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Background: Children with hydrocephalus are at risk for epilepsy both due to their underlying condition and as a consequence of surgical treatment; however, the relative contributions of these factors remain unknown.Objective: The authors sought to characterize epilepsy among children with infancy-onset hydrocephalus and to examine the risks of epilepsy associated with hydrocephalus subtype and with factors related to surgical treatment.Methods: We conducted a longitudinal cohort study of all children with infancy-onset hydrocephalus treated at a major regional children's hospital during 2002 to 2012, with follow-up to ascertain risk factors and epilepsy outcome through April 2015. Poisson regression was used to calculate adjusted risk ratios and 95% confidence intervals for associations.Results: Among 379 children with hydrocephalus, 86 (23%) developed epilepsy (mean onset age = 2.7 years), almost one fifth of whom had a history of infantile spasms. Relative to spina bifida-associated hydrocephalus, children with other major hydrocephalus subtypes had fourfold higher risks of developing epilepsy. Among children who underwent surgery, surgical infection doubled the risk of epilepsy (risk ratio = 2.0, 95% confidence interval = 1.4 to 3.0). Epilepsy was associated with surgical failure for intracranial reasons but not extracranial reasons (risk ratio = 1.7, 95% confidence interval = 1.1 to 2.7; risk ratio = 1.1, 95% confidence interval = 0.7 to 1.9, respectively).Conclusions: Epilepsy is common among children with hydrocephalus. Compared with children with spina bifida-associated hydrocephalus, children with other major hydrocephalus subtypes have a markedly increased risk of epilepsy. Surgical infection doubles the risk of epilepsy. [ABSTRACT FROM AUTHOR]

Psychosis in Alzheimer's Disease (AD) is prevalent and indicates poor prognosis. However, the neuropathological, cognitive and brain atrophy patterns underlying these symptoms have not been fully elucidated. In this study, we evaluated 178 patients with AD neuropathological change (ADNC) and ante-mortem volumetric brain magnetic resonance imaging (MRI). Presence of psychosis was determined using the Neuropsychiatric Inventory Questionnaire. Clinical Dementia Rating Sum-of-boxes (CDR-SB) was longitudinally compared between groups with a follow-up of 3000 days using mixed-effects multiple linear regression. Neuropsychological tests closest to the time of MRI and brain regional volumes were cross-sectionally compared. Psychosis was associated with lower age of death, higher longitudinal CDR-SB scores, multi-domain cognitive deficits, higher neuritic plaque severity, Braak stage, Lewy Body pathology (LB) and right temporal lobe regional atrophy. Division according to the presence of LB showed differential patterns of AD-typical pathology, cognitive deficits and regional atrophy. In conclusion, psychosis in ADNC with and without LB has clinical value and associates with subgroup patterns of neuropathology, cognition and regional atrophy. • Psychosis in AD is prevalent and associates with worse prognosis. • Psychosis in AD associates with neuropathological heterogeneity. • Psychosis in AD has differential cognitive symptoms and brain atrophy. [ABSTRACT FROM AUTHOR]

Studies a group of elderly patients with adverse drug reactions associated with cognitive impairment to identify drugs responsible for impairment. Difficulty in the recognition of drug toxicity in dementia patients; Classification of adverse drug reactions; Importance of drugs causing cognitive impairment.

Editorial. Focuses on the issue of dementias of the Alzheimer type (DAT). Reference to article in same issue by White et al, a landmark study on the epidemiology of DAT in that it uses the powerful approach of cross-cultural comparison involving population migration; Reasons why this type of epidemiologic research is so difficult.

Background: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. Methods: We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Results: Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10–9). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10–8) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10–8). GRN (rs5848, P = 4.21 × 10–8) and PURG (rs117523305, P = 1.73 × 10–8) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10–8) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10–9) and PTPRD (rs145989094, P = 8.34 × 10–9) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10–8) and PTPRD (rs145989094, P = 3.85 × 10–8) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Conclusion: Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias. [ABSTRACT FROM AUTHOR]

Thyroid hormone disease is common among older adults and is associated with cognitive impairment. However, pathologic correlates are not well understood. We studied pathologic and clinical factors associated with hypothyroidism, the most common manifestation of thyroid disease, in research subjects seen annually for clinical evaluations at U.S. Alzheimer's Disease Centers. Thyroid disease and treatment status were assessed during clinician interviews. Among autopsied subjects, there were 555 participants with treated hypothyroidism and 2146 without known thyroid disease; hypothyroidism was associated with severe atherosclerosis (odds ratio: 1.35; 95% confidence interval: 1.02, 1.79) but not Alzheimer's disease pathologies (amyloid plaques or neurofibrillary tangles). Among participants who did not undergo autopsy (4598 with treated hypothyroidism and 20,945 without known thyroid hormone disease), hypercholesterolemia and cerebrovascular disease (stroke and/or transient ischemic attack) were associated with hypothyroidism, complementing findings in the smaller autopsy sample. This is the first large-scale evaluation of neuropathologic concomitants of hypothyroidism in aged individuals. Clinical hypothyroidism was prevalent (>20% of individuals studied) and was associated with cerebrovascular disease but not Alzheimer's disease–type neuropathology. [ABSTRACT FROM AUTHOR]

Editorial. References an article in the same issue by Tang et al. Finding that African Americans and Hispanics living in New York City have a higher relative risk of possible or probable Alzheimer disease (AD) than whites; Conclusion that the risk of AD varies by race and ethnicity, regardless of apolipoprotein E genotype; Implications of the study.

Background: Lesbian and gay older adults have health disparities that are risk factors for Alzheimer's disease, yet little is known about the neurocognitive aging of sexual minority groups. Objective: To explore cross-sectional and longitudinal dementia outcomes for adults in same-sex relationships (SSR) and those in mixed-sex relationships (MSR). Methods: This prospective observational study utilized data from the National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS) collected from contributing Alzheimer's Disease Research Centers. Participants were adults aged 55+ years at baseline with at least two visits in NACC UDS (from September 2005 to March 2021) who had a spouse, partner, or companion as a co-participant. Outcome measures included CDR® Dementia Staging Instrument, NACC UDS neuropsychological testing, and the Functional Activities Questionnaire. Multivariable linear mixed-effects models accounted for center clustering and repeated measures by individual. Results: Both MSR and SSR groups experienced cognitive decline regardless of baseline diagnosis. In general, MSR and SSR groups did not differ statistically on cross-sectional or longitudinal estimates of functioning, dementia severity, or neuropsychological testing, with two primary exceptions. People in SSR with mild cognitive impairment showed less functional impairment at baseline (FAQ M = 2.61, SD = 3.18 vs. M = 3.97, SD = 4.53, respectively; p < 0.01). The SSR group with dementia had less steep decline in attention/working memory (β estimates = –0.10 versus –0.18; p < 0.01). Conclusion: Participants in SSR did not show cognitive health disparities consistent with a minority stress model. Additional research into protective factors is warranted. [ABSTRACT FROM AUTHOR]

Blacks/African Americans have been reported to be ∼2-4 times more likely to develop clinical Alzheimer's disease (AD) compared to Whites. Unfortunately, study design challenges (e.g., recruitment bias), racism, mistrust of healthcare providers and biomedical researchers, confounders related to socioeconomic status, and other sources of bias are often ignored when interpreting differences in human subjects categorized by race. Failure to account for these factors can lead to misinterpretation of results, reification of race as biology, discrimination, and missed or delayed diagnoses. Here we provide a selected historical background, discuss challenges, present opportunities, and suggest considerations for studying health outcomes among racial/ethnic groups. We encourage neuroscientists to consider shifting away from using biologic determination to interpret data, and work instead toward a paradigm of incorporating both biological and socio-environmental factors known to affect health outcomes with the goal of understanding and improving dementia treatments for Blacks/African Americans and other underserved populations. [ABSTRACT FROM AUTHOR]

Our study compared brain MRI with neuropathological findings in patients with primary age-related tauopathy (PART) and Alzheimer's disease (AD), while assessing the relationship between brain atrophy and clinical impairment. We analyzed 233 participants: 32 with no plaques ("definite" PART—BRAAK stage higher than 0 and CERAD 0), and 201 cases within the AD spectrum, with 25 with sparse (CERAD 1), 76 with moderate (CERAD 2), and 100 with severe (CERAD 3) degrees of neuritic plaques. Upon correcting for age, sex, and age difference at MRI and death, there were significantly higher levels of atrophy in CERAD 3 compared to CERAD 1–2 and a trend compared to PART (p = 0.06). In the anterior temporal region, there was a trend for higher levels of atrophy in PART compared to Alzheimer's disease spectrum cases with CERAD 1 (p = 0.08). We then assessed the correlation between regional brain atrophy and CDR sum of boxes score for PART and AD, and found that overall cognition deficits are directly correlated with regional atrophy in the AD continuum, but not in definite PART. We further observed correlations between regional brain atrophy with multiple neuropsychological metrics in AD, with PART showing specific correlations between language deficits and anterior temporal atrophy. Overall, these findings support PART as an independent pathologic process from AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568 patients and 8101 controls identified FMNL2 (p = 6.6 × 10–7). A significant increase in FMNL2 expression was observed in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood–brain-barrier by controlling gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To identify factors associated with functional change in an older population and investigate interactions among selected potential risk factors. DESIGN: A population-based prospective cohort study. SETTING: A random sample was selected from the Group Health Cooperative members in the Seattle area from 1994 to 1996 and followed biennially. PARTICIPANTS: Two thousand five hundred eighty-one people aged 65 and older, cognitively intact at baseline. MEASUREMENTS: Functional status was measured by activities of daily living, instrumental activities of daily living, and performance-based physical function testing. RESULTS: The cohort status at the time of these analyses was: deceased, 391; withdrawn, 179; dementia, 152; and on study, 1,873. The mean follow-up time was 3.4 years. Using linear regressions with Generalized Estimating Equation, selected medical conditions (diabetes mellitus, hypertension, coronary heart disease, cerebrovascular disease (CVD), osteoporosis, arthritis, and cancer), low cognitive function, depression, and smoking were associated with worse functional outcomes. Exercise and moderate alcohol use were associated with better functional outcomes. Over the follow-up period, coronary heart disease, CVD, and depression were associated with increased rates of functional decline. Exercise and moderate alcohol consumption were associated with decreased rates of functional decline. Significant interactions were observed between exercise and coronary heart disease, moderate alcohol use and CVD, and cognition and CVD. CONCLUSIONS: Our study has identified not only risk factors associated with functional decline but also the interactions among these factors. These observations, along with other published research, add to the growing understanding of the underlying process of functional change and could provide a basis to design effective strategies to delay functional decline. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To learn whether managed care patients with Alzheimer's disease (AD) are more or less costly to care for than patients with other forms of dementia or patients without dementia during the last few years of life. DESIGN: Case control study. SETTING: A health maintenance organization base population. PARTICIPANTS: Three groups of subjects (mean age 85) who were deceased members of a dementia registry obtained from a health maintenance organization base population: 263 subjects with clinically diagnosed probable AD, 133 subjects with other forms of dementia, and 100 cognitively intact controls. MEASUREMENTS: Utilization records were examined for the 3 years preceding death. RESULTS: In all subcategories and in aggregate, utilization and costs of care were either similar or lower for patients with AD than for the other groups, even after controlling for age, gender, and comorbidity. CONCLUSIONS: Persons with AD do not incur higher costs than persons with other types of dementia or age-matched persons without dementia in a mature health maintenance organization during the last few years of life, when utilization is likely to be highest. [ABSTRACT FROM AUTHOR]

Background: Seizures are an important comorbidity in Alzheimer's disease (AD). Conflicting results regarding clinical parameters associated with seizures in AD were previously reported. Data on seizure recurrence risk, a crucial parameter for treatment decisions, are lacking. Methods: National Alzheimer's Coordinating Center data were analyzed. Seizure prevalence in AD and an association with disease duration were investigated. Associations of seizures with age of AD onset and with cognitive and functional performance, and seizure recurrence risk were studied. Results: 20,745 individuals were investigated. In AD dementia, seizure recurrence risk was 70.4% within 7.5 months. Seizure history was associated with an earlier age of onset of cognitive symptoms (seizures vs. no seizures: 64.7 vs. 70.4 years; p < 0.0001) and worse cognitive and functional performance (mean MMSE score: 16.6 vs. 19.6; mean CDR-sum of boxes score: 9.3 vs. 6.8; p < 0.0001; adjusted for disease duration and age). Seizure prevalence increased with duration of AD dementia (standardized OR = 1.55, 95% CI = 1.39–1.73, p < 0.0001), rising from 1.51% at 4.8 years to 5.43% at 11 years disease duration. Seizures were more frequent in AD dementia compared to normal controls (active seizures: 1.51% vs. 0.35%, p < 0.0001, OR = 4.34, 95% CI = 3.01–6.27; seizure history: 3.14% vs. 1.57%, p < 0.0001, OR = 2.03, 95% CI = 1.67–2.46). Conclusion: Seizures in AD dementia feature an exceptionally high recurrence risk and are associated with a poor course of cognitive symptoms. AD patients are at an increased risk for seizures, particularly in later disease stages. Our findings emphasize a need for seizure history assessment in AD, inform individual therapeutic decisions and underline the necessity of systematic treatment studies of AD-associated epilepsy. [ABSTRACT FROM AUTHOR]

Sex differences in the manifestations of Alzheimer's disease are under intense investigation. Despite the emerging importance of polygenic predictions for Alzheimer's disease, sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on Alzheimer's disease can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Relative to sex-mismatched scores, sex-matched polygenic hazard scores showed significantly stronger associations with age-at-disease-onset, clinical progression, amyloid deposition, neurofibrillary tangles, and composite neuropathological scores, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores, showed lower predictive power than polygenic hazard scores with no evidence for sex differences. Our results indicate that revealing sex-dependent genetic architecture requires the consideration of temporal processes of Alzheimer's disease. This has strong implications not only for the genetic underpinning of Alzheimer's disease but also for how we estimate sex-dependent polygenic effects for clinical use. [ABSTRACT FROM AUTHOR]

Primary age-related tauopathy is increasingly recognized as a separate neuropathological entity different from Alzheimer's disease. Both share the neuropathological features of tau aggregates and neuronal loss in the temporal lobe, but primary age-related tauopathy lacks the requisite amyloid plaques central to Alzheimer's disease. While both have similar clinical presentations, individuals with symptomatic primary age-related tauopathy are commonly of more advanced ages with milder cognitive dysfunction. Direct comparison of the neuropsychological trajectories of primary age-related tauopathy and Alzheimer's disease has not been thoroughly evaluated and thus, our objective was to determine how cognitive decline differs longitudinally between these two conditions after the onset of clinical symptoms. Data were obtained from the National Alzheimer's Coordinating Center on participants with mild cognitive impairment at baseline and either no neuritic plaques (i.e. primary age-related tauopathy) or moderate to frequent neuritic plaques (i.e. Alzheimer neuropathological change) at subsequent autopsy. For patients with Alzheimer's disease and