = 9.0; 50 with dementia; 54 with mild cognitive impairment [MCI], 616 unimpaired). Results Neurodegeneration and glial activation biomarkers were elevated in pTau181/Aβ42+ MCI/dementia participants relative to all pTau181/Aβ42‐ participants. Neurodegeneration biomarkers increased with clinical severity among…

INTRODUCTION: The LipiDiDiet trial investigates the effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease (AD). Based on previous results we hypothesized that benefits increase with long-term intervention. METHODS: In this randomized, double-blind, placebo-controlled trial, 311 people with prodromal AD were recruited using the International Working Group-1 criteria and assigned to active product (125 mL once-a-day drink) or an isocaloric, same tasting, placebo control drink. Main outcome was change in cognition (Neuropsychological Test Battery [NTB] 5-item composite). Analyses were by modified intention-to-treat, excluding (ie, censoring) data collected after the start of open-label active product and/or AD medication. RESULTS: Of the 382 assessed for eligibility, 311 were randomized, of those 162 participants completed the 36-month study, including 81 with 36-month data eligible for efficacy analysis. Over 36 months, significant reductions in decline were observed for the NTB 5-item composite (-60%;…

OBJECTIVE: The present work evaluates the relationship between postoperative immune and neurovascular changes and the pathogenesis of surgery-induced delirium superimposed on dementia. BACKGROUND AND RATIONALE: Postoperative delirium is a common complication in many older adults and in patients with dementia including Alzheimer's disease (AD). The course of delirium can be particularly debilitating, while its pathophysiology remains poorly defined. HISTORICAL EVOLUTION: As of 2019, an estimated 5.8 million people of all ages have been diagnosed with AD, 97% of whom are >65 years of age. Each year, many of these patients require surgery. However, anesthesia and surgery can increase the risk for further cognitive decline. Surgery triggers neuroinflammation both in animal models and in humans, and a failure to resolve this inflammatory state may contribute to perioperative neurocognitive disorders as well as neurodegenerative pathology. UPDATED HYPOTHESIS: We propose an immunovascular hypothesis whereby dysregulated innate immunity negatively affects the blood-brain interface, which…

INTRODUCTION: We examined whether educational attainment differentially contributes to cognitive reserve (CR) across race/ethnicity. METHODS: A total of 1553 non-Hispanic Whites (Whites), non-Hispanic Blacks (Blacks), and Hispanics in the Washington Heights-Inwood Columbia Aging Project (WHICAP) completed structural magnetic resonance imaging. Mixture growth curve modeling was used to examine whether the effect of brain integrity indicators (hippocampal volume, cortical thickness, and white matter hyperintensity [WMH] volumes) on memory and language trajectories was modified by education across racial/ethnic groups. RESULTS: Higher educational attainment attenuated the negative impact of WMH burden on memory (β = -0.03; 99% CI: -0.071, -0.002) and language decline (β = -0.024; 99% CI:- 0.044, -0.004), as well as the impact of cortical thinning on level of language performance for Whites, but not for Blacks or Hispanics. DISCUSSION: Educational attainment does not contribute to CR similarly across racial/ethnic groups.

INTRODUCTION: The Cognitive Debt hypothesis proposes that repetitive negative thinking (RNT), a modifiable process common to many psychological risk factors for Alzheimer's disease (AD) may itself increase risk. We sought to empirically examine relationships between RNT and markers of AD, compared with anxiety and depression symptoms. METHODS: Two hundred and ninety-two older adults with longitudinal cognitive assessments, including 113 with amyloid-positron emission tomography (PET) and tau-PET scans, from the PREVENT-AD cohort and 68 adults with amyloid-PET scans from the IMAP+ cohort were included. All participants completed RNT, anxiety, and depression questionnaires. RESULTS: RNT was associated with decline in global cognition (P = .02); immediate (P = .03) and delayed memory (P = .04); and global amyloid (PREVENT-AD: P = .01; IMAP+: P = .03) and entorhinal tau (P = .02) deposition. Relationships remained after adjusting for potential confounders. DISCUSSION: RNT was associated with decline in cognitive domains affected early in AD and with neuroimaging AD biomarkers. Future…

INTRODUCTION: Reliable estimates of time from diagnosis until institutionalization and death in people with dementia from routine nationally representative databases are lacking. METHODS: We selected 9230 people with dementia and 24,624 matched controls from family physicians' electronic records linked with national administrative databases to analyze time until institutionalization and death and associated factors. RESULTS: Median time from recorded diagnosis until institutionalization and until death for people with dementia was 3.9 and 5.0 years, respectively, which was considerably shorter than for controls. Once institutionalized, median time to death was longer for persons with dementia (2.5 years) than for controls (1.2 years). Older age and receiving home care were the strongest predictors of shorter time until institutionalization and death in people with dementia. Gender, cohabitation, migration status, frailty, polypharmacy, and dementia medication were other significant factors. DISCUSSION: The estimates could help to inform patients, their families, and policymakers…

Improved medical care of individuals with Down syndrome (DS) has led to an increase in life expectancy to over the age of 60 years. In conjunction, there has been an increase in age-related co-occurring conditions including Alzheimer's disease (AD). Understanding the factors that underlie symptom and age of clinical presentation of dementia in people with DS may provide insights into the mechanisms of sporadic and DS-associated AD (DS-AD). In March 2019, the Alzheimer's Association, Global Down Syndrome Foundation and the LuMind IDSC Foundation partnered to convene a workshop to explore the state of the research on the intersection of AD and DS research; to identify research gaps and unmet needs; and to consider how best to advance the field. This article provides a summary of discussions, including noting areas of emerging science and discovery, considerations for future studies, and identifying open gaps in our understanding for future focus.

INTRODUCTION: Exposure to noise might influence risk of Alzheimer's disease (AD) dementia. METHODS: Participants of the Chicago Health and Aging Project (≥65 years) underwent triennial cognitive assessments. For the 5 years preceding each assessment, we estimated 5227 participants' residential level of noise from the community using a spatial prediction model, and estimated associations of noise level with prevalent mild cognitive impairment (MCI) and AD, cognitive performance, and rate of cognitive decline. RESULTS: Among these participants, an increment of 10 A-weighted decibels (dBA) in noise corresponded to 36% and 29% higher odds of prevalent MCI (odds ratio [OR] = 1.36; 95% confidence interval [CI], 1.15 to 1.62) and AD (OR = 1.29, 95% CI, 1.08 to 1.55). Noise level was associated with worse global cognitive performance, principally in perceptual speed (-0.09 standard deviation per 10 dBA, 95% CI: -0.16 to -0.03), but not consistently associated with cognitive decline. DISCUSSION: These results join emerging evidence suggesting that noise may influence late-life cognition and…

INTRODUCTION: It is unclear how different proteinopathies (tau, transactive response DNA-binding protein 43 [TDP-43], amyloid β [Aβ], and α-synuclein) contribute to atrophy within medial temporal lobe (MTL) subregions in Alzheimer's disease (AD). METHODS: We utilized antemortem structural magnetic resonance imaging (MRI) data to measure MTL substructures and examined the relative contribution of tau, TDP-43, Aβ, and α-synuclein measured in post-mortem tissue from 92 individuals with intermediate to high AD neuropathology. Receiver-operating characteristic (ROC) curves were analyzed for each subregion in order to discriminate TDP-43-negative and TDP-43-positive patients. RESULTS: TDP-43 was strongly associated with anterior MTL regions, whereas tau was relatively more associated with the posterior hippocampus. Among the MTL regions, the anterior hippocampus showed the highest area under the ROC curve (AUC). DISCUSSION: We found specific contributions of different pathologies on MTL substructure in this population with AD neuropathology. The anterior hippocampus may be a relevant…

INTRODUCTION: Few studies have examined memory decline among patients with type 2 diabetes using different oral hypoglycemic drugs. METHODS: Participants with normal cognition (NC) or Alzheimer's disease (AD) dementia using a hypoglycemic medication (2005 to 2019) were identified from the National Alzheimer's Coordinating Center database. Delayed memory was assessed using the Wechsler Memory Scale Revised-Logical Memory test. Associations between oral drug classes and memory over time were examined using mixed-effects models with inverse probability treatment weights. RESULTS: In NC (n = 1192), metformin use was associated with better memory performance over time, whereas in AD (n = 807), dipeptidyl peptidase-4 (DPP4) inhibitor use was associated with a slower rate of memory decline. Interaction effects suggested greater benefit associated with DPP4 inhibitor use among APOE ε4 carriers. DISCUSSION: Associations between different oral hypoglycemic drugs and memory change were not consistent between cognitively normal elderly and those with AD dementia. APOE ε4 genotype modified some…

INTRODUCTION: This study tested the self-reported sleep characteristics associated with cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in cognitively intact older adults. METHODS: The linear and non-linear regression analyses were conducted in 736 cognitively normal participants (mean [standard deviation; SD] age, 62.3 [10.5] years, range 40 to 88 years, 59% female) who had measurements of cerebrospinal fluid (CSF) amyloid beta (Aβ) and tTau proteins and sleep characteristics, after adjusting for age, gender, education, apolipoprotein E gene (APOE) ε4 status, and general cognition. RESULTS: Greater daytime sleepiness was associated with higher CSF indicators of amyloid deposition in female patients. No significant associations were revealed for CSF tTau proteins after Bonferroni correction. A U-shaped relationship was revealed for nocturnal sleep habits, such that those with insufficient or excessive nocturnal sleep duration had greater CSF biomarkers of amyloid deposition (the reflection range: bedtime: around 10:00 p.m. and sleep duration: 6.0 to 6.5 hours).…

INTRODUCTION: High dietary intake of long chain, polyunsaturated fatty acids is associated with lower Alzheimer's disease (AD) risk. METHODS: Washington Heights-Hamilton Heights-Inwood Columbia Aging Project is a multiethnic, prospective observational study of aging and dementia among elderly (≥ 65 years). Dietary intake was measured using a food frequency questionnaire. Dietary short-, medium-, and long-chain fatty acid intakes were categorized by number of carbons and double bonds. Consensus AD diagnoses were made. Associations between AD risk and dietary fatty acid and cholesterol intakes were estimated using multivariable Cox proportional hazards regression models. RESULTS: Of 2612 multiethnic women (67%) and men (baseline age 76.3 [6.4] years), 380 developed AD over an average 4.5 years follow-up. Lower risk of AD was associated with increasing intakes of docosahexaenoic acid (DHA; hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.57 to 0.95, P = 0.018) and eicosapentaenoic acid (EPA; HR = 0.74, 95% CI: 0.57 to 0.95, P = 0.021), and longer AD-free survival (P < 0.05).…

INTRODUCTION: The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported. METHODS: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors. Measures included the 3-Domain Composite Cognition Score (CCS-3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding. RESULTS: Verubecestat showed worsening on the CCS-3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency. DISCUSSION: In both studies, many measures showed…

INTRODUCTION: We investigated and compared associations of objective estimates of sleep and 24-hour activity rhythms using actigraphy with risk of dementia. METHODS: We included 1322 non-demented participants from the prospective, population-based Rotterdam Study cohort with valid actigraphy data (mean age 66 ± 8 years, 53% women), and followed them for up to 11.2 years to determine incident dementia. RESULTS: During follow-up, 60 individuals developed dementia, of which 49 had Alzheimer's disease (AD). Poor sleep as indicated by longer sleep latency, wake after sleep onset, and time in bed and lower sleep efficiency, as well as an earlier "lights out" time, were associated with increased risk of dementia, especially AD. We found no associations of 24-hour activity rhythms with dementia risk. DISCUSSION: Poor sleep, but not 24-hour activity rhythm disturbance, is associated with increased risk of dementia. Actigraphy-estimated nighttime wakefulness may be further targeted in etiologic or risk prediction studies.

INTRODUCTION: Reduced hippocampal volume is associated with late-life cognitive decline, but prior studies have not determined whether this association persists after accounting for Alzheimer's disease (AD) and other neuropathologies. METHODS: Participants were 531 deceased older adults from community-based cohort studies of aging who had undergone annual cognitive evaluations. At death, brain tissue underwent neuropathologic examination and magnetic resonance imaging (MRI). Linear mixed models examined whether hippocampal volume measured via MRI accounted for variation in decline rate of global cognition and five cognitive domains, above and beyond neuropathologic indices. RESULTS: Demographics and indices of AD, cerebrovascular disease, Lewy body disease, hippocampal sclerosis, TDP-43, and atherosclerosis accounted for 42.6% of the variation in global cognitive decline. Hippocampal volume accounted for an additional 5.4% of this variation and made similar contributions in four of the five cognitive domains. DISCUSSION: Hippocampal volume is associated with late-life cognitive…

INTRODUCTION: The PSENs/APP mutation distribution in Chinese patients with familial Alzheimer's disease (FAD) remains unclear. We aimed to analyze the genetic features of Chinese FAD pedigrees with and without PSENs/APP mutations. METHODS: In total, 1330 patients with Alzheimer's disease (AD) or mild cognitive impairment in 404 pedigrees were enrolled from the Chinese Familial Alzheimer's Disease Network. PSENs/APP mutations and APOE frequencies were determined. RESULTS: In total, 13.12% of pedigrees carried PSENs/APP missense mutations, 3.71% carried PSENs/APP synonymous/untranslated region variants, and 83.17% did not carry PSENs/APP mutations. Eleven missense mutations were first identified. In patients without PSENs/APP mutations, 44.31% carried one APOEε4 allele, and 14.85% two APOEε4 alleles. DISCUSSION: The new PSENs/APP mutations indicate heterogeneity in AD pathogenesis between Chinese and other ethnic groups. The low mutation rate suggests the involvement of other genes/factors in Chinese FAD. APOEε4 might be a major gene for some FAD without PSENs/APP mutations.

Abstract Background Aducanumab is a human monoclonal antibody that selectively targets aggregated forms of Aβ, including soluble oligomers and insoluble fibrils. EMERGE and ENGAGE are two 18‐month, randomized, double‐blind, placebo‐controlled, global Phase 3 studies with identical design that evaluated the efficacy and safety of aducanumab in patients aged 50–85 years with early Alzheimer’s disease (MCI due to AD or mild AD dementia). Method Key inclusion criteria included positive amyloid PET, MMSE score of 24–30, CDR Global score of 0.5, and an RBANS‐DMI score ≤85. During the 18‐month placebo‐controlled period, patients were randomized 1:1:1 to low‐dose aducanumab, high‐dose aducanumab, or placebo, administered via IV infusion every 4 weeks. The primary endpoint for EMERGE and ENGAGE was change from baseline at Week 78 on the CDR‐SB. Secondary endpoints included change from baseline on MMSE, ADAS‐Cog13, and ADCS‐ADL‐MCI. Result Following pre‐planned futility analysis, analysis of the data from the final database lock showed that EMERGE met its primary endpoint, based on the…

INTRODUCTION: Neuronal extracellular vesicle (nEV) tau and insulin signaling biomarkers may detect preclinical Alzheimer's disease and age-associated cognitive decline. METHODS: This case-control study used repeated serum samples from 73 cognitively declining and 73 stable Wisconsin Registry for Alzheimer's Prevention participants (62.4 ± 6.3 years old). We immunocaptured nEVs; measured tau and insulin signaling biomarkers; and examined biomarker differences by group, their performance in group classification in training and test datasets (97, 49 individuals, respectively), and whether they predict cognitive performance change. RESULTS: Declining compared to stable individuals showed higher baseline total, p231-, and p181-tau with older age and higher annualized change for p-IR and p-IGF-1R. Combining biomarkers classified decliners with 94% area under the curve (AUC), 86.0% sensitivity and 86.7% specificity, in training data, and 75% AUC, 71.4% sensitivity, and 77.3% specificity, in test data. Insulin biomarkers predicted cognitive performance change prospectively. DISCUSSION:…

INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers can identify individuals with Alzheimer's disease (AD) pathology (eg, amyloid plaques, neurofibrillary tangles), but defined analyte cut-points using high-throughput automated assays are necessary for general clinical use. METHODS: CSF amyloid β42 peptide (Aβ42), t-tau, and t-tau/Aβ42 were quantified by the Lumipulse platform in two test cohorts (A/B: Eisai BAN2401-201/MISSION AD E2609-301/302, n = 138; C: Knight Alzheimer's Disease Research Center (ADRC), n = 198), and receiver operating characteristic (ROC) curve analyses defined cut-points corresponding best to amyloid determinations using positron emission tomography (PET) imaging. The best-performing cut-point was then validated as a predictor of amyloid status in an independent cohort (D: MISSION AD E2609-301/302, n = 240). RESULTS: Virtually identical t-tau/Aβ42 cut-points (∼0.54) performed best in both test cohorts and with similar accuracy (areas under ROC curve [AUCs] [A/B: 0.95; C: 0.94]). The cut-point yielded an overall percent agreement with amyloid PET of 85.0% in…

INTRODUCTION: Triggering receptor expressed on myeloid cells-2 (TREM2) is an immune receptor expressed on microglia that also can become soluble (sTREM2). How TREM2 engages different ligands remains poorly understood. METHODS: We used comprehensive biolayer interferometry (BLI) analysis to investigate TREM2 and sTREM2 interactions with apolipoprotein E (apoE) and monomeric amyloid beta (Aβ) (mAβ42). RESULTS: TREM2 engagement of apoE was protein mediated with little effect of lipidation, showing slight affinity differences between isoforms (E4 > E3 > E2). Another family member, TREML2, did not bind apoE. Disease-linked TREM2 variants within a "basic patch" minimally impact apoE binding. Instead, TREM2 uses a unique hydrophobic surface to bind apoE, which requires the apoE hinge region. TREM2 and sTREM2 directly bind mAβ42 and potently inhibit Aβ42 polymerization, suggesting a potential role for soluble sTREM2 in preventing AD pathogenesis. DISCUSSION: These findings demonstrate that TREM2 has at least two ligand-binding surfaces that might be therapeutic targets and uncovers a…

INTRODUCTION: The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes. METHODS: We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies. RESULTS: Among the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein…

Empirical evidence suggests that a fair proportion of dementia cases are preventable, that some preventive actions can be taken immediately, and others may soon be implemented. Primary prevention may target cognitively normal persons with modifiable risk factors through lifestyle and multiple domain interventions (including general cardiovascular health). While the effect on individuals may be modest, it might have a large societal impact by decreasing overall dementia incidence by up to 35%. Secondary prevention will target cognitively normal persons at high risk of dementia due to Alzheimer's disease pathology with future anti-amyloid, anti-tau, or other drugs. This approach is likely to have major benefits to both individuals and society. Memory clinics will need structural and functional changes to adapt to novel technologies and increased patients' demands, and brand-new services may need to be developed with specific skills on risk profiling, risk communication, and personalized risk reduction plans.

INTRODUCTION: The cytoprotective PTEN-induced kinase 1 (PINK1)-parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65-Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis. METHODS: Morphology, levels, and distribution of the mitophagy tag pS65-Ub were evaluated by biochemical analyses combined with tissue and single cell imaging in AD autopsy brain and in transgenic mouse models. RESULTS: Analyses revealed significant increases of pS65-Ub levels in AD brain, which strongly correlated with granulovacuolar degeneration (GVD) and early phospho-tau deposits, but were independent of amyloid beta pathology. Single cell analyses revealed predominant co-localization of pS65-Ub with mitochondria, GVD bodies, and/or lysosomes depending on the brain region analyzed. DISCUSSION: Our study highlights mitophagy alterations in AD that are associated with early tau…

INTRODUCTION: Blood-brain barrier (BBB) breakdown and loss of brain capillary pericytes contributes to cognitive impairment. Pericytes express platelet-derived growth factor receptor-β (PDGFRβ) that regulates brain angiogenesis and blood vessel stability. Elevated soluble PDGFRβ (sPDGFRβ) levels in cerebrospinal fluid (CSF) indicate pericyte injury and BBB breakdown, which is an early biomarker of human cognitive dysfunction. METHODS: A combination of reagents and conditions were tested, optimized, and validated on the Meso Scale Discovery electrochemiluminescence platform to develop a new sPDGFRβ immunoassay that was used to measure sPDGFRβ in human CSF from 147 individuals. RESULTS: We developed standard operating procedures for a highly sensitive and reproducible sPDGFRβ immunoassay with a dynamic range from 100 to 26,000 pg/mL, and confirmed elevated CSF sPDGFRβ levels in individuals with cognitive dysfunction. DISCUSSION: This assay could be applied at different laboratories to study brain pericytes and microvascular damage in relation to cognition in disorders associated with…

INTRODUCTION: Developing cross-validated multi-biomarker models for the prediction of the rate of cognitive decline in Alzheimer's disease (AD) is a critical yet unmet clinical challenge. METHODS: We applied support vector regression to AD biomarkers derived from cerebrospinal fluid, structural magnetic resonance imaging (MRI), amyloid-PET and fluorodeoxyglucose positron-emission tomography (FDG-PET) to predict rates of cognitive decline. Prediction models were trained in autosomal-dominant Alzheimer's disease (ADAD, n = 121) and subsequently cross-validated in sporadic prodromal AD (n = 216). The sample size needed to detect treatment effects when using model-based risk enrichment was estimated. RESULTS: = 25%) in sporadic AD. Model-based risk-enrichment reduced the sample size required for detecting simulated intervention effects by 50%-75%. DISCUSSION: Our independently validated machine-learning model predicted cognitive decline in sporadic prodromal AD and may substantially reduce sample size needed in clinical trials in AD.

INTRODUCTION: Longitudinal studies examining the effect of endogenous estrogens on dementia risk are needed to understand why women have higher dementia incidence than men after age 85. METHODS: A population-based sample of women with natural menopause (N = 1364) from Gothenburg, Sweden, was followed from 1968-2012. Information on endogenous estrogens (age at menarche and menopause, number of pregnancies, and months of breastfeeding) was obtained from interviews in 1968-1992. Dementia was diagnosed according to established criteria based on information from neuropsychiatric examinations and close informant interviews. RESULTS: We found that longer reproductive period was associated with increased risk of dementia (hazard ratio [HR] per year 1.06, 95% confidence interval [CI] 1.03-1.20) and Alzheimer's disease (AD) (1.06, 1.02-1.11), particularly for those with dementia (1.10, 1.04-1.17) and AD (1.15, 1.06-1.26) onset after age 85. DISCUSSION: These results may explain why women have higher dementia incidence compared to men after age 85, the age with the highest number of dementia…

INTRODUCTION: Apolipoprotein E (APOE) alleles are associated with cognitive decline, mild cognitive impairment (MCI), and Alzheimer's disease in Whites, but have weaker and inconsistent effects reported in Latinos. We hypothesized that this heterogeneity is due to ancestry-specific genetic effects. METHODS: We investigated the associations of the APOE alleles with significant cognitive decline and MCI in 4183 Latinos, stratified by six Latino backgrounds, and explored whether the proportion of continental genetic ancestry (European, African, and Amerindian) modifies these associations. RESULTS: APOE ε4 was associated with an increased risk of significant cognitive decline (odds ratio [OR] = 1.15, P-value = 0.03), with the strongest association in Cubans (OR = 1.46, P-value = 0.007). APOE-ε2 was associated with decreased risk of MCI (OR = 0.37, P-value = 0.04) in Puerto Ricans. Amerindian genetic ancestry was found to protect from the risk conferred by APOE ε4 on significant cognitive decline. DISCUSSION: Results suggest that APOE alleles' effects on cognitive outcomes differ across…

INTRODUCTION: Published reports of associations between β-amyloid (Aβ) and cortical integrity conflict. Tau biomarkers may help elucidate the complex relationship between pathology and neurodegeneration in aging. METHODS: We measured cortical thickness using magnetic resonance imaging, Aβ using Pittsburgh compound B positron emission tomography (PiB-PET), and tau using flortaucipir (FTP)-PET in 125 cognitively normal older adults. We examined relationships among PET measures, cortical thickness, and cognition. RESULTS: Cortical thickness was reduced in PiB+/FTP+ participants compared to the PiB+/FTP- and PiB-/FTP- groups. Continuous PiB associations with cortical thickness were weak but positive in FTP- participants and negative in FTP+. FTP strongly negatively predicted thickness regardless of PiB status. FTP was associated with memory and cortical thickness, and mediated the association of PiB with memory. DISCUSSION: Past findings linking Aβ and cortical thickness are likely weak due to opposing effects of Aβ on cortical thickness relative to tau burden. Tau, in contrast to Aβ,…

INTRODUCTION: Metabolomics provide a promising tool to understand the pathogenesis and to identify novel biomarkers of dementia. This study aimed to determine circulating metabolites associated with incident dementia in a Chinese cohort, and whether a selected metabolite panel could predict dementia. METHODS: Thirty-eight metabolites in baseline serum were profiled by nuclear magnetic resonance in 1440 dementia-free participants followed 5 years in the Shanghai Aging Study. RESULTS: Higher serum levels of glutamine and O-acetyl-glycoproteins were associated with increased risk of dementia, whereas glutamate, tyrosine, acetate, glycine, and phenylalanine were negatively related to incident dementia. A panel of five metabolites selected by least absolute shrinkage and selection operator within cross-validation regression analysis could predict incident dementia with an area under the receiver-operating characteristic curve of 0.72. DISCUSSION: We identified seven candidate serum metabolic biomarkers for dementia. These findings and the underlying biological mechanisms need to be…

China has the largest number of patients with dementia in the world. However, dementia in the Chinese population is still poorly understood and under-researched. Given the differences in genetic, demographic, sociocultural, lifestyle, and health profiles among Chinese and other ethnic/racial groups, it is crucial to build appropriate infrastructure for long-term longitudinal studies to advance Chinese cognitive aging and dementia research. We initiated a community-based prospective cohort-the Taizhou Imaging Study (TIS)-to accelerate the understanding of dementia and cerebrovascular diseases in Chinese. This article presents the rationale, aims, study design, and organization of TIS. In addition, we described some examples of the types of studies such a resource might support. The TIS provides a new framework for facilitating Chinese dementia research, encompassing invaluable resources including detailed epidemiological, sociocultural, neuroimaging, and omics data.

INTRODUCTION: Several pharmacoepidemiological studies indicate that proton pump inhibitors (PPIs) significantly increase the risk of dementia. Yet, the underlying mechanism is not known. Here, we report the discovery of an unprecedented mode of action of PPIs that explains how PPIs may increase the risk of dementia. METHODS: Advanced in silico docking analyses and detailed enzymological assessments were performed on PPIs against the core-cholinergic enzyme, choline-acetyltransferase (ChAT), responsible for biosynthesis of acetylcholine (ACh). RESULTS: This report shows compelling evidence that PPIs act as inhibitors of ChAT, with high selectivity and unprecedented potencies that lie far below their in vivo plasma and brain concentrations. DISCUSSION: Given that accumulating evidence points at cholinergic dysfunction as a driving force of major dementia disorders, our findings mechanistically explain how prolonged use of PPIs may increase incidence of dementia. This call for restrictions for prolonged use of PPIs in elderly, and in patients with dementia or amyotrophic lateral…

INTRODUCTION: The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) Prognostic and Natural History Study (PNHS) aims at understanding the role of amyloid imaging in the earliest stages of Alzheimer's disease (AD). AMYPAD PNHS adds (semi-)quantitative amyloid PET imaging to several European parent cohorts (PCs) to predict AD-related progression as well as address methodological challenges in amyloid PET. METHODS: AMYPAD PNHS is an open-label, prospective, multi-center, cohort study recruiting from multiple PCs. Around 2000 participants will undergo baseline amyloid positron emission tomography (PET), half of whom will be invited for a follow-up PET 12 at least 12 months later. RESULTS: ), and secondary are their changes from baseline, relationship to other amyloid markers (cerebrospinal fluid and visual assessment), and predictive value of AD-related decline. EXPECTED IMPACT: Determining the role of amyloid PET for the understanding of this complex disease and potentially improving secondary prevention trials.

We propose the altered lipidostasis hypothesis of Alzheimer's disease (AD). It holds that vulnerable neurons of the entorhinal region generate a neurodegenerative lipid during normal function, adenosine triphosphate-binding cassette transporter subfamily A member 7 (ABCA7) protects from AD pathogenesis by removing it out of the cell, generation of the lipid increases with age, and the minimal amount of ABCA7 needed to dispose of the rising volumes of the lipid also increases with age. A survey of ABCA7 protein levels in the hippocampus or parietal cortex of 123 individuals with or without AD neuropathology showed that individuals with low ABCA7 developed AD neuropathology at a younger age, those with intermediate ABCA7 developed it later, and individuals who developed it very late had high ABCA7, the same as the youngest controls. ABC transporters closely similar to ABCA7 protect cells by removing toxic lipids. ABCA7 may have analogous functions. The hypothesis predicts lipidosis and membrane protein dysfunction in neurons with low ABCA7. Further work will identify the…

INTRODUCTION: Patients with early onset dementia (EOD), defined as dementia with symptom onset at age <65, frequently present with atypical syndromes. However, the epidemiology of different EOD presentations, including variants of Alzheimer's disease (AD) and frontotemporal dementia (FTD), has never been investigated all together in a population-based study. Epidemiologic data of all-cause EOD are also scarce. METHODS: We investigated EOD epidemiology by identifying patients with EOD seen in the extended network of dementia services of the Modena province, Northern Italy (≈700,000 inhabitants) from 2006 to 2019. RESULTS: In the population age 30 to 64, incidence was 13.2 per 100,000/year, based on 160 new cases from January 2016 to June 2019, and prevalence 74.3 per 100,000 on June 30, 2019. The most frequent phenotypes were the amnestic variant of AD and behavioral variant of FTD. DISCUSSION: EOD affects a significant number of people. Amnestic AD is the most frequent clinical presentation in this understudied segment of the dementia population.

ABSTRACT Microglial TYROBP (also known as DAP12) has been identified by computational transcriptomics as a network hub and driver in late-onset sporadic Alzheimer’s disease (AD) and as an important regulator of the microglial environmental sensing function. TYROBP is the transmembrane adaptor of AD-related receptors TREM2 and CR3, but importantly, TYROBP interacts with many other receptors, and little is known about its roles in microglial action and/or in the pathogenesis of AD. Herein, using dual RNA in situ hybridization and immunohistochemistry, we demonstrate that endogenous Tyrobp transcription is increased specifically in recruited microglia in the brains of wild-type and AD-related mouse models. To determine whether chronically elevated TYROBP might modify microglial phenotype and/or progression of AD pathogenesis, we generated a novel transgenic mouse overexpressing TYROBP in microglia. TYROBP-overexpressing mice were crossed with either APP/PSEN1 or MAPT P301S mice, resulting in a decrease of the amyloid burden in the former and an increase of TAU phosphorylation in the…

Abstract Introduction Reference materials based on human cerebrospinal fluid were certified for the mass concentration of amyloid beta (Aβ)1‐42 (Aβ42). They are intended to be used to calibrate diagnostic assays for Aβ42. Methods The three certified reference materials (CRMs), ERM‐DA480/IFCC, ERM‐DA481/IFCC and ERM‐DA482/IFCC, were prepared at three concentration levels and characterized using isotope dilution mass spectrometry methods. Roche, EUROIMMUN, and Fujirebio used the three CRMs to re‐calibrate their immunoassays. Results The certified Aβ42 mass concentrations in ERM‐DA480/IFCC, ERM‐DA481/IFCC, and ERM‐DA482/IFCC are 0.45, 0.72, and 1.22 μg/L, respectively, with expanded uncertainties (k = 2) of 0.07, 0.11, and 0.18 μg/L, respectively. Before re‐calibration, a good correlation (Pearson's r > 0.97), yet large biases, were observed between results from different commercial assays. After re‐calibration the between‐assay bias was reduced to < 5%. Discussion The Aβ42 CRMs can ensure the equivalence of results between methods and across platforms for the measurement of Aβ42.

INTRODUCTION: The mechanism behind the strong association between the ɛ2/ɛ3/ɛ4 apolipoprotein E gene (APOE) polymorphism and Alzheimer's disease is not well-characterized. Because low plasma levels of apoE associate with risk of dementia, genetic variants altering apoE levels in general may also associate with dementia. METHODS: The APOE gene was sequenced in 10,369 individuals, and nine amino acid-changing variants with frequencies ≥2/10,000 were further genotyped in 95,228 individuals. Plasma apoE levels were measured directly. RESULTS: after APOE ɛ2/ɛ3/ɛ4 adjustment). Hazard ratios (95% confidence intervals) for all dementia and AD were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29) for the group with the genetically lowest apoE versus ɛ33. DISCUSSION: We found that genetically low apoE levels increase and genetically high levels decrease risk, beyond ɛ2/ɛ3/ɛ4. This underscores that dementia risk more likely relates to variants affecting levels of apoE.

INTRODUCTION: This work aims to characterize the sequence in which cognitive deficits appear in two dementia syndromes. METHODS: ) at the UCL Dementia Research Centre. Our neuropsychological battery assessed memory, vision, arithmetic, and general cognition. We adapted the event-based model to handle highly non-Gaussian data such as cognitive test scores where ceiling/floor effects are common. RESULTS: Experiments revealed differences and similarities in the fine-grained ordering of cognitive decline in PCA (vision first) and tAD (memory first). Simulation experiments reveal that our new model equals or exceeds performance of the classic event-based model, especially for highly non-Gaussian data. DISCUSSION: Our model recovered realistic, phenotypical progression signatures that may be applied in dementia clinical trials for enrichment, and as a data-driven composite cognitive end-point.

Abstract Introduction Apolipoprotein E (APOE) interacts with Alzheimer's disease pathology to promote disease progression. We investigated the moderating effect of APOE on independent associations of amyloid and tau positron emission tomography (PET) with cognition. Methods For 297 nondemented older adults from the Alzheimer's Disease Neuroimaging Initiative, regression equations modeled associations between cognition and (1) cortical amyloid beta (Aβ) PET levels adjusting for tau and (2) medial temporal lobe (MTL) tau PET levels adjusting for Aβ, including interactions with APOE ε4‐carrier status. Results Adjusting for tau PET, Aβ was not associated with cognition and did not interact with APOE. In contrast, adjusting for Aβ PET, MTL tau was associated with all cognitive domains. Further, there was a stronger moderating effect of APOE on MTL tau and memory associations in ε4‐carriers, even among Aβ‐negative individuals. Discussion Findings suggest that APOE may interact with tau independently of Aβ and that elevated MTL tau confers negative cognitive consequences in Aβ‐negative ε4…

INTRODUCTION: There is limited research on difficulties with activities of daily living (I/ADLs) among older adults living alone with cognitive impairment, including differences by race/ethnicity. METHODS: For U.S. Health and Retirement Study (2000-2014) participants aged 55+ living alone with cognitive impairment (4,666 individuals; 9,091 observations), we evaluated I/ADL difficulty and help. RESULTS: Among 4.3 million adults aged 55+ living alone with cognitive impairment, an estimated 46% reported an I/ADL difficulty; 72% reported not receiving help with an I/ADL. Women reported more difficulty than men. Compared to white women, black women were 22% more likely to report a difficulty without help, and Latina women were 36% more likely to report a difficulty with help. Among men, racial/ethnic differences in outcomes were not significant. Patterns of difficulty without help by race/ethnicity were similar among Medicaid beneficiaries. DISCUSSION: Findings call for targeted efforts to support older adults living alone with cognitive impairment.

Delirium is an acute disorder of attention and cognition. It occurs across the life span, yet it is particularly common among older adults, and is closely linked with underlying neurocognitive disorders. Evidence is mounting that intervening on delirium may represent an important opportunity for delaying the onset or progression of dementia. To accelerate the current understanding of delirium, the Network for Investigation of Delirium: Unifying Scientists (NIDUS) held a conference "Advancing Delirium Research: A Scientific Think Tank" in June 2019. This White Paper encompasses the major knowledge and research gaps identified at the conference: advancing delirium definition and measurement, understanding delirium pathophysiology, and prevention and treatment of delirium. A roadmap of research priorities is proposed to advance the field in a systematic, interdisciplinary, and coordinated fashion. A call is made for an international consortium and biobank targeted to delirium, as well as a public health campaign to advance the field.

Abstract Introduction Spatial navigation deficits are observed in Alzheimer's disease cross‐sectionally, but prediction of longitudinal clinical decline has been less examined. Methods Cognitive mapping (CM) was assessed in 95 participants and route learning (RL) was assessed in 65 participants at baseline. Clinical progression over an average of 4 to 5 years was assessed using the clinical dementia rating (CDR) scale. Relative predictive ability was compared to episodic memory, hippocampus, and cerebrospinal fluid biomarkers (phosphorylated tau/amyloid β 42 (ptau181/Aβ42) ratio). Results CM and RL were predictors of clinical progression (P’s < 0.032). All measures, except RL‐Learning remained predictors with episodic memory in models (P’s < 0.048). Only RL‐Retrieval remained a predictor when ptau181/Aβ42 was included (P < 0.001). CM interacted with hippocampus and ptau181/Aβ42 in prediction (P’s < 0.013). CM, RL, and episodic memory evidenced strong diagnostic accuracy (area under the curve (AUC) = 0.894, 0.794, and 0.735, respectively); CM tended to perform better than episodic…

INTRODUCTION: The impact of prediabetes and diabetes on stroke and the development of dementia after a stroke remain unclear. METHODS: A total of 2655 dementia-free participants (including a stroke-free cohort and a prevalent stroke cohort) were followed-up for 12 years. Dementia and post-stroke dementia were determined by clinical examinations and national registry data. Diabetes was ascertained via medical examination, medication use, medical records, or glycated hemoglobin (HbA1c) ≥6.5%. Prediabetes was defined as HbA1c ≥5.7% in diabetes-free participants. RESULTS: In the stroke-free cohort, 236 participants developed ischemic stroke, and 47 developed post-stroke dementia. Diabetes was associated with ischemic stroke (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.16 to 2.67) and post-stroke dementia (HR 2.56, 95% CI 1.04 to 6.25). In the prevalent stroke cohort, diabetes was also related to dementia risk. Prediabetes was not significantly related to stroke or post-stroke dementia. DISCUSSION: Diabetes, but not prediabetes, is associated with an increased risk of ischemic…

Presently, there is a clear societal and demographic imperative to\nidentify and deliver interventions that are effective in reducing\ndementia. With the high failure rate of compounds in clinical trials, and\nwith pharmaceutical development cycles typically lasting decades,\na hybrid person-with-dementia-centered approach that precisely inte-\ngrates pharmaceutical, non-pharmaceutical, lifestyle modification, and care\ninterventions for the individual may offer more immediate results for\nreducing dementia burden. One important, tangible, and overlooked\nstrategy with this proposed approach may be through the recognition\nand prevention of delirium.

INTRODUCTION: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy. METHODS: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling. RESULTS: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions. DISCUSSION: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD.

INTRODUCTION: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). METHODS: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. RESULTS: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. DISCUSSION: Our findings suggest that the maintenance of…

INTRODUCTION: Cerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood-brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases. METHODS: We performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin-5 (CLDN5) and occludin (OCLN), and major AD-related molecules (amyloid beta [Aβ40], Aβ42, tau, p-tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA. RESULTS: Higher levels of soluble tau, insoluble p-tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aβ40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels. DISCUSSION: Refining the molecular mechanisms connecting tau, Aβ, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis…

INTRODUCTION: A biphasic model for brain structural changes in preclinical Alzheimer's disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti-amyloid clinical trials. METHODS: In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity-a novel marker of cortical microstructure-changes in 389 participants from the Dominantly Inherited Alzheimer Network. RESULTS: In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations. DISCUSSION: These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance…

INTRODUCTION: Microstructural alterations as assessed by diffusion tensor imaging (DTI) are key findings in both Alzheimer's disease (AD) and small vessel disease (SVD). We determined the contribution of each of these conditions to diffusion alterations. METHODS: We studied six samples (N = 365 participants) covering the spectrum of AD and SVD, including genetically defined samples. We calculated diffusion measures from DTI and free water imaging. Simple linear, multivariable random forest, and voxel-based regressions were used to evaluate associations between AD biomarkers (amyloid beta, tau), SVD imaging markers, and diffusion measures. RESULTS: SVD markers were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analysis across all memory clinic samples. Voxel-wise analyses between tau and diffusion measures were not significant. DISCUSSION: In memory clinic patients, the effect of SVD on diffusion alterations largely exceeds the effect of AD, supporting the value of diffusion measures as markers of SVD.

OBJECTIVE: We also will discuss if such Lf decrease could be due to a downregulation of the sAD associated systemic immunity. BACKGROUND: Several non-neurological alterations have been described in sAD, mainly in skin, blood cell, and immunological capacities. We reviewed briefly the main pathophysiological theories of sAD (amyloid cascade, tau, unfolder protein tau, and amyloid deposits) emphasizing the most brain based hypotheses such as the updated tau-related neuron skeletal hypothesis; we also comment on the systemic theories that emphasize the fetal origin of the complex disorders that include the low inflammatory and immunity theories of sAD. NEW/UPDATED HYPOTHESIS: Lf has important anti-infectious and immunomodulatory roles in health and disease. We present the hypothesis that the reduced levels of saliva Lf could be an effect of immunological disturbances associated to sAD. Under this scenario, two alternative pathways are possible: first, whether sAD could be a systemic disorder (or disorders) related to early immunological and low inflammatory alterations; second, if…

INTRODUCTION: Similar symptoms, comorbidities and suboptimal diagnostic tests make the distinction between different types of dementia difficult, although this is essential for improved work-up and treatment optimization. METHODS: We calculated temporal disease trajectories of earlier multi-morbidities in Alzheimer's disease (AD) dementia and vascular dementia (VaD) patients using the Danish National Patient Registry covering all hospital encounters in Denmark (1994 to 2016). Subsequently, we reduced the comorbidity space dimensionality using a non-linear technique, uniform manifold approximation and projection. RESULTS: We found 49,112 and 24,101 patients that were diagnosed with AD or VaD, respectively. Temporal disease trajectories showed very similar disease patterns before the dementia diagnosis. Stratifying patients by age and reducing the comorbidity space to two dimensions, showed better discrimination between AD and VaD patients in early-onset dementia. DISCUSSION: Similar age-associated comorbidities, the phenomenon of mixed dementia, and misdiagnosis create great…

INTRODUCTION: The association of lifespan cognitive reserve (CR) with mild cognitive impairment (MCI) remains controversial. We aimed to examine the association of lifespan CR indicator with the risk of MCI and its progression to dementia, taking brain pathologies into account. METHODS: In a community-based cohort study (mean age, 79 years) with annual follow-up (median, 5.16 years; maximum, 20 years), a cognitively intact group (n = 1182) and an MCI group (n = 420) were identified at baseline. During the follow-up, 611 participants died and underwent autopsies. CR indicator encompassing education, early life to late-life cognitive and social activities were obtained and tertiled. RESULTS: The multi-adjusted hazard ratio (HR) of MCI was 0.72 (95% confidence interval [CI] 0.58 to 0.90) in the cognitively intact group, and the HR of dementia was 0.66 (95% CI 0.45 to 0.97) in the MCI group for participants with the highest CR indicator (reference: the lowest CR indicator). Among MCI participants with brain pathologies, dementia incidence was about 50% lower in people with the highest…

INTRODUCTION: Familial frontotemporal lobar degeneration (f-FTLD) due to autosomal dominant mutations is an important entity for developing treatments for FTLD. The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) longitudinal studies were designed to describe the natural history of f-FTLD. METHODS: We summarized recent publications from the ARTFL and LEFFTDS studies, along with other recent publications describing the natural history of f-FTLD. RESULTS: Published and emerging studies are producing data on all phases of f-FTLD, including the asymptomatic and symptomatic phases of disease, as well as the transitional phase when symptoms are just beginning to develop. These data indicate that rates of change increase along with disease severity, which is consistent with commonly cited models of neurodegeneration, and that measurement of biomarkers may predict onset of symptoms. DISCUSSION: Data from large multisite studies are producing important data on the natural history…

INTRODUCTION: We searched for consistent associations of an omega-3 index in plasma (sum of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) with several dementia-related outcomes in a large cohort of older adults. METHODS: We included 1279 participants from the Three-City study, non-demented at the time of blood measurements at baseline, with face-to-face neuropsychological assessment and systematic detection of incident dementia over a 17-year follow-up. An ancillary study included 467 participants with up to three repeated brain imaging exams over 10 years. RESULTS: In multivariable models, higher levels of plasma EPA+DHA were consistently associated with a lower risk of dementia (hazard ratio for 1 standard deviation = 0.87 [95% confidence interval, 0.76-0.98]), and a lower decline in global cognition (P = .04 for change over time), memory (P = .06), and medial temporal lobe volume (P = .02). DISCUSSION: This prospective study provides compelling evidence for a relationship between long-chain omega-3 fatty acids levels and lower risks for dementia and related outcomes.

OBJECTIVE: Recent clinical trials targeting amyloid beta (Aβ) and tau in Alzheimer's disease (AD) have yet to demonstrate efficacy. Reviewing the hypotheses for AD pathogenesis and defining possible links between them may enhance insights into both upstream initiating events and downstream mechanisms, thereby promoting discovery of novel treatments. Evidence that in Down syndrome (DS), a population markedly predisposed to develop early onset AD, increased APP gene dose is necessary for both AD neuropathology and dementia points to normalization of the levels of the amyloid precursor protein (APP) and its products as a route to further define AD pathogenesis and discovering novel treatments. BACKGROUND: AD and DS share several characteristic manifestations. DS is caused by trisomy of whole or part of chromosome 21; this chromosome contains about 233 protein-coding genes, including APP. Recent evidence points to a defining role for increased expression of the gene for APP and for its 99 amino acid C-terminal fragment (C99, also known as β-CTF) in dysregulating the endosomal/lysosomal…

INTRODUCTION: The genetic risk effects of apolipoprotein E (APOE) on familial Alzheimer's disease (FAD) with or without gene mutations, sporadic AD (SAD), and normal controls (NC) remain unclear in the Chinese population. METHODS: In total, 15 119 subjects, including 311 FAD patients without PSEN1, PSEN2, APP, TREM2, and SORL1 pathogenic mutations (FAD [unknown]); 126 FAD patients with PSENs/APP mutations (FAD [PSENs/APP]); 7234 SAD patients; and 7448 NC were enrolled. The risk effects of APOE ε4 were analyzed across groups. RESULTS: The prevalence of the APOE ε4 genotype in FAD (unknown), FAD (PSENs/APP), SAD, and NC groups was 56.27%, 26.19%, 36.23%, and 19.54%, respectively. Further, the APOE ε4 positive genotype had predictive power for FAD (unknown) risk (odds ratio: 4.51, 95% confidence interval: 3.57-5.45, P < .001). DISCUSSION: APOE ε4 positive genotype may cause familial aggregation, and the investigation of multiple interventions targeting APOE pathological function to reduce the risk for this disease warrants attention.

Abstract Introduction Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome‐wide association study to examine rate of cognitive decline (ROD) in patients with AD. Methods We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. Results Suggestive associations ( P < 1.0 × 10 −6 ) were observed on chromosome 15 in DNA polymerase‐γ (rs3176205, P = 1.11 × 10 −7 ), chromosome 7 (rs60465337, P = 4.06 × 10 −7 ) in contactin‐associated protein‐2, in RP11‐384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10 −7 ), family with sequence similarity 214 member‐A on chromosome 15 (rs2899492, P = 5.94 × 10 −7 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10 −7 ) and 4 (rs1304013, P = 7.73 × 10 −7 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. Discussion Pathways related to AD, intelligence, and neurological function…

INTRODUCTION: Both beta-amyloid (Ab) deposition and decline in white matter integrity, are brain alterations observed in Alzheimer's disease (AD) and start to occur by the fourth and fifth decades. However, the association between both brain alterations in asymptomatic subjects is unclear. METHODS: Amyloid positron emission tomography (PET) and diffusion tensor imaging (DTI) were obtained in 282 cognitively normal subjects (age 30-89 years). We assessed the interaction of age by abnormal amyloid PET status (Florbetapir F-18 PET >1.2 standard uptake value ratio [SUVR]) on regional mean diffusivity (MD) and global white matter hyperintensity (WMH) volume, controlled for sex, education, and hypertension. RESULTS: Subjects with abnormal amyloid PET (n = 87) showed stronger age-related increase in global WMH and regional MD, particularly within the posterior parietal regions of the white matter. DISCUSSION: Sporadic Aβ deposition is associated with white matter alterations in AD predilection areas in an age-dependent manner in cognitively normal individuals.

INTRODUCTION: Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) biomarkers in cognitively normal (CN) and mild cognitive impaired (MCI) participants. However, independent and combined effects of OSA, amyloid beta (Aβ) and tau-accumulation on AD time-dependent progression risk is unclear. METHODS: Study participants grouped by biomarker profile, as described by the A/T/N scheme, where "A" refers to aggregated Aβ, "T" aggregated tau, and "N" to neurodegeneration, included 258 CN (OSA-positive [OSA+] [A+TN+ n = 10, A+/TN- n = 6, A-/TN+ n = 10, A-/TN- n = 6 and OSA-negative [OSA-] [A+TN+ n = 84, A+/TN- n = 11, A-/TN+ n = 96, A-/TN- n = 36]) and 785 MCI (OSA+ [A+TN+ n = 35, A+/TN- n = 15, A-/TN+ n = 25, A-/TN- n = 16] and OSA- [A+TN+ n = 388, A+/TN- n = 28, A-/TN+ n = 164, A-/TN- n = 114]) older-adults from the Alzheimer's Disease Neuroimaging Initiative cohort. Cox proportional hazards regression models estimated the relative hazard of progression from CN-to-MCI and MCI-to-AD, among baseline OSA CN and MCI patients, respectively. Multi-level logistic…

INTRODUCTION: Recent studies suggest that Alzheimer's disease (AD) biomarker disclosure has no discernable psychological impact on cognitively healthy persons. Far less is known about how such results affect symptomatic individuals and their caregivers. METHODS: Randomized controlled trial of 82 mild cognitive impairment (MCI) patient and caregiver dyads (total n = 164) to determine the effect of receiving amyloid positron emission tomography results on understanding of, and perceived efficacy to cope with, MCI over 52 weeks of follow-up. RESULTS: Gains in the primary outcomes were not consistently observed. Amyloid negative patients reported greater perceived ambiguity regarding MCI at follow-up, while moderate and sustained emotional distress was observed in patients, and to a lesser extent, caregivers, of those who were amyloid positive. There was no corresponding increase in depressive symptoms. DISCUSSION: These findings point to the possibility that both MCI patients and caregivers may need emotional support after the disclosure of amyloid scan results.

INTRODUCTION: In animal models, refined carbohydrates (RF) worsen Alzheimer's disease (AD). However, the long-term effects of high RF intake on the risk of dementia and AD are poorly described in epidemiological studies. Moreover, the interaction between RF and the apolipoprotein E ε4 allele (APOE-ε4) is unknown. Our study investigated whether RF-rich diets are associated with the risk of dementia and AD. METHODS: The glycemic load (GL) was quantified in 2777 elderly participants from the French Three-City Study to estimate RF intake. Then, the associations between GL and risk of dementia and AD, and the interaction with APOE-ε4 over a 12-year period were assessed using proportional hazards models. RESULTS: After adjustment for potential confounders, high afternoon-snack GL was associated with increased dementia and AD risk in APOE-ε4 carriers (hazard ratio = 1.27 [1.03-1.56]). DISCUSSION: This study highlights that RF-rich diets are a risk factor for dementia and AD in APOE-ε4 carriers.

INTRODUCTION: Cognitive composite scores offer a means of precisely measuring executive functioning (EF). METHODS: We developed the Uniform Data Set v3.0 EF composite score (UDS3-EF) in 3507 controls from the National Alzheimer's Coordinating Center dataset using item-response theory and applied nonlinear and linear demographic adjustments. The UDS3-EF was validated with other neuropsychological tests and brain magnetic resonance imaging from independent research cohorts using linear models. RESULTS: Final model fit was good-to-excellent: comparative fit index = 0.99; root mean squared error of approximation = 0.057. UDS3-EF scores differed across validation cohorts (controls > mild cognitive impairment > Alzheimer's disease-dementia ≈ behavioral variant frontotemporal dementia; P < 0.001). The UDS3-EF correlated most strongly with other EF tests (βs = 0.50 to 0.85, Ps < 0.001) and more with frontal, parietal, and temporal lobe gray matter volumes (βs = 0.18 to 0.33, Ps ≤ 0.004) than occipital gray matter (β = 0.12, P = 0.04). The total sample needed to detect a 40% reduction in…

By full disclosure, MNS advises Biogen's aducanumab, Eisai's BAN2401 program, Roche's Gantanerumab, Alzheon's Alz801 program, Cortexyme COR388 program, and Athira's NDX1017. In the past, MNS was on the steering committee of the Pfizer/Wyeth Bapineuzemab program and advised Lilly's solanazumab and Axovant's Interpredine program and VTV therapeutics Azeliragon program. This disclosure is intended for transparency and to give the reader the perspective of no exclusionary bias toward or against aducanumab. Dr. Cummings has provided consultation to Acadia, Actinogen, Acumen, Alector, Alkahest, Alzheon, AriBio, Avanir, Axsome, Behren Therapeutics, Biogen, Cassava, Cerecin, Cerevel, Cortexyme, Cytox, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Merck, Novo Nordisk, Otsuka, ReMYND, Resverlogix, Roche, Samumed, Samus, Signant Health, Sunovion, Suven, and United Neuroscience pharmaceutical and assessment companies. A US Food and Drug Administration (FDA) Advisory Committee will soon review data submitted by Biogen for approval of aducanumab for the…

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior…

INTRODUCTION: A few studies suggest that working night and rotating shifts increase the risk of dementia. We examined the association between shift work and the incidence of dementia in a cohort of female Danish nurses. METHODS: We linked Danish Nurse Cohort participants, who reported work schedules (day, evening, night, rotating shifts) in 1993 and/or 1999 and their duration in 2009, to Danish registers to obtain information on dementia hospitalizations and prescription medication until November 2018. RESULTS: Among 6048 nurses who reported work schedules in 1993 and 1999, nurses working night shifts ≥6 years had higher dementia incidence (hazard ratio: 2.43, 95% confidence interval: 1.39 to 4.23) than those working day shifts ≥6 years. Among 8059 nurses who reported shift work duration, nurses working night shifts ≥6 years had higher dementia incidence than those working night shifts <1 year (1.47, 1.06 to 2.06). DISCUSSION: Persistent night shift work may increase the risk of dementia.

INTRODUCTION: Small observational studies with short-term follow-up suggest that cancer patients are at reduced risk of Alzheimer's disease (AD) compared to the general population. METHODS: A nationwide cohort study using Danish population-based health registries (1980-2013) with cancer patients (n = 949,309) to identify incident diagnoses of AD. We computed absolute reductions in risk attributed to cancer and standardized incidence rate ratios (SIRs) accounting for survival time, comparing the observed to expected number of AD cases. RESULTS: During up to 34 years of follow-up of cancer survivors, the attributable risk reduction was 1.3 per 10,000 person-years, SIR = 0.94 (95% confidence interval 0.92-0.96). SIRs were similar after stratification by sex, age, and cancer stage, and approached that of the general population for those surviving >10 years. DISCUSSION: Inverse associations between cancer and AD were small and diminished over time. Incidence rates in cancer survivors approached those of the general population, suggesting limited association between cancer and AD risk.

INTRODUCTION: The aim is to test whether adding a simple physical test such as walking speed (WS) to the neuropsychological assessment increases the predictive ability to detect dementia. METHODS: The 2546 dementia-free people from the SNAC-K study were grouped into four profiles: (1) healthy profile; (2) isolated cognitive impairment, no dementia (CIND, scoring 1.5 standard deviation below age-specific means on ≥1 cognitive domains); (3) isolated slow WS (<0.8 m/s); (4) CIND+ slow WS. The hazard of dementia (Cox regression), the positive and negative predictive values (PPV, NPV), and the area under the curve (AUC) were estimated. RESULTS: Participants with CIND +slow WS demonstrated the highest hazard of dementia (3.4; 95% confidence interval [CI]: 2.5-4.8). The AUC increased from 0.69 for isolated CIND to 0.83 for CIND+ slow WS. Such an increase was due to the improvement of the PPV, the NPV remaining optimal. DISCUSSION: Adding WS to the cognitive assessment dramatically increases the diagnostic accuracy of prodromal dementia.

INTRODUCTION: Although not designed as such, dementia risk scores might be useful surrogate outcomes for dementia prevention trials. Their suitability may be improved by using continuous scoring systems, taking into account all changes in risk factors, not only those crossing cut-off values. METHODS: In three large multidomain dementia prevention trials with 1.5 to 2 years of follow-up (Multidomain Alzheimer Preventive Trial, Prevention of Dementia by Intensive Vascular Care and Healthy Ageing Through Internet Counselling in the Elderly) we assessed (1) responsiveness (sensitivity to change) and (2) actual and simulated intervention effects of the original and crude/weighted z-score versions of the cardiovascular risk factors, aging and incidence of dementia, and Lifestyle for Brain Health scores. RESULTS: All versions of the risk scores were generally responsive, and able to detect small though statistically significant between-group differences after multidomain interventions. Simulated intervention effects were well detected in z-score versions as well as in the original scores.…

Abstract Introduction Abnormal gene expression patterns may contribute to the onset and progression of late‐onset Alzheimer's disease (LOAD). Methods We performed transcriptome‐wide meta‐analysis (N = 1440) of blood‐based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis. Results We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis‐expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10−8), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [18F]Florbetapir positron emission tomography and CSF Aβ1‐42. Discussion RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes…

The repeated failure of clinical trials targeting the amyloid beta (Aβ) protein has challenged the amyloid cascade hypothesis. In this perspective, I discuss the biogenesis and biology of Aβ, from the arrangement of its atoms to its effects on the human brain. I hope that this analysis will help guide future attempts to home in on this elusive therapeutic target.

INTRODUCTION: Recent reports from high-income countries have suggested a declining incidence of dementia. METHODS: Trends in dementia incidence over 25 years among people ≥75 years of age were examined using two population-based cohort studies: the Kungsholmen Project (KP, n = 1473, 1987-1998) and the Swedish National study on Aging and Care in Kungsholmen (SNAC-K, n = 1746, 2001-2013). RESULTS: We identified 440 (29.9%) and 388 (22.2%) incident dementia cases in the KP and SNAC-K cohorts, respectively. The incidence of dementia declined by 30% (hazard ratio [HR] = 0.70; 95% confidence interval [CI] 0.61-0.80) during the second decade. Adjustment of education, psychosocial working conditions, lifestyle, and vascular diseases did not substantially change the results (HR = 0.77, 95% CI 0.65-0.90). This decline was observed particularly in women and people with elementary education. DISCUSSION: Our study provides direct evidence of a declining trend in dementia incidence. Improved cognitive reserve and cardiovascular health could partially explain the decline.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in…

The Washington University School of Medicine Knight Alzheimer Disease Research Center's "African American Participation in Alzheimer Disease Research: Effective Strategies" Workshop convened to address a major limitation of the ongoing scientific progress regarding Alzheimer's disease and related dementias (ADRD): participants in most ADRD research programs overwhelmingly have been limited to non-Hispanic white persons, thus precluding knowledge as to how ADRD may be represented in non-white individuals. Factors that may contribute to successful recruitment and retention of African Americans into ADRD research were discussed and organized into actionable next steps as described within this report.

INTRODUCTION: To examine associations of history of traumatic brain injuries (TBIs) with loss of consciousness (LOC) with dementia incidence and memory decline. METHODS: We studied 2718 participants from the 1992 enrollment cohort of the Health and Retirement Study (HRS) aged 65 years or older in 2000. History of TBI with LOC was self-reported in 1992. Dementia was assessed using four algorithms established in HRS. Participants were followed from 2000 to 2014 with repeated measures of dementia and memory performance. Cox models and linear mixed-effects models were used. RESULTS: In 1992, 11.9% of the participants reported a history of TBI with LOC. In fully adjusted models for all four algorithms, participants with a history of TBI with LOC had no statistically significant difference in dementia incidence nor in memory decline, compared to participants without TBI history. DISCUSSION: Our study did not find evidence of a long-term association between history of TBI with LOC (of unknown frequency and severity) and dementia incidence or memory decline.