The 100 most-cited articles in Alzheimer s & Dementia, 2017

This article describes the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality rates, costs of care, and the overall impact on caregivers and society. The Special Report examines how the use of biomarkers may influence the AD diagnostic process and estimates of prevalence and incidence of the disease. An estimated 5.5 million Americans have Alzheimer's dementia. By mid‐century, the number of people living with Alzheimer's dementia in the United States is projected to grow to 13.8 million, fueled in large part by the aging baby boom generation. Today, someone in the country develops Alzheimer's dementia every 66 seconds. By 2050, one new case of Alzheimer's dementia is expected to develop every 33 seconds, resulting in nearly 1 million new cases per year. In 2014, official death certificates recorded 93,541 deaths from AD, making AD the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age ≥65 years. Between 2000 and 2014, deaths resulting from stroke, heart disease, and prostate cancer…

INTRODUCTION: A classification framework for posterior cortical atrophy (PCA) is proposed to improve the uniformity of definition of the syndrome in a variety of research settings. METHODS: Consensus statements about PCA were developed through a detailed literature review, the formation of an international multidisciplinary working party which convened on four occasions, and a Web-based quantitative survey regarding symptom frequency and the conceptualization of PCA. RESULTS: A three-level classification framework for PCA is described comprising both syndrome- and disease-level descriptions. Classification level 1 (PCA) defines the core clinical, cognitive, and neuroimaging features and exclusion criteria of the clinico-radiological syndrome. Classification level 2 (PCA-pure, PCA-plus) establishes whether, in addition to the core PCA syndrome, the core features of any other neurodegenerative syndromes are present. Classification level 3 (PCA attributable to AD [PCA-AD], Lewy body disease [PCA-LBD], corticobasal degeneration [PCA-CBD], prion disease [PCA-prion]) provides a more…

INTRODUCTION: Cerebrospinal fluid analysis and other measurements of amyloidosis, such as amyloid-binding positron emission tomography studies, are limited by cost and availability. There is a need for a more practical amyloid β (Aβ) biomarker for central nervous system amyloid deposition. METHODS: We adapted our previously reported stable isotope labeling kinetics protocol to analyze the turnover kinetics and concentrations of Aβ38, Aβ40, and Aβ42 in human plasma. RESULTS: Aβ isoforms have a half-life of approximately 3 hours in plasma. Aβ38 demonstrated faster turnover kinetics compared with Aβ40 and Aβ42. Faster fractional turnover of Aβ42 relative to Aβ40 and lower Aβ42 and Aβ42/Aβ40 concentrations in amyloid-positive participants were observed. DISCUSSION: Blood plasma Aβ42 shows similar amyloid-associated alterations as we have previously reported in cerebrospinal fluid, suggesting a blood-brain transportation mechanism of Aβ. The stability and sensitivity of plasma Aβ measurements suggest this may be a useful screening test for central nervous system amyloidosis.

INTRODUCTION: It is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis. METHODS: Within the autopsy cohort of the Baltimore Longitudinal Study of Aging, we measured brain glucose concentration and assessed the ratios of the glycolytic amino acids, serine, glycine, and alanine to glucose. We also quantified protein levels of the neuronal (GLUT3) and astrocytic (GLUT1) glucose transporters. Finally, we assessed the relationships between plasma glucose measured before death and brain tissue glucose. RESULTS: Higher brain tissue glucose concentration, reduced glycolytic flux, and lower GLUT3 are related to severity of AD pathology and the expression of AD symptoms. Longitudinal increases in fasting plasma glucose levels are associated with higher brain tissue glucose concentrations. DISCUSSION: Impaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis. Abnormalities in brain glucose homeostasis may begin several years before the onset of clinical symptoms.

Abstract Introduction The Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance. Methods Fasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ‐p180 kit. Performance was validated in blinded replicates, and values were medication adjusted. Results Multivariable‐adjusted analyses showed that sphingomyelins and ether‐containing phosphatidylcholines were altered in preclinical…

INTRODUCTION: Higher midlife body mass index (BMI) is suggested to increase the risk of dementia, but weight loss during the preclinical dementia phase may mask such effects. METHODS: We examined this hypothesis in 1,349,857 dementia-free participants from 39 cohort studies. BMI was assessed at baseline. Dementia was ascertained at follow-up using linkage to electronic health records (N = 6894). We assumed BMI is little affected by preclinical dementia when assessed decades before dementia onset and much affected when assessed nearer diagnosis. RESULTS: increase in BMI for dementia were 0.71 (95% confidence interval = 0.66-0.77), 0.94 (0.89-0.99), and 1.16 (1.05-1.27) when BMI was assessed 10 years, 10-20 years, and >20 years before dementia diagnosis. CONCLUSIONS: The association between BMI and dementia is likely to be attributable to two different processes: a harmful effect of higher BMI, which is observable in long follow-up, and a reverse-causation effect that makes a higher BMI to appear protective when the follow-up is short.

INTRODUCTION: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two-phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS-1) and protocols (VICCCS-2) for diagnosis of VCI. We present VICCCS-2. METHODS: We used VICCCS-1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI. RESULTS: Six survey rounds comprising 65-79 participants agreed guidelines for diagnosis of VICCCS-revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders-Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging. DISCUSSION: The VICCCS-2 suggests standardized use of the National Institute of Neurological Disorders-Canadian Stroke Network recommendations on…

INTRODUCTION: The 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) multidomain lifestyle intervention trial (NCT01041989) demonstrated beneficial effects on cognition. We investigated whether sociodemographics, socioeconomic status, baseline cognition, or cardiovascular factors influenced intervention effects on cognition. METHODS: The FINGER recruited 1260 people from the general Finnish population (60-77 years, at risk for dementia). Participants were randomized 1:1 to multidomain intervention (diet, exercise, cognition, and vascular risk management) and regular health advice. Primary outcome was change in cognition (Neuropsychological Test Battery z-score). Prespecified analyses to investigate whether participants' characteristics modified response to intervention were carried out using mixed-model repeated-measures analyses. RESULTS: Sociodemographics (sex, age, and education), socioeconomic status (income), cognition (Mini-Mental State Examination), cardiovascular factors (body mass index, blood pressure, cholesterol, fasting…

INTRODUCTION: We forecast the prevalence of preclinical and clinical Alzheimer's disease (AD) and evaluated potential impacts of primary and secondary preventions in the United States. METHODS: We used a multistate model incorporating biomarkers for preclinical AD with US population projections. RESULTS: Approximately 6.08 million Americans had either clinical AD or mild cognitive impairment due to AD in 2017 and that will grow to 15.0 million by 2060. In 2017, 46.7 million Americans had preclinical AD (amyloidosis, neurodegeneration, or both), although many may not progress to clinical disease during their lifetimes. Primary and secondary preventions have differential impact on future disease burden. DISCUSSION: Because large numbers of persons are living with preclinical AD, our results underscore the need for secondary preventions for persons with existing AD brain pathology who are likely to develop clinical disease during their lifetimes as well as primary preventions for persons without preclinical disease.

INTRODUCTION: We examined whether obesity at ages 50, 60, and 70 years is associated with subsequent dementia. Changes in body mass index (BMI) for more than 28 years before dementia diagnosis were compared with changes in BMI in those free of dementia. METHODS: A total of 10,308 adults (33% women) aged 35 to 55 years in 1985 were followed up until 2015. BMI was assessed six times and 329 cases of dementia were recorded. RESULTS: ) at age 50 years (hazard ratio = 1.93; 1.35-2.75) but not at 60 or 70 years was associated with risk of dementia. Trajectories of BMI differed in those with dementia compared with all others (P < .0001) or to matched control subjects (P < .0001) such that BMI in dementia cases was higher from 28 years (P = .001) to 16 years (P = .05) and lower starting 8 years before diagnosis. DISCUSSION: Obesity in midlife and weight loss in the preclinical phase characterizes dementia; the current obesity epidemic may affect future dementia rates.

Essential Hypertension (EHT)is one of the main risk factors for Alzheimer's disease(AD). The aim of our study was to point out experimental data on the potential role of some serum factors from blood of patients with (EHT) in determining some changes in the ionic flow and neuromediators uptake by the rat cerebral cortex, cardiac and arterial smooth muscle cell receptors with a view to estimate the relevance of these factors in the development of cardiovascular pathology and (AD) and the possible therapeutic management of these agents under study. Our study has been conducted on 34 patients :17 aged 35–86 with EHT (10 men and 7 women) and 17 normotensive subjects (aged 30–84 years old) hospitalized in NIGG Ana Aslan. The radioactive incubation experiments of rat cerebral cortex, heart and aorta have been done according with the published technique. The uptake of 45CaCl2,3H Serotonine,3H Cortisol and 3H Norepinephrine by animal tissues in the presence of serum from (EHT) and normotensive patients has been assayed using a Beta Berthold Scintilator Counter. Our data have pointed out a a…

INTRODUCTION: Family carers of people with dementia are their most important support in practical, personal, and economic terms. Carers are vital to maintaining the quality of life (QOL) of people with dementia. This review aims to identify factors related to the QOL of family carers of people with dementia. METHODS: Searches on terms including "carers," "dementia," "family," and "quality of life" in research databases. Findings were synthesized inductively, grouping factors associated with carer QOL into themes. RESULTS: A total of 909 abstracts were identified. Following screening, lateral searches, and quality appraisal, 41 studies (n = 5539) were included for synthesis. A total of 10 themes were identified: demographics; carer-patient relationship; dementia characteristics; demands of caring; carer health; carer emotional well-being; support received; carer independence; carer self-efficacy; and future. DISCUSSION: The quality and level of evidence supporting each theme varied. We need further research on what factors predict carer QOL in dementia and how to measure it.

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. METHODS: We used standard searches to find publications using ADNI data. RESULTS: (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy…

Abstract This article updates the Calcium Hypothesis of Alzheimer's disease and brain aging on the basis of emerging evidence since 1994 (The present article, with the subtitle “New evidence for a central role of Ca2+ in neurodegeneration,” includes three appendices that provide context and further explanations for the rationale for the revisions in the updated hypothesis—the three appendices are as follows: Appendix I “Emerging concepts on potential pathogenic roles of [Ca2+],” Appendix II “Future studies to validate the central role of dysregulated [Ca2+] in neurodegeneration,” and Appendix III “Epilogue: towards a comprehensive hypothesis.”) (Marx J. Fresh evidence points to an old suspect: calcium. Science 2007; 318:384–385). The aim is not only to re‐evaluate the original key claims of the hypothesis with a critical eye but also to identify gaps in knowledge required to validate relevant claims and delineate additional studies and/or data that are needed. Some of the key challenges for this effort included examination of questions regarding (1) the temporal and spatial…

INTRODUCTION: Profiling the spatial-temporal expression pattern and characterizing the regulatory networks of brain tissues are vital for understanding the pathophysiology of Alzheimer's disease (AD). METHODS: We performed a systematic integrated analysis of expression profiles of AD-affected brain tissues (684 AD and 562 controls). A network-based convergent functional genomic approach was used to prioritize possible regulator genes during AD development, followed by functional characterization. RESULTS: We generated a complete list of differentially expressed genes and hub genes of the transcriptomic network in AD brain and constructed a Web server (www.alzdata.org) for public access. Seventeen hub genes active at the early stages, especially YAP1, were recognized as upstream regulators of the AD network. Cellular assays proved that early alteration of YAP1 could promote AD by influencing the whole transcriptional network. DISCUSSION: Early expression disturbance of hub genes is an important feature of AD development, and interfering with this process may reverse the disease…

The brain is highly enriched in lipids, and an intensive study of these lipids may be informative, not only of normal brain function but also of changes with age and in disease. In recent years, the development of highly sensitive mass spectrometry platforms and other high-throughput technologies has enabled the discovery of complex changes in the entire lipidome. This lipidomics approach promises to be a particularly useful tool for identifying diagnostic biomarkers for early detection of age-related neurodegenerative disease, such as Alzheimer's disease (AD), which has till recently been limited to protein- and gene-centric approaches. This review highlights known lipid changes affecting the AD brain and presents an update on the progress of lipid biomarker research in AD. Important considerations for designing large-scale lipidomics experiments are discussed to help standardize findings across different laboratories, as well as challenges associated with moving toward clinical application.

INTRODUCTION: Cortical mean diffusivity (MD) and free water fraction (FW) changes are proposed biomarkers for Alzheimer's disease (AD). METHODS: We included healthy control subjects (N = 254), mild cognitive impairment (N = 41), and AD dementia (N = 31) patients. Participants underwent a lumbar puncture and a 3 T magnetic resonance imaging. Healthy control subjects were classified following National Institute on Aging-Alzheimer's Association stages (stage 0, N = 220; stage 1, N = 25; and stage 2/3, N = 9). We assessed the cortical MD, cortical FW, and cortical thickness (CTh) changes along the AD continuum. RESULTS: Microstructural and macrostructural changes show a biphasic trajectory. Stage 1 subjects showed increased CTh and decreased MD and FW with respect the stage 0 subjects. Stage 2/3 subjects showed decreased CTh and increased cortical MD and FW, changes that were more widespread in symptomatic stages. DISCUSSION: These results support a biphasic model of changes in AD, which could affect the selection of patients for clinical trials and the use of magnetic resonance imaging…

INTRODUCTION: Sensitive detection of cognitive decline over the course of preclinical Alzheimer's disease is critical as the field moves toward secondary prevention trials. METHODS: We examined amyloid β (Aβ)-related change in several variations of the preclinical Alzheimer cognitive composite (PACC) and each individual PACC component in clinically normal (CN) older participants in the Harvard Aging Brain Study. We then examined the PACC variations in the Alzheimer's Disease Cooperative Study Prevention Instrument Study as a replication cohort. RESULTS: Aβ+ CN individuals demonstrated longitudinal decline on all individual PACC components and all PACC variations. Aβ group differences emerged earlier when Free and Cued Selective Reminding Test Free Recall was included in the PACC. PACC decline was associated with Clinical Dementia Rating progression. DISCUSSION: This independent data set and a replication cohort confirm the ability of the PACC to capture both early and late cognitive decline during the preclinical stages of Alzheimer's disease, which may prove advantageous in the…

INTRODUCTION: This study tested the hypotheses that late-midlife obstructive sleep apnea (OSA) and short and long sleep duration are associated with dementia over 15 years of follow-up. METHODS: A total of 1667 Atherosclerosis Risk in Communities Study participants underwent in-home polysomnography (1996-1998) and were followed for dementia. Dementia was defined by (1) hospitalization diagnosis codes (1996-2012) and (2) a comprehensive neurocognitive examination (2011-2013) with adjudication. RESULTS: OSA and sleep duration were not associated with risk of incident dementia. When using adjudicated outcomes, severe OSA (≥30 vs. <5 apnea-hypopnea events/hour) was associated with higher risk of all-cause dementia (risk ratio [95% confidence interval], 2.35 [1.06-5.18]) and Alzheimer's disease dementia (1.66 [1.03-2.68]); associations were attenuated with cardiovascular risk factor adjustment. Sleeping <7 versus 8 to ≤9 hours was associated with higher risk of all-cause dementia (2.00 [1.03-3.86]). DISCUSSION: When adjudicated outcome definitions were used, late-midlife OSA and short…

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for…

INTRODUCTION: We investigated the association between age of onset of hypertension and dementia risk in an oldest-old cohort. METHODS: Participants are from The 90+ Study, a population-based longitudinal study of people aged 90+ who are survivors from the Leisure World Cohort Study. We estimated hypertension onset age using self-reported information from The 90+ Study and Leisure World Cohort Study, collected about 20 years earlier. A total of 559 participants without dementia were followed every 6 months for up to 10 years. RESULTS: A total of 224 participants developed dementia during follow-up (mean = 2.8 years). Compared with those without hypertension, participants whose hypertension onset age was 80 to 89 years had a lower dementia risk (hazard ratio = 0.58, P = .04) and participants with an onset age of 90+ years had the lowest risk (hazard ratio = 0.37, P = .004). DISCUSSION: Developing hypertension at older ages may protect against dementia. Understanding the mechanisms for this lower risk is important for determining ways to prevent dementia in the very elderly.

INTRODUCTION: The relative contributions of vascular and degenerative pathology to dementia are unknown. We aim to quantify the proportion of dementia explained by potentially preventable vascular lesions. METHODS: We systematically searched for population-based cohorts before February 2017 reporting clinicopathological data for individuals with and without dementia. We calculated the summary proportion and absolute risk of dementia comparing subjects with and without the pathology. RESULTS: We identified 10 studies comprising 2856 subjects. Vascular-type pathology and mixed pathology are respectively two and three times more likely in demented patients. The summary proportion of dementia is 77%-86% in subjects with mixed degenerative and vascular pathology and 45% in subjects with pure Alzheimer-type pathology. DISCUSSION: Patients with mixed pathologies have nearly twice the incremental risk of dementia compared with patients with only Alzheimer-type lesions. Consequently, many cases of dementia could be prevented or delayed by targeting the vascular component.

INTRODUCTION: Hypovitaminosis D has been associated with several chronic conditions; yet, its association with cognitive decline and the risk of dementia and Alzheimer's disease (AD) has been inconsistent. METHODS: The study population consisted of 916 participants from the Three-City Bordeaux cohort aged 65+, nondemented at baseline, with assessment of vitamin D status and who were followed for up to 12 years. RESULTS: In multivariate analysis, compared with individuals with 25(OH)D sufficiency (n = 151), participants with 25(OH)D deficiency (n = 218) exhibited a faster cognitive decline. A total of 177 dementia cases (124 AD) occurred: 25(OH)D deficiency was associated with a nearly three-fold increased risk of AD (hazard ratio = 2.85, 95% confidence interval 1.37-5.97). DISCUSSION: This large prospective study of French older adults suggests that maintaining adequate vitamin D status in older age could contribute to slow down cognitive decline and to delay or prevent the onset of dementia, especially of AD etiology.

INTRODUCTION: Existing studies predominantly consider the association of late-life lipid levels and subsequent cognitive change. However, midlife rather than late-life risk factors are often most relevant to cognitive health. METHODS: We quantified the association between measured serum lipids in midlife and subsequent 20-year change in performance on three cognitive tests in 13,997 participants of the Atherosclerosis Risk in Communities study. RESULTS: Elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides were associated with greater 20-year decline on a test of executive function, sustained attention, and processing speed. Higher total cholesterol and triglycerides were also associated with greater 20-year decline in memory scores and a measure summarizing performance on all three tests. High-density lipoprotein cholesterol was not associated with cognitive change. Results were materially unchanged in sensitivity analyses addressing informative missingness. DISCUSSION: Elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides…

INTRODUCTION: Comparative transcriptome analyses in Alzheimer's disease (AD) and other neurodegenerative proteinopathies can uncover both shared and distinct disease pathways. METHODS: We analyzed 940 brain transcriptomes including patients with AD, progressive supranuclear palsy (PSP; a primary tauopathy), and control subjects. RESULTS: We identified transcriptional coexpression networks implicated in myelination, which were lower in PSP temporal cortex (TCX) compared with AD. Some of these associations were retained even after adjustments for brain cell population changes. These TCX myelination network structures were preserved in cerebellum but they were not differentially expressed in cerebellum between AD and PSP. Myelination networks were downregulated in both AD and PSP, when compared with control TCX samples. DISCUSSION: Downregulation of myelination networks may underlie both PSP and AD pathophysiology, but may be more pronounced in PSP. These data also highlight conservation of transcriptional networks across brain regions and the influence of cell type changes on these…

INTRODUCTION: An animal model of late-onset Alzheimer's disease is needed to research what causes degeneration in the absence of dominant genetic insults and why the association cortex is particularly vulnerable to degeneration. METHODS: We studied the progression of tau and amyloid cortical pathology in the aging rhesus macaque using immunoelectron microscopy and biochemical assays. RESULTS: Aging macaques exhibited the same qualitative pattern and sequence of tau and amyloid cortical pathology as humans, reaching Braak stage III/IV. Pathology began in the young-adult entorhinal cortex with protein kinase A-phosphorylation of tau, progressing to fibrillation with paired helical filaments and mature tangles in oldest animals. Tau pathology in the dorsolateral prefrontal cortex paralleled but lagged behind the entorhinal cortex, not afflicting the primary visual cortex. DISCUSSION: The aging rhesus macaque provides the long-sought animal model for exploring the etiology of late-onset Alzheimer's disease and for testing preventive strategies.

Abstract Objective To determine whether the extent of overlap of the genetic architecture among the sporadic late‐onset Alzheimer's Disease (sLOAD), familial late‐onset AD (fLOAD), sporadic early‐onset AD (sEOAD), and autosomal dominant early‐onset AD (eADAD). Methods Polygenic risk scores (PRSs) were constructed using previously identified 21 genome‐wide significant loci for LOAD risk. Results We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10 −7 ) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10 −7 ) and sLOAD (OR = 1.40; P = 1.21 × 10 −3 ). The PRS was associated with cerebrospinal fluid ptau 181 ‐Aβ 42 on eADAD ( P = 4.36 × 10 −2 ). Conclusion Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not…

INTRODUCTION: This systematic review synthesizes current evidence for associations between cortical amyloid β, visualized on amyloid positron emission tomography imaging, and white matter hyperintensity (WMH) burden on magnetic resonance imaging in healthy elderly adults and individuals with cognitive impairment and dementia. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) systematic review guidelines, we systematically searched MEDLINE, Embase, Cochrane, and PsycINFO databases from January 2000 to September 2015. RESULTS: Our search returned 492 articles, 34 of which met criteria for inclusion in the final selection. Most studies reported no significant relationships between amyloid β and WMH burden across diagnostic groups. DISCUSSION: Findings of this systematic review suggest that amyloid accumulation and WMH are independent but additive processes. The limited number of independent cohorts, lack of longitudinal data, and exclusion of individuals with mixed dementia limit the generalizability of these findings. Further studies are…

Abstract Introduction The identification of novel biomarkers associated with Alzheimer's disease (AD) could provide key biological insights and permit targeted preclinical prevention. We investigated circulating metabolites associated with incident dementia and AD using metabolomics. Methods Plasma levels of 217 metabolites were assessed in 2067 dementia‐free Framingham Offspring Cohort participants (mean age = 55.9 ± 9.7 years; 52.4% women). We studied their associations with future dementia and AD risk in multivariate Cox models. Results Ninety‐three participants developed incident dementia (mean follow‐up = 15.6 ± 5.2 years). Higher plasma anthranilic acid levels were associated with greater risk of dementia (hazard ratio [HR] = 1.40; 95% confidence interval [CI] = [1.15–1.70]; P = 8.08 × 10−4). Glutamic acid (HR = 1.38; 95% CI = [1.11–1.72]), taurine (HR = 0.74; 95% CI = [0.60–0.92]), and hypoxanthine (HR = 0.74; 95% CI = [0.60–0.92]) levels also showed suggestive associations with dementia risk. Discussion We identified four biologically plausible, candidate plasma biomarkers…

INTRODUCTION: Alzheimer apolipoprotein E (APOE) ɛ4/ɛ4 carriers have earlier disease onset and more protein aggregates than patients with other APOE genotypes. Autophagy opposes aggregation, and important autophagy genes are coordinately regulated by transcription factor EB (TFEB) binding to "coordinated lysosomal expression and regulation" (CLEAR) DNA motifs. METHODS: Autophagic gene expression was assessed in brains of controls and Alzheimer's disease (AD) patients parsed by APOE genotype and in a glioblastoma cell line expressing either apoE3 or apoE4. Computational modeling assessed interactions between apoE and mutated apoE with CLEAR or modified DNA. RESULTS: Three TFEB-regulated mRNA transcripts-SQSTM, MAP1LC3B, and LAMP2-were lower in AD ɛ4/ɛ4 than in AD ɛ3/ɛ3 brains. Computational modeling predicted avid specific binding of apoE4 to CLEAR motifs. ApoE was found in cellular nuclei, and in vitro binding assays suggest competition between apoE4 and TFEB at CLEAR sites. CONCLUSION: ApoE4-CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this…

Abstract Introduction We examined whether cortical microvascular blood volume and hemodynamics in Alzheimer's disease (AD) are consistent with tissue hypoxia and whether they correlate with cognitive performance and the degree of cortical thinning. Methods Thirty‐two AD patients underwent cognitive testing, structural magnetic resonance imaging (MRI), and perfusion MRI at baseline and after 6 months. We measured cortical thickness, microvascular cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and capillary transit time heterogeneity (CTH) and estimated tissue oxygen tension (P t O 2 ). Results At baseline, poor cognitive performance and regional cortical thinning correlated with lower CBF and CBV, with higher MTT and CTH and with low P t O 2 across the cortex. Cognitive decline over time was associated with increasing whole brain relative transit time heterogeneity (RTH = CTH/MTT). Discussion Our results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate…

INTRODUCTION: The Mediterranean and Dietary Approaches to Stop Hypertension diets have been associated with lower dementia risk. We evaluated dietary inflammatory potential in relation to mild cognitive impairment (MCI)/dementia risk. METHODS: Baseline food frequency questionnaires from n = 7085 women (aged 65-79 years) were used to calculate Dietary Inflammatory Index (DII) scores that were categorized into four groups. Cognitive function was evaluated annually, and MCI and all-cause dementia cases were adjudicated centrally. Mixed effect models evaluated cognitive decline on over time; Cox models evaluated the risk of MCI or dementia across DII groups. RESULTS: Over an average of 9.7 years, there were 1081 incident cases of cognitive impairment. Higher DII scores were associated with greater cognitive decline and earlier onset of cognitive impairment. Adjusted hazard ratios (HRs) comparing lower (anti-inflammatory; group 1 referent) DII scores to the higher scores were group 2-HR: 1.01 (0.86-1.20); group 3-HR: 0.99 (0.82-1.18); and group 4-HR: 1.27 (1.06-1.52). CONCLUSIONS: Diets…

INTRODUCTION: To examine the risk of Alzheimer's disease (AD) among cancer survivors in a national database. METHODS: Retrospective cohort of 3,499,378 mostly male US veterans aged ≥65 years were followed between 1996 and 2011. We used Cox models to estimate risk of AD and alternative outcomes (non-AD dementia, osteoarthritis, stroke, and macular degeneration) in veterans with and without a history of cancer. RESULTS: Survivors of a wide variety of cancers had modestly lower AD risk, but increased risk of the alternative outcomes. Survivors of screened cancers, including prostate cancer, had a slightly increased AD risk. Cancer treatment was independently associated with decreased AD risk; those who received chemotherapy had a lower risk than those who did not. DISCUSSION: Survivors of some cancers have a lower risk of AD but not other age-related conditions, arguing that lower AD diagnosis is not simply due to bias. Cancer treatment may be associated with decreased risk of AD.

In the history of medicine, one means to progress is when we make the decision that our assumptions and definitions of disease are no longer consistent with the scientific evidence, and no longer serve our health care needs. The arc of scientific progress is now requiring a change in how we diagnose Alzheimer's disease. Both the National Institute on Aging-Alzheimer's Association (NIA-AA) 2011 workgroup and the International Work Group (IWG) have proposed guidelines that use detectable measures of biological changes in the brain, commonly known as biological markers, or biomarkers, as part of the diagnosis. This Special Report examines how the development and validation of Alzheimer's disease biomarkers-including those detectable in the blood or cerebral spinal fluid, or through neuroimaging-is a top research priority. This has the potential to markedly change how we diagnose Alzheimer's disease and, as a result, how we count the number of people with this disease. As research advances a biomarker-based method for diagnosis and treatment at the earliest stages of Alzheimer's…

INTRODUCTION: DNA methylation is a key epigenetic mechanism in brain aging and Alzheimer's disease (AD). The newly discovered 5-hydroxymethylcytosine mediates DNA demethylation, is highly abundant in the brain, and is dynamically regulated by life experiences. However, little is known about its genome-wide patterns and potential role in AD. METHODS: Using a genome-wide capture followed by high-throughput sequencing, we studied the genome-wide distribution of 5-hydroxymethylcytosine at specific genomic loci in human AD brain and identified differentially hydroxymethylated regions (DhMRs) associated with AD pathology. RESULTS: We identified 517 DhMRs significantly associated with neuritic plaques and 60 DhMRs associated with neurofibrillary tangles. DNA hydroxymethylation in gene bodies was predominantly positively correlated with cis-acting gene expression. Moreover, genes showing differential hydroxymethylation were significantly enriched in neurobiological processes and clustered in functional gene ontology categories. DISCUSSION: Our results reveal a critical role of DNA…

INTRODUCTION: Information on anticipated survival time after dementia diagnosis among racially/ethnically diverse patients is needed to plan for care and evaluate disparities. METHODS: Dementia-free health care members aged ≥64 years were followed (1/1/2000-12/31/2013) for dementia diagnosis and subsequent survival (n = 23,032 Asian American; n = 18,778 African American; n = 21,000 Latino; n = 4543 American Indian/Alaska Native; n = 206,490 white). Kaplan-Meier curves were estimated for survival after dementia diagnosis by race/ethnicity. We contrasted mortality patterns among people with versus without dementia using Cox proportional hazards models. RESULTS: After dementia diagnosis (n = 59,494), whites had shortest median survival (3.1 years), followed by American Indian/Alaska Natives (3.4 years), African Americans (3.7 years), Latinos (4.1 years), and Asian Americans (4.4 years). Longer postdiagnosis survival among racial/ethnic minorities compared with whites persisted after adjustment for comorbidities. Racial/ethnic mortality inequalities among dementia patients mostly…

INTRODUCTION: We sought to assess the individual and combined contribution of limbic and neocortical α-synuclein, tau, and amyloid β (Aβ) to duration of illness in dementia with Lewy bodies (DLB). METHODS: Quantitative digital pathology of limbic and neocortical α-synuclein, tau, and Aβ was assessed in 49 patients with clinically probable DLB. Regression modeling examined the unique and shared contribution of each pathology to the variance of illness duration. RESULTS: Patients with diffuse Lewy body disease had more severe pathology of each type and a shorter duration of illness than individuals with transitional Lewy body disease. The three pathologies accounted for 25% of the total variance of duration of illness, with 19% accounted for by α-synuclein alone or in combination with tau and Aβ. When the diffuse Lewy body disease group was examined separately, α-synuclein deposition significantly exceeded that of tau and Aβ. In this model, 20% of 24% total variance in the model for duration of illness was accounted for independently by α-synuclein. DISCUSSION: In DLB, α-synuclein is…

INTRODUCTION: Post-traumatic stress disorder (PTSD) is associated with an increased risk of dementia in male veterans, but little is known in females and civilians. METHODS: PTSD and comorbidities were abstracted from medical records from 1/1/1996 to 12/31/2001. Dementia incidence from 1/1/2002 to 12/31/2014 in 499,844 health care members aged 60+ years over an average of 8.2 years. Cox proportional hazard models were adjusted for age, demographics, and comorbidities. RESULTS: PTSD was associated with increased risk of dementia over an average of 8 years of follow-up (females: hazard ratio [HR] = 1.59, 95% confidence interval [CI] = 1.30-1.95; males: HR = 1.96, 95% CI = 1.51-2.55). There was a two-fold risk of dementia in those with both PTSD and depression (females: HR = 2.08; 95% CI = 1.66-2.59; males: HR = 2.06; 95% CI = 1.47-2.91) versus those without. DISCUSSION: PTSD was a risk factor for dementia in both sexes, with a heightened risk in those with comorbid depression.

INTRODUCTION: Misfolded tau and amyloid β (Aβ) proteins progressively accumulate in the human brain, causing altered neuronal function and neurodegeneration. This study sought to investigate whether the wide spectrum of functional reorganization in aging brains of cognitively normal individuals relates to specific pathological patterns of tau and Aβ deposits. METHODS: We used functional connectivity neuroimaging and in vivo tau and Aβ positron emission tomography scans to study cortical spatial relationships between imaging modalities. RESULTS: We found that a negative association between tau and functional connectivity combined with a positive association between Aβ and functional connectivity is the most frequent cortical pattern among elderly subjects. Moreover, we found specific brain areas that interrelate hypoconnectivity and hyperconnectivity regions. DISCUSSION: Our findings have critical implications to understanding how the two main elements of Alzheimer's disease-related pathology affect the aging brain and how they cause alterations in large-scale neuronal circuits.

INTRODUCTION: Synapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid β (Aβ) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aβ induces Dickkopf-1 (Dkk1), which in turn activates the Wnt-planar cell polarity (Wnt-PCP) pathway to drive tau pathology and neuronal death. METHODS: We compared the effects of Aβ and of Dkk1 on synapse morphology and memory impairment while inhibiting or silencing key elements of the Wnt-PCP pathway. RESULTS: We demonstrate that Aβ synaptotoxicity is also Dkk1 and Wnt-PCP dependent, mediated by the arm of Wnt-PCP regulating actin cytoskeletal dynamics via Daam1, RhoA and ROCK, and can be blocked by the drug fasudil. DISCUSSION: Our data add to the importance of aberrant Wnt signaling in Alzheimer's disease neuropathology and indicate that fasudil could be repurposed as a treatment for the disease.

INTRODUCTION: Although biomarker studies of late-onset Alzheimer's disease suggest pathology to be present decades before diagnosis, little is known about cognitive performance at this stage. METHODS: A sample of 210 adults (aged 40-59) of whom 103 have a parent diagnosed with dementia (family history subgroup) underwent computerized cognitive testing. Apolipoprotein E (apoE) status was determined, and 193 subjects had magnetic resonance imaging. Distance from dementia onset was estimated in relation to age of parental diagnosis, and Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Scores were calculated. RESULTS: Lower hippocampal volumes (P = .04) were associated with poorer spatial location recall and higher Dementia Risk Scores with poorer visual recognition (P = .0005), and lower brain and hippocampal volume (P < .0001, P = .04, respectively). Family history subgroup participants closer to dementia onset had lower scores on visual working memory (P = .05), whereas those with an APOE ε4 allele performed better on form perception (P = .005). DISCUSSION:…

INTRODUCTION: A national consensus panel was convened to develop recommendations on future directions for home-based dementia care (HBDC). METHODS: The panel summarized advantages and challenges of shifting to HBDC as the nexus of care and developed consensus-based recommendations. RESULTS: The panel developed five core recommendations: (1) HBDC should be considered the nexus of new dementia models, from diagnosis to end of life in dementia; (2) new payment models are needed to support HBDC and reward integration of care; (3) a diverse new workforce that spans the care continuum should be prepared urgently; (4) new technologies to promote communication, monitoring/safety, and symptoms management must be tested, integrated, and deployed; and (5) targeted dissemination efforts for HBDC must be employed. DISCUSSION: HBDC represents a promising paradigm shift to improve care for those living with dementia and their family caregivers: these recommendations provide a framework to chart a course forward for HBDC.

INTRODUCTION: The aim was to examine associations between midlife cardiovascular health (CVH) and 20-year cognitive decline among blacks and whites. METHODS: Midlife CVH metrics (American Heart Association's Life's Simple 7) were calculated and examined in relation to midlife and 20-year change in cognitive function among 13,270 whites and blacks from the Atherosclerosis Risk in Communities Cohort Study. We used linear mixed models to estimate adjusted associations of midlife CVH with midlife cognitive status and change. RESULTS: Higher midlife (Life's Simple 7) scores and individual metrics, particularly blood pressure and glucose, were associated with better midlife cognition and reduced 20-year decline. Midlife CVH 20-year neuroprotection was more pronounced among whites than blacks. DISCUSSION: Better midlife CVH was associated with higher midlife and reduced decline in cognitive function 20 years later. However, the benefits of midlife CVH on cognition were stronger for whites than for blacks. Our findings suggest that improved midlife CVH may promote enduring cognitive health.

INTRODUCTION: Tau-mediated toxicity in Alzheimer's disease is thought to operate through low-n oligomers, rather than filamentous aggregates. However, the nature of oligomers and pathways of toxicity are poorly understood. Therefore, we investigated structural and functional aspects of highly purified oligomers of a pro-aggregant tau species. METHODS: Purified oligomers of the tau repeat domain were characterized by biophysical and structural methods. Functional aspects were investigated by cellular assays ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of cell viability, lactate dehydrogenase release assay [for cell toxicity], reactive oxygen species production, and calcium assay), combined with analysis of neuronal dendritic spines exposed to oligomers. RESULTS: Purified low-n oligomers are roughly globular, with sizes around 1.6 to 5.4 nm, exhibit an altered conformation, but do not have substantial β-structure. Treatment of primary neurons with oligomers impairs spine morphology and density, accompanied by increased reactive oxygen species and intracellular…

Dementia is a major public health issue with rising prevalence rates, but many individuals remain undiagnosed. Accurate and timely diagnosis is key for the optimal targeting of interventions. A noninvasive, easily measurable peripheral biomarker would have greatest utility in population-wide diagnostic screening. Epigenetics, including DNA methylation, is implicated in dementia; however, it is unclear whether epigenetic changes can be detected in peripheral tissue. This study aimed to systematically review the evidence for an association between dementia and peripheral DNA methylation. Forty-eight studies that measured DNA methylation in peripheral blood were identified, and 67% reported significant associations with dementia. However, most studies were underpowered and limited by their case-control design. We emphasize the need for future longitudinal studies on large well-characterized populations, measuring epigenetic patterns in asymptomatic individuals. A biomarker detectable in the preclinical stages of the disease would have the greatest utility in future intervention and…

Patient registries are valuable tools helping to address significant challenges in research, care, and policy. Registries, well embedded in many fields of medicine and public health, are relatively new in dementia. This systematic review presents the current situation in regards to dementia registries worldwide. We identified 31 dementia registries operating on an international, national, or local level between 1986 and 2016. More than half of the registries aimed to conduct or facilitate research, including preclinical research registries and registries recruiting research volunteers. Other dementia registries collected epidemiological or quality of care data. We present evidence of practical and economic outcomes of registries for research, clinical practice and policy, and recommendations for future development. Global harmonization of recruitment methods and minimum data would facilitate international comparisons. Registries provide a positive return on investment; their establishment and maintenance require ongoing support by government, policy makers, research funding bodies,…

INTRODUCTION: The etiologies of dementia are complex and influenced by genetic and environmental factors including medical conditions. METHODS: We used Cox regression model to estimate the individual and joint effects of physical activity (PA), apolipoprotein E (APOE) ε4, and diabetes status on risk of dementia and cognitive impairment without dementia (CIND) among 1438 cognitively intact Mexican American elderly who were followed up to 10 years. RESULTS: The risk of developing dementia/CIND was increased more than threefold in APOE ε4 carriers or diabetics with low levels of PA compared with ε4 noncarriers or nondiabetics who engaged in high PA (ε4: hazard ratio [HR] = 3.44, 95% confidence interval [CI] = 1.85-6.39; diabetes: HR = 3.11, 95% CI = 1.87-5.18); the presence of all three risk factors increased risk by nearly 10-fold (HR = 9.49, 95% CI = 3.57-25.3). DISCUSSION: PA in elderly Hispanics protects strongly against the onset of dementia/CIND, especially in APOE ε4 carriers and those who have diabetes.

INTRODUCTION: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). METHODS: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid β (Aβ) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). RESULTS: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in Aβ040 levels between groups or between subjects with and without CAA. DISCUSSION: CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid Aβ40 levels are not a useful biomarker for CAA in AD.

INTRODUCTION: The International Working Group recommended the Free and Cued Selective Reminding Test (FCSRT) as a sensitive detector of the amnesic syndrome of the hippocampal type in typical Alzheimer's disease (AD). But does it differentiate AD from other neurodegenerative diseases? METHODS: We assessed the FCSRT and cerebrospinal fluid (CSF) AD biomarkers in 992 cases. Experts, blinded to biomarker data, attributed in 650 cases a diagnosis of typical AD, frontotemporal dementia, posterior cortical atrophy, Lewy body disease, progressive supranuclear palsy, corticobasal syndrome, primary progressive aphasias, "subjective cognitive decline," or depression. RESULTS: The FCSRT distinguished typical AD from all other conditions with a sensitivity of 100% and a specificity of 75%. Non-AD neurodegenerative diseases with positive AD CSF biomarkers ("atypical AD") did not have lower FCSRT scores than those with negative biomarkers. DISCUSSION: The FCSRT is a reliable tool for diagnosing typical AD among various neurodegenerative diseases. At an individual level, however, its specificity…

INTRODUCTION: Alzheimer's disease and diabetes mellitus are linked by epidemiology, genetics, and molecular pathogenesis. They may also be linked by the remarkable observation that insulin signaling sets the limits on longevity. In worms, flies, and mice, disrupting insulin signaling increases life span leading to speculation that caloric restriction might extend life span in man. It is our contention that man is already a long-lived organism, specifically with a remarkably high postfertility life span, and that it is this that results in the prevalence of Alzheimer's disease and diabetes. METHODS: We review evidence for this hypothesis that carries specific predictions including that other animals with exceptionally long postreproductive life span will have increased risk of both diabetes and Alzheimer's disease. RESULTS AND CONCLUSIONS: We present novel evidence that Dolphin, like man, an animal with exceptional longevity, might be one of the very few natural models of Alzheimer's disease.

INTRODUCTION: Patients with Alzheimer's disease (AD) show heterogeneity in profile of cognitive impairment. We aimed to identify cognitive subtypes in four large AD cohorts using a data-driven clustering approach. METHODS: We included probable AD dementia patients from the Amsterdam Dementia Cohort (n = 496), Alzheimer's Disease Neuroimaging Initiative (n = 376), German Dementia Competence Network (n = 521), and University of California, San Francisco (n = 589). Neuropsychological data were clustered using nonnegative matrix factorization. We explored clinical and neurobiological characteristics of identified clusters. RESULTS: In each cohort, a two-clusters solution best fitted the data (cophenetic correlation >0.9): one cluster was memory-impaired and the other relatively memory spared. Pooled analyses showed that the memory-spared clusters (29%-52% of patients) were younger, more often apolipoprotein E (APOE) ɛ4 negative, and had more severe posterior atrophy compared with the memory-impaired clusters (all P < .05). CONCLUSIONS: We could identify two robust cognitive clusters in…

INTRODUCTION: Dementia may be associated with discontinuation of regular dental checkups, which in turn results in poorer oral health. METHODS: We investigated the trend of change in dental care utilization and the number of teeth before and after being diagnosed with dementia. Longitudinal cognitive- and dental health-related information were merged using data on 58,037 newly diagnosed individuals from the Swedish Dementia Registry and Swedish Dental Health Register during 2007 to 2015. RESULTS: Following dementia diagnosis, rate of dental care visits significantly declined. Individuals with mixed dementia, dementia with parkinsonism, and those with more severe and faster cognitive impairment had significantly higher rate of decline in dental care utilization. Vascular dementia and lower baseline Mini-Mental State Examination score were significant predictors of faster loss of teeth. DISCUSSION: Dental care utilization markedly declines following dementia diagnosis. The reduction is more prominent in those with rapid progressive cognitive impairment and the ones with extra frailty…

INTRODUCTION: Disclosing amyloid status to cognitively normal individuals remains controversial given our lack of understanding the test's clinical significance and unknown psychological risk. METHODS: We assessed the effect of amyloid status disclosure on anxiety and depression before disclosure, at disclosure, and 6 weeks and 6 months postdisclosure and test-related distress after disclosure. RESULTS: Clinicians disclosed amyloid status to 97 cognitively normal older adults (27 had elevated cerebral amyloid). There was no difference in depressive symptoms across groups over time. There was a significant group by time interaction in anxiety, although post hoc analyses revealed no group differences at any time point, suggesting a minimal nonsustained increase in anxiety symptoms immediately postdisclosure in the elevated group. Slight but measureable increases in test-related distress were present after disclosure and were related to greater baseline levels of anxiety and depression. DISCUSSION: Disclosing amyloid imaging results to cognitively normal adults in the clinical research…

Abstract Introduction Biomarkers that identify individuals at risk of Alzheimer's disease (AD) development would be highly valuable. Plasma concentration of amyloid β (Aβ)—central in the pathogenesis of AD—is a logical candidate, but studies to date have produced conflicting results on its utility. Methods Plasma samples from 339 preclinical AD cases (76.4% women, mean age 61.3 years) and 339 age‐ and sex‐matched dementia‐free controls, taken an average of 9.4 years before AD diagnosis, were analyzed using Luminex xMAP technology and INNO‐BIA plasma Aβ form assays to determine concentrations of free plasma Aβ40 and Aβ42. Results Plasma concentrations of free Aβ40 and Aβ42 did not differ between preclinical AD cases and dementia‐free controls, in the full sample or in subgroups defined according to sex and age group (<60 and ≥ 60 years). The interval between sampling and AD diagnosis did not affect the results. Aβ concentrations did not change in the years preceding AD diagnosis among individuals for whom longitudinal samples were available. Discussion Plasma concentrations of free…

Preclinical Alzheimer's disease (AD) is a relatively recent concept describing an entity characterized by the presence of a pathophysiological biomarker signature characteristic for AD in the absence of specific clinical symptoms. There is rising interest in the scientific community to define such an early target population mainly because of failures of all recent clinical trials despite evidence of biological effects on brain amyloidosis for some compounds. A conceptual framework has recently been proposed for this preclinical phase of AD. However, few data exist on this silent stage of AD. We performed a systematic review to investigate how the concept is defined across studies. The review highlights the substantial heterogeneity concerning the three main determinants of preclinical AD: "normal cognition," "cognitive decline," and "AD pathophysiological signature." We emphasize the need for a harmonized nomenclature of the preclinical AD concept and standardized population-based and case-control studies using unified operationalized criteria.

In May 2017, the World Health Assembly adopted the global action plan on the public health response to dementia 2017–2025. The plan envisions “a world in which dementia is prevented and people with dementia and their carers live well and receive the care and support they need to fulfil their potential with dignity, respect, autonomy and equality.” It provides a comprehensive blueprint for action in seven strategic areas: making dementia a public health priority; increasing dementia awareness and establishing a dementia-friendly society; reducing the risk of dementia; improving diagnosis, treatment and care for people with dementia; supporting dementia carers; enhancing information systems for dementia and fostering dementia research and innovation. The plan highlights the importance of protecting and promoting human rights, providing community-based care and support, need for a multisectoral response to dementia by integrating health and social care approaches, and aligning dementia actions with those for mental health, noncommunicable diseases, ageing and disability. To move the…

INTRODUCTION: We examined mortality, dementia, and progression of hydrocephalic symptoms among untreated individuals with idiopathic normal-pressure hydrocephalus (iNPH) in a population-based sample. METHODS: A total of 1235 persons were examined between 1986 and 2012. Shunted individuals were excluded. We examined 53 persons with hydrocephalic ventricular enlargement (probable iNPH: n = 24, asymptomatic or possible iNPH: n = 29). Comparisons were made with individuals without hydrocephalic ventricular enlargement. RESULTS: The 5-year mortality was 87.5% among those with probable iNPH. The hazard ratio (HR) for death was 3.8 (95% confidence interval [CI]: 2.5-6.0) for probable iNPH. Those with possible iNPH and asymptomatic hydrocephalic ventricular enlargement had increased risk of developing dementia, HR 2.8 (95% CI: 1.5-5.2). Only two individuals with hydrocephalic ventricular enlargement remained asymptomatic. DISCUSSION: In the present sample, persons with clinical and imaging signs of iNPH had excess mortality and an increased risk of dementia. The data also suggest that…

Abstract Introduction In recent prospective studies, low plasma levels of apolipoprotein E (apoE) are associated with high risk of dementia. Whether this reflects a causal association remains to be established. Methods Using a Mendelian randomization approach, we studied 106,562 and 75,260 individuals from the general population in observational and genetic analyses, respectively. Results In observational analyses risk of Alzheimer's disease and all dementia increased stepwise as a function of stepwise lower apoE levels (P for trend, 2 × 10−17 and 9 × 10−21). APOE‐weighted allele scores were associated with stepwise decreases in apoE (P for trend, <1 × 10−300). In instrumental variable analysis, the causal risk ratios for a 1 mg/dL genetically determined lower apoE were 1.41 (1.27–1.57) for Alzheimer's disease and 1.33 (1.25–1.43) for all dementia (F‐statistics = 3821). Discussion Genetic and hence lifelong low apoE is associated with high risk of dementia in the general population. The concordance between observational and genetic estimates suggests a potential causal relationship.

Abstract Introduction We aimed to investigate factors defining amyloid β (1–42) (Aβ1–42) adsorption during preanalytical workup of cerebrospinal fluid (CSF). Methods CSF was transferred to new tubes ≤4 times. Variables tested were different polypropylene tube brands, volumes, CSF Aβ1–42 concentrations, incubation times, pipettes, vortex intensities, and other CSF proteins, including hyperphosphorylated tau and Interleukin 1 Receptor Accessory Protein (IL‐1RAcP). An enquiry assessed the number of transfers in current practice. Results In diagnostic practice, the number of transfers varied between 1 and 3. Every tube transfer resulted in 5% loss of Aβ1–42 concentration, even 10% in small volumes. Adsorption was observed after 30 seconds and after contact with the pipette tip. Tube brand, vortexing, or continuous tube movement did not influence adsorption. Adsorption for Aβ1–40 was similar, resulting in stable Aβ1–42/Aβ1–40 ratios over multiple tube transfers. Discussion We confirmed that adsorption of CSF Aβ1–42 during preanalytical processing is an important confounder. However, use…

Abstract Introduction Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated. Methods We conducted genome‐wide association studies for AD‐related endophenotypes including hippocampal volume, logical memory scores, and cerebrospinal fluid Aβ42 and total/phosphorylated tau in cognitively normal (CN), mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative study. Results In CN subjects, study‐wide significant (P < 8.3 × 10−9) loci were identified for total tau near SRRM4 and C14orf79 and for hippocampal volume near MTUS1. In mild cognitive impairment subjects, study‐wide significant association was found with single nucleotide polymorphisms (SNPs) near ZNF804B for logical memory test of delayed recall scores. We found consistent expression patterns of C14orf40 and MTUS1 in carriers with risk alleles of expression SNPs and in brains of AD patients, compared with in the noncarriers and in brains of controls. Discussion Our findings for AD‐related brain changes…

It is hypothesized that retrotransposons have played a fundamental role in primate evolution and that enhanced neurologic retrotransposon activity in humans may underlie the origin of higher cognitive function. As a potential consequence of this enhanced activity, it is likely that neurons are susceptible to deleterious retrotransposon pathways that can disrupt mitochondrial function. An example is observed in the TOMM40 gene, encoding a β-barrel protein critical for mitochondrial preprotein transport. Primate-specific Alu retrotransposons have repeatedly inserted into TOMM40 introns, and at least one variant associated with late-onset Alzheimer's disease originated from an Alu insertion event. We provide evidence of enriched Alu content in mitochondrial genes and postulate that Alus can disrupt mitochondrial populations in neurons, thereby setting the stage for progressive neurologic dysfunction. This Alu neurodegeneration hypothesis is compatible with decades of research and offers a plausible mechanism for the disruption of neuronal mitochondrial homeostasis, ultimately cascading…

INTRODUCTION: There may be biologically relevant heterogeneity within typical late-onset Alzheimer's dementia. METHODS: We analyzed cognitive data from people with incident late-onset Alzheimer's dementia from a prospective cohort study. We determined individual averages across memory, visuospatial functioning, language, and executive functioning. We identified domains with substantial impairments relative to that average. We compared demographic, neuropathology, and genetic findings across groups defined by relative impairments. RESULTS: During 32,286 person-years of follow-up, 869 people developed Alzheimer's dementia. There were 393 (48%) with no domain with substantial relative impairments. Some participants had isolated relative impairments in memory (148, 18%), visuospatial functioning (117, 14%), language (71, 9%), and executive functioning (66, 8%). The group with isolated relative memory impairments had higher proportions with ≥ APOE ε4 allele, more extensive Alzheimer's-related neuropathology, and higher proportions with other Alzheimer's dementia genetic risk variants.…

INTRODUCTION: Functional and cognitive features of subjective cognitive decline (SCD) were identified in a longitudinal database from the National Alzheimer's Coordinating Center. METHODS: Cognitively normal older adults with (SCD+) and without (SCD-) self-reported memory complaints (N = 3915) were compared on (1) baseline Functional Assessment Questionnaire ratings, (2) baseline scores and longitudinal rate of change estimates from nine neuropsychological tests, and (3) final clinical diagnoses. RESULTS: SCD+ had higher baseline ratings of functional impairment, reduced episodic memory practice effects and poorer performance on neuropsychological tests of psychomotor speed and language, and higher frequencies of mild cognitive impairment and dementia diagnoses at the end of follow-up compared with the SCD-group. DISCUSSION: Subtle clinical features of SCD identified in this large cohort are difficult to detect at the individual level. More sensitive tests are needed to identify those with SCD who are vulnerable to cognitive decline and dementia.

INTRODUCTION: With a rapidly aging population, general practitioners are confronting the challenge of how to determine those who are at greatest risk for dementia and potentially need more specialized follow-up to mitigate symptoms early in its course. We created a practical dementia risk score and provided individualized estimates of future dementia risk. METHODS: Using the Framingham Heart Study data, we built our prediction model using Cox proportional hazard models and developed a point system for the risk score and risk estimates. RESULTS: The score system used total points ranging from -1 to 31 and stratifies individuals into different levels of risk. We estimated 5-, 10-, and 20-year dementia risk prediction and incorporated these into the points system. DISCUSSION: This risk score system provides a practical tool because all included predictors are easy to assess by practitioners. It can be used to estimate future probabilities of dementia for individuals.

INTRODUCTION: A fall in hospital deaths in dementia has been interpreted as indicating an improvement in end-of-life care. Whether other indicators of quality of end-of-life care, such as emergency department (ED) attendance, show a similar trend is unclear. METHODS: Retrospective cohort study using electronic medical records from a large mental health care provider, linked to national mortality and hospital use data (2008-2013). RESULTS: Of 4867 patients, 78.6% (3824) had at least one ED attendance during their last year of life (mean 2.13, standard deviation 2.34, range 0-54). ED attendance increased over the time period (incidence rate ratio 1.62, 95% confidence interval 1.46-1.80 for 2012-2013 compared with 2008-2009). DISCUSSION: ED attendance in the last year of life for people with dementia is common and is increasing. Policy makers must pay attention to a broader range of indicators of poor end-of-life care alongside the place of death.

The Mayo Clinic Study of Aging is an epidemiological study of human aging. Most MRI standard template spaces such as MNI152 are generated from scans of younger individuals. Because population-matched templates provide better quantitative MRI analysis, the goal of this work was to construct and make publically available a template for the analysis needs of aging and Alzheimer's Disease (AD) population studies. Subject Characteristics: This template was constructed from T1-weighted scans of 202 subjects including: 39 young clinically-normal subjects (age 30–49); 4 groups of 20 (each 10 men + 10 women) clinically normal subjects from each age range 50–59, 60–69, 70–79, 80–89; and 83 subjects with probable AD dementia. Input images were acquired using two 3T GE scanners (models 750, Signa Excite) with ADNI-1 MP-RAGE protocols and corrected for gradient distortion in 3D and nonuniformity using N3 and SPM5. SPM12b was used to segment these preprocessed images with stock priors, and these segmentations were validated by image analysts. DARTEL was used to produce new tissue priors and…

Abstract Introduction The objective of this study was to evaluate the relationship between self‐reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers. Methods In 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self‐reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aβ42, and CSF tau levels was evaluated using linear regression. Results No differences in brain amyloid load, CSF Aβ42, or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels. Discussion Our findings indicate a relationship exists between self‐reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers.

INTRODUCTION: Primary age-related tauopathy (PART) is a neuropathological diagnosis characterized by tau neurofibrillary tangles (NFTs) in the absence of amyloid plaque pathology. Although most individuals over 50 years of age have evidence of NFTs, the clinical and cognitive consequences of PART are not known. METHODS: We evaluated 226 neuropathologically confirmed PART cases from the National Alzheimer's Coordinating Center database who participated in a total of 846 longitudinal neuropsychological assessments from the Alzheimer's Disease Center program's Uniform Data Set. Mixed-effects statistical models tested whether cognitive decline was associated with Braak stage NFT burden. RESULTS: Higher stages of NFT burden in PART, with no evidence or minimal evidence of amyloid pathology, were associated with more rapid decline on tasks involving episodic and semantic memory along with tests of processing speed and attention. DISCUSSION: We conclude that PART has cognitive consequences that should be considered in the context of emerging tau-targeted therapies in age-associated…

INTRODUCTION: AF710B (aka ANAVEX 3-71) is a novel selective allosteric M1 muscarinic and sigma-1 receptor agonist. In 3×Tg-AD mice, AF710B attenuates cognitive deficits and decreases Alzheimer-like hallmarks. We now report on the long-lasting disease-modifying properties of AF710B in McGill-R-Thy1-APP transgenic (Tg) rats. METHODS: Chronic treatment with AF710B (10 μg/kg) was initiated in postplaque 13-month-old Tg rats. Drug or vehicle was administered orally daily for 4.5 months and interrupted 5 weeks before behavioral testing. RESULTS: AF710B long-term treatment reverted the cognitive deficits associated with advanced Alzheimer-like amyloid neuropathology in Tg rats. These effects were accompanied by reductions in amyloid pathology and markers of neuroinflammation and increases in amyloid cerebrospinal fluid clearance and levels of a synaptic marker. Importantly, these effects were maintained following a 5-week interruption of the treatment. DISCUSSION: With M1/sigma-1 activity and long-lasting disease-modifying properties at low dose, AF710B is a promising novel therapeutic…

INTRODUCTION: Older adults, including those with mild cognitive impairment (MCI), are increasingly undergoing surgery. METHODS: Relative risks (RRs) of MCI alone or with delirium on adverse outcomes were estimated in an ongoing prospective, observational cohort study of 560 nondemented adults aged ≥70 years. RESULTS: MCI (n = 61, 11%) was associated with increased RR of delirium (RR = 1.9, P < .001) and delirium severity (RR = 4.6, P < .001). Delirium alone (n = 107), but not MCI alone (n = 34), was associated with multiple adverse outcomes including more major postoperative complication(s) (RR = 2.5, P = .002) and longer length of stay (RR = 2.2, P < .001). Patients with concurrent MCI and delirium (n = 27) were more often discharged to a postacute facility (RR = 1.4, P < .001) and had synergistically increased risk for new impairments in cognitive functioning (RR = 3.6, P < .001). DISCUSSION: MCI is associated with increased risk of delirium incidence and severity. Patients with delirium and MCI have synergistically elevated risk of developing new difficulties in cognitively…

INTRODUCTION: Medicare beneficiaries with Alzheimer's disease and related dementias (ADRDs) may have more potentially avoidable hospitalizations and readmissions than people without dementia. These hospitalizations may be indicative of access barriers, problems in continuity of care, inefficient resource use, and poor patient outcomes. METHODS: We examined national frequency and costs of ambulatory care sensitive condition hospitalizations and unplanned, all-cause, and condition-specific 30-day readmissions in >2.7 million fee-for-service ADRD patients using 2013 Medicare claims data. RESULTS: In 2013, 410,000 Medicare ADRD patients had ambulatory care sensitive condition hospitalizations or unplanned 30-day readmissions costing $4.7 billion. One in 10 ADRD patients were hospitalized for a potentially avoidable condition. Almost one in five hospitalized ADRD patients had an unplanned 30-day readmission. Readmission rates were highest among ADRD patients initially hospitalized for heart failure (22%) and chronic obstructive pulmonary disease (21%). DISCUSSION: Our findings may…

INTRODUCTION: We discovered a concomitant decline in stroke and dementia incidence rates at a whole population level in Ontario, Canada. This study explores these trends within demographic subgroups. METHODS: We analyzed administrative data sources using validated algorithms to calculate stroke and dementia incidence rates from 2002 to 2013. RESULTS: For more than 12 years, stroke incidence remained unchanged among those aged 20 to 49 years and decreased for those aged 50 to 64, 65 to 79, and 80+ years by 22.7%, 36.9%, and 37.9%, respectively. Dementia incidence increased by 17.3% and 23.5% in those aged 20 to 49 and 50 to 64 years, respectively, remained unchanged in those aged 65 to 79 years, and decreased by 15.4% in those aged 80+ years. DISCUSSION: The concomitant decline in stroke and dementia incidence rates may depict how successful stroke prevention has targeted shared risk factors of both conditions, especially at advanced ages where such risk factors are highly prevalent. We lend support for the development of an integrated system of stroke and dementia prevention.

INTRODUCTION: Cognitive and/or memory impairment are the main clinical markers currently used to identify subjects at risk of developing dementia. This study aimed to explore the relationship between the presence of neuropsychiatric symptoms and dementia incidence. METHODS: We analyzed the association between neuropsychiatric symptoms and incident dementia in a cohort of 1355 Mexican older adults from the general population over 3 years of follow-up, modeling cumulative incidence ratios using Poisson models. RESULTS: Five neuropsychiatric symptoms were associated with incident dementia: delusions, hallucinations, anxiety, aberrant motor behavior, and depression. The simultaneous presence of two symptoms had a relative risk, adjusted for mild cognitive impairment, diabetes, indicators of cognitive function, and sociodemographic factors, of 1.9 (95% confidence interval, 1.2-2.9), whereas the presence of three to five, similarly adjusted, had a relative risk of 3.0 (95% confidence interval, 1.9-4.8). DISCUSSION: Neuropsychiatric symptoms are common in predementia states and may…

INTRODUCTION: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. METHODS: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. RESULTS: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. DISCUSSION: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.

INTRODUCTION: Spatial navigation deficits are reported in dementia, but their temporal relationship to cognitive decline is not established. METHODS: This is a prospective cohort study in 442 nondemented adults (mean age 79.9 years). Spatial navigation measured with the Floor Maze Test and reported as immediate maze time (IMT) and delayed maze time (DMT). Predementia syndromes, mild cognitive impairment syndrome (MCI) and motoric cognitive risk syndrome (MCR), were primary outcomes. RESULTS: Over a mean follow-up of 16.5 ± 13.7 months, 41 participants developed MCI and 30 participants developed MCR. In Cox models adjusted for age, sex, education, cognitive status, comorbid illnesses, and maze errors, a 10-second increment on IMT predicted incident MCI (adjusted hazard ratio [aHR]: 1.25; 95% confidence interval [CI]: 1.06-1.48) and MCR (aHR: 1.53; 95% CI: 1.23-1.90). DMT predicted MCR but not MCI. DISCUSSION: Spatial navigation performance predicted predementia syndromes in aging and implicates navigational impairments as an early feature in dementias.

INTRODUCTION: Although some studies have previously addressed the clinical impact of amyloid positron emission tomography (PET), none has specifically addressed its selective and hierarchical implementation in relation to cerebrospinal fluid analysis in a naturalistic setting. METHODS: This multicenter study was performed at French tertiary memory clinics in patients presenting with most complex clinical situations (i.e., early-onset, atypical clinical profiles, suspected mixed etiological conditions, unexpected rate of progression), for whom cerebrospinal fluid analysis was indicated but either not feasible or considered as noncontributory (ClinicalTrials.gov: NCT02681172). RESULTS: Two hundred five patients were enrolled with evaluable florbetaben PET scans; 64.4% of scans were amyloid positive. PET results led to changed diagnosis and improved confidence in 66.8% and 81.5% of patients, respectively, and altered management in 80.0% of cases. DISCUSSION: High-level improvement of diagnostic certainty and management is provided by selective and hierarchical implementation of…

INTRODUCTION: The European Medical Information Framework consortium has assembled electronic health record (EHR) databases for dementia research. We calculated dementia prevalence and incidence in 25 million persons from 2004 to 2012. METHODS: Six EHR databases (three primary care and three secondary care) from five countries were interrogated. Dementia was ascertained by consensus harmonization of clinical/diagnostic codes. Annual period prevalences and incidences by age and gender were calculated and meta-analyzed. RESULTS: The six databases contained 138,625 dementia cases. Age-specific prevalences were around 30% of published estimates from community samples and incidences were around 50%. Pooled prevalences had increased from 2004 to 2012 in all age groups but pooled incidences only after age 75 years. Associations with age and gender were stable over time. DISCUSSION: The European Medical Information Framework initiative supports EHR data on unprecedented number of people with dementia. Age-specific prevalences and incidences mirror estimates from community samples in pattern…

INTRODUCTION: In North Africa and the Middle East, studies about dementia prevalence are scarce. A pilot study was conducted in Lebanon to assess dementia prevalence, using the Arabic-validated 10/66 Dementia Research Group (DRG) diagnostic assessment for case ascertainment. The study also examined care arrangement and access to care. METHODS: A random sample of 502 persons older than 65 years and their informant were recruited from Beirut and Mount Lebanon governorates through multistage cluster sampling. RESULTS: The crude and age-standardized dementia prevalences were 7.4% and 9.0%, respectively. People with dementia were mainly cared for by relatives at home. Access to formal care was very limited. DISCUSSION: Dementia prevalence in Lebanon ranks high within the global range of estimates. These first evidence-based data about disease burden and barriers to care serve to raise awareness and call for social and health care reform to tackle the dementia epidemic in Lebanon and in North Africa and the Middle East.

INTRODUCTION: The living environment affects general health and may influence cognitive aging; however, the relationships between neighborhood characteristics and dementia are still poorly understood. METHODS: We used data from a French population-based prospective study (the Three-City cohort) that included 7016 participants aged 65 years and older with a 12-year follow-up. We used principal components analysis of neighborhood composition indicators to construct the Three-City deprivation score. To study its impact on dementia incidence, we performed survival analyses using a marginal Cox model to take into account intraneighborhood correlations. As interaction with sex was significant, analyses were stratified by sex. RESULTS: Even after controlling on individual factors, women living in deprived neighborhoods were at higher risk of dementia (hazard ratio = 1.29, 95% confidence interval 1.00-1.67) and Alzheimer's disease (hazard ratio = 1.42, 95% confidence interval 1.09-1.84). No association was found for men. DISCUSSION: Living in a deprived neighborhood is associated with…

INTRODUCTION: Excess sugar consumption has been linked with Alzheimer's disease (AD) pathology in animal models. METHODS: We examined the cross-sectional association of sugary beverage consumption with neuropsychological (N = 4276) and magnetic resonance imaging (N = 3846) markers of preclinical Alzheimer's disease and vascular brain injury (VBI) in the community-based Framingham Heart Study. Intake of sugary beverages was estimated using a food frequency questionnaire. RESULTS: Relative to consuming less than one sugary beverage per day, higher intake of sugary beverages was associated with lower total brain volume (1-2/day, β ± standard error [SE] = -0.55 ± 0.14 mean percent difference, P = .0002; >2/day, β ± SE = -0.68 ± 0.18, P < .0001), and poorer performance on tests of episodic memory (all P < .01). Daily fruit juice intake was associated with lower total brain volume, hippocampal volume, and poorer episodic memory (all P < .05). Sugary beverage intake was not associated with VBI in a consistent manner across outcomes. DISCUSSION: Higher intake of sugary beverages was…

INTRODUCTION: Many previous studies have been limited by self- or proxy-reported injury or short follow-up. We investigated whether head or brain injuries are associated with Alzheimer's disease (AD), possible modifying factors and dose-response relationship. METHODS: Nested register-based case-control study of all community dwellers who received clinically verified AD diagnosis in Finland in 2005 to 2011 (n = 70,719) and one to four matched controls for each case (n of controls = 282,862). RESULTS: The magnitude of association between hospital-treated head and/or brain injuries was strongly dependent on the lag time between exposure and outcome. With a 5-year lag time, head injury (adjusted odds ratio; 95% confidence interval 1.19; 1.15-1.23) or brain injury (1.23; 1.18-1.29) was associated with higher risk of AD. Dose-response relationship with number and severity of injuries was observed. Associations were stronger in those with earlier onset of AD. CONCLUSIONS: Stronger associations with shorter lag times indicate that head and/or brain injuries may also reflect the ongoing AD…

INTRODUCTION: Although amyloid β peptide (Aβ) is cleared from the brain to cerebrospinal fluid and the peripheral circulation, mechanisms for its removal from blood remain unresolved. Primates have uniquely evolved a highly effective peripheral clearance mechanism for pathogens, immune adherence, in which erythrocyte complement receptor 1 (CR1) plays a major role. METHODS: Multidisciplinary methods were used to demonstrate immune adherence capture of Aβ by erythrocytes and its deficiency in Alzheimer's disease (AD). RESULTS: Aβ was shown to be subject to immune adherence at every step in the pathway. Aβ dose-dependently activated serum complement. Complement-opsonized Aβ was captured by erythrocytes via CR1. Erythrocytes, Aβ, and hepatic Kupffer cells were colocalized in the human liver. Significant deficits in erythrocyte Aβ levels were found in AD and mild cognitive impairment patients. DISCUSSION: CR1 polymorphisms elevate AD risk, and >80% of human CR1 is vested in erythrocytes to subserve immune adherence. The present results suggest that this pathway is pathophysiologically…

INTRODUCTION: We assessed the diagnostic accuracy of cerebrospinal fluid (CSF) YKL-40 in discriminating (1) clinical Alzheimer's disease (AD) from cognitively healthy controls (HCs) and frontotemporal dementia (FTD) (level I) and (2) patients stratified by different pathophysiological profiles from HCs and FTD following a novel unbiased/descriptive categorization based on CSF biomarkers, independent of cognitive impairment severity (level II). METHODS: YKL-40 was compared among HCs (n = 21), mild cognitive impairment (n = 41), AD (n = 35), and FTD (n = 9) (level I) and among HCs (n = 21), AD pathophysiology (tau and amyloid β) negative (n = 15), tau positive (n = 15), amyloid β positive (n = 13), AD pathophysiology positive (n = 33), and FTD (n = 9) (level II). RESULTS: Level I: YKL-40 discriminated AD from HC and FTD (area under the receiver operating characteristic curves [AUROCs] = 0.69, 0.71). Level II: YKL-40 discriminated tau-positive individuals and AD pathophysiology-positive individuals from HC, AD pathophysiology-positive patients from FTD (AUROCs = 0.76, 0.72, 0.73).…

INTRODUCTION: To provide a crosswalk between the recently proposed short Montreal Cognitive Assessment (s-MoCA) and Mini-Mental State Examination (MMSE) within a clinical cohort. METHODS: A total of 791 participants, with and without neurologic conditions, received both the MMSE and the MoCA at the same visit. s-MoCA scores were calculated and equipercentile equating was used to create a crosswalk between the s-MoCA and MMSE. RESULTS: As expected, s-MoCA scores were highly correlated (Pearson r = 0.82, P < .001) with MMSE scores. s-MoCA scores correctly classified 85% of healthy older adults and 91% of individuals with neurologic conditions that impair cognition. In addition, we provide an easy to use table that enables the conversion of s-MoCA score to MMSE score. DISCUSSION: The s-MoCA is quick to administer, provides high sensitivity and specificity for cognitive impairment, and now can be compared directly with the MMSE.

INTRODUCTION: The best-established cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease are levels of amyloid β 42 (Aβ42), total tau (tau), and phosphorylated tau 181 (ptau). We examined whether a widely used commercial immunoassay for CSF Aβ42, tau, and ptau provided stable measurements for more than ∼10 years. METHODS: INNOTEST assay values for CSF Aβ42, tau, and ptau from Washington University in St. Louis and VU Medical Center, Amsterdam, were evaluated. RESULTS: Aβ42 values as measured by the INNOTEST assay drifted upward by approximately 3% per year over the past decade. Tau values remained relatively stable, whereas results for ptau were mixed. DISCUSSION: Assay drift may reduce statistical power or even confound analyses. The drift in INNOTEST Aβ42 values may reduce diagnostic accuracy for Alzheimer's disease in the clinic. We recommend methods to account for assay drift in existing data sets and to reduce assay drift in future studies.

INTRODUCTION: A harmonized protocol (HarP) for manual hippocampal segmentation on magnetic resonance imaging (MRI) has recently been developed by an international European Alzheimer's Disease Consortium-Alzheimer's Disease Neuroimaging Initiative project. We aimed at providing consensual certified HarP hippocampal labels in Montreal Neurological Institute (MNI) standard space to serve as reference in automated image analyses. METHODS: Manual HarP tracings on the high-resolution MNI152 standard space template of four expert certified HarP tracers were combined to obtain consensual bilateral hippocampus labels. Utility and validity of these reference labels is demonstrated in a simple atlas-based morphometry approach for automated calculation of HarP-compliant hippocampal volumes within SPM software. RESULTS: = 0.89/0.91) with gold standard volumes in the HarP benchmark data set (N = 135 MRIs), with a mean volume difference of 9% (standard deviation 7%). CONCLUSION: The consensual HarP hippocampus labels in the MNI152 template can serve as a reference standard for automated image…

INTRODUCTION: Amyloid imaging is a tool that has recently become available to dementia specialists evaluating patients with possible Alzheimer's disease. Studies have assessed the impact of amyloid imaging on diagnostic and treatment decisions, but patient and family perspectives have received less attention. METHODS: To examine how amyloid imaging affects the diagnostic experience of patients and families, we interviewed members of 26 patient-caregiver dyads with whom a neurologist discussed the option of amyloid positron emission tomography. RESULTS: Most participants who chose to undergo amyloid imaging would choose to do so again. Regardless of the scan outcome, patients and caregivers commonly expressed relief on learning the scan results. Some participants expressed expectations that were beyond scan capabilities. DISCUSSION: Amyloid imaging may provide information that patients and their families find useful. Clinicians must set correct expectations and ensure that families understand the limitations of amyloid imaging.

A humanized antibody engineered to bind and neutralize soluble tau aggregate was characterized to determine its epitope, specificity and pharmacokinetic properties in rats and primates. LY3303560 was tested in surface plasmon resonance binding and ELISA assays to assess its selectivity to tau aggregates over monomer, as well as to determine the antibody epitope. Serum concentrations of LY3303560 in monkey and rats were measured using an antigen capture ELISA. LY3303560 demonstrated very high affinity to soluble tau aggregate in vitro (KD: <220 pM), compared to monomer tau (KD: 235 nM). The antibody recognizes a conformational epitope of tau with primary epitope located in the N-terminal region. The high affinity binding to aggregates was driven by avidity. After IV administration to monkeys, the mean clearance was 0.15 ml/h/kg and mean terminal half-life of 310 hours. After SC administration the mean bioavailability was approximately 79%. Rat CSF concentrations were 0.1% of plasma concentrations at 24 hours after IV administration. LY3303560, engineered to target aggregated tau, was…

INTRODUCTION: Subtle changes in instrumental activities of daily living often accompany the onset of mild cognitive impairment (MCI) but are difficult to measure using conventional tests. METHODS: Weekly online survey metadata metrics, annual neuropsychological tests, and an instrumental activity of daily living questionnaire were examined in 110 healthy older adults with intact cognition (mean age = 85 years) followed up for up to 3.6 years; 29 transitioned to MCI during study follow-up. RESULTS: In the baseline period, incident MCI participants completed their weekly surveys 1.4 hours later in the day than stable cognitively intact participants, P = .03, d = 0.47. Significant associations were found between earlier survey start time of day and higher memory (r = -0.34; P < .001) and visuospatial test scores (r = -0.37; P < .0001). Longitudinally, incident MCI participants showed an increase in survey completion time by 3 seconds per month for more than the year before diagnosis compared with stable cognitively intact participants (β = 0.12, SE = 0.04, t = 2.8; P = .006).…

Abstract Introduction We examined the association between cognitive ability in young adulthood and dementia in Danish men, brothers, and male twins. Methods In total, 666,986 men born between 1939 and 1959 were identified for dementia diagnosis in national registries from 1969 to 2016. The association between cognitive ability from draft board examination and dementia was examined using Cox regression. Results During a 44‐year follow‐up, 6416 (0.96%) men developed dementia, 1760 (0.26%) and 970 (0.15%) of which were classified as Alzheimer's and vascular dementia, respectively. Low cognitive ability was associated with increased risk of dementia (hazard ratio [HR]per SD decrease 1.33 [95% confidence interval {CI} = 1.30–1.35]) with the strongest associations for vascular dementia (HRper SD decrease 1.47 [95% CI = 1.31–1.56]) and a weaker for Alzheimer's disease (HRper SD decrease 1.07 [95% CI = 1.03–1.13]). The intrabrother and twin analyses (taking shared family factors into account) showed attenuated risk estimates but with wide CIs. Discussion Low early‐life cognitive ability…

INTRODUCTION: There are few longitudinal studies of dementia in developing countries. We used longitudinal data from the Maracaibo Aging Study to accurately determine the age- and sex-specific incidence of dementia in elderly Latin Americans. METHODS: The Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) was used to diagnose dementia, which was classified as Alzheimer's disease, vascular dementia, or other. Age- and sex-specific incidence was estimated as the number of new cases of dementia divided by person-years (p-y) of follow-up. RESULTS: The incidence of all dementia diagnoses was 9.10 per 1000 p-y (95% confidence interval [CI] 7.13-11.44; 8026 total p-y), 5.18 for Alzheimer's disease (95% CI 3.72-7.03; 7916 total p-y), and 3.35 for vascular dementia (95% CI 2.19-4.91; 7757 total p-y). DISCUSSION: Among Maracaibo Aging Study participants younger than 65 years, the incidence of dementia was higher than that of US Whites. Among individuals older than 65 years, the incidence was comparable to the mean of previous incidence estimates for other…

Available data and models for the health-economic evaluation of treatment in Alzheimer's disease (AD) have limitations causing uncertainty to decision makers. Forthcoming treatment strategies in preclinical or early AD warrant an update on the challenges associated with their economic evaluation. The perspectives of the co-authors were complemented with a targeted review of literature discussing methodological issues and data gaps in AD health-economic modelling. The methods and data available to translate treatment efficacy in early disease into long-term outcomes of relevance to policy makers and payers are limited. Current long-term large-scale data accurately representing the continuous, multifaceted, and heterogeneous disease process are missing. The potential effect of disease-modifying treatment on key long-term outcomes such as institutionalization and death is uncertain but may have great effect on cost-effectiveness. Future research should give priority to collaborative efforts to access better data on the natural progression of AD and its association with key long-term…

INTRODUCTION: Subjective cognitive decline (SCD) has been proposed as a potential preclinical stage of Alzheimer's disease (AD). Nevertheless, the genetic and biomarker profiles of SCD individuals remain mostly unexplored. METHODS: We evaluated apolipoprotein E (APOE) ε4's effect in the risk of presenting SCD, using the Fundacio ACE Healthy Brain Initiative (FACEHBI) SCD cohort and Spanish controls, and performed a meta-analysis addressing the same question. We assessed the relationship between APOE dosage and brain amyloid burden in the FACEHBI SCD and Alzheimer's Disease Neuroimaging Initiative cohorts. RESULTS: Analysis of the FACEHBI cohort and the meta-analysis demonstrated SCD individuals presented higher allelic frequencies of APOE ε4 with respect to controls. APOE dosage explained 9% (FACEHBI cohort) and 11% (FACEHBI and Alzheimer's Disease Neuroimaging Initiative cohorts) of the variance of cerebral amyloid levels. DISCUSSION: The FACEHBI sample presents APOE ε4 enrichment, suggesting that a pool of AD patients is nested in our sample. Cerebral amyloid levels are partially…

INTRODUCTION: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci. METHODS: We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aβ proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions. RESULTS: We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aβ toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex. DISCUSSION: Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.

INTRODUCTION: We aimed to determine the added value of cerebrospinal fluid (CSF) to clinical and imaging tests to predict progression from mild cognitive impairment (MCI) to any type of dementia. METHODS: The risk of progression to dementia was estimated using two logistic regression models based on 250 MCI participants: the first included standard clinical measures (demographic, clinical, and imaging test information) without CSF biomarkers, and the second included standard clinical measures with CSF biomarkers. RESULTS: Adding CSF improved predictive accuracy with 0.11 (scale from 0-1). Of all participants, 136 (54%) had a change in risk score of 0.10 or higher (which was considered clinically relevant), of whom in 101, it was in agreement with their dementia status at follow-up. DISCUSSION: An individual person's risk of progression from MCI to dementia can be improved by relying on CSF biomarkers in addition to recommended clinical and imaging tests for usual care.

INTRODUCTION: Clinical features of dementia (cognition, function, and behavioral and psychological symptoms) may differentially affect out-of-pocket medical and nursing home (NH) expenditures and informal care received (outcomes). METHODS: We used cross-sectional data (Aging, Demographics, and Memory Study) to estimate probabilities of experiencing outcomes by clinical features. For those experiencing an outcome, we estimated effects of clinical features on the amount of the outcome. RESULTS: No clinical feature predicted the probability of having out-of-pocket medical expenditures. For those with medical expenditures, higher cognition and poorer function were associated with more spending. Poorer function predicted having out-of-pocket NH expenditures. For those with NH expenditures, no clinical feature predicted the amount. Poorer function and a greater number of behavioral and psychological symptoms predicted the probability of receiving caregiving. For those receiving care, poorer function was associated with more caregiving. CONCLUSIONS: Clinical features differentially impact…

INTRODUCTION: We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. METHODS: Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. RESULTS: Longitudinal percent change between placebo and solanezumab using CBL was not significant (P = .536) but was significant for SSWMnr (P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements…

INTRODUCTION: We examined the relationship between health care expenditures and cognition, focusing on differences across cognitive systems defined by global cognition, executive function, or episodic memory. METHODS: We used linear regression models to compare annual health expenditures by cognitive status in 8125 Nurses' Health Study participants who completed a cognitive battery and were enrolled in Medicare parts A and B. RESULTS: Adjusting for demographics and comorbidity, executive impairment was associated with higher total annual expenditures of $1488 per person (P < .01) compared with those without impairment. No association for episodic memory impairment was found. Expenditures exhibited a linear relationship with executive function, but not episodic memory ($584 higher for every 1 standard deviation decrement in executive function; P < .01). DISCUSSION: Impairment in executive function is specifically and linearly associated with higher health care expenditures. Focusing on management strategies that address early losses in executive function may be effective in reducing…

Abstract Introduction Hippocampal volume is a core biomarker of Alzheimer's disease (AD). However, its contribution over the standard diagnostic workup is unclear. Methods Three hundred fifty‐six patients, under clinical evaluation for cognitive impairment, with suspected AD and Mini–Mental State Examination ≥20, were recruited across 17 European memory clinics. After the traditional diagnostic workup, diagnostic confidence of AD pathology (DCAD) was estimated by the physicians in charge. The latter were provided with the results of automated hippocampal volumetry in standardized format and DCAD was reassessed. Results An increment of one interquartile range in hippocampal volume was associated with a mean change of DCAD of −8.0% (95% credible interval: [−11.5, −5.0]). Automated hippocampal volumetry showed a statistically significant impact on DCAD beyond the contributions of neuropsychology, 18F‐fluorodeoxyglucose positron emission tomography/single‐photon emission computed tomography, and cerebrospinal fluid markers (−8.5, CrI: [−11.5, −5.6]; −14.1, CrI: [−19.3, −8.8]; −10.6,…

INTRODUCTION: Cerebral small vessel disease (SVD) is thought to contribute to Alzheimer's disease (AD) through abnormalities in white matter networks. Gray matter (GM) hub covariance networks share only partial overlap with white matter connectivity, and their relationship with SVD has not been examined in AD. METHODS: We developed a multivariate analytical pipeline to elucidate the cortical GM thickness systems that covary with major network hubs and assessed whether SVD and neurodegenerative pathologic markers were associated with attenuated covariance network integrity in mild AD and normal elderly control subjects. RESULTS: SVD burden was associated with reduced posterior cingulate corticocortical GM network integrity and subneocorticocortical hub network integrity in AD. DISCUSSION: These findings provide evidence that SVD is linked to the selective disruption of cortical hub GM networks in AD brains and point to the need to consider GM hub covariance networks when assessing network disruption in mixed disease.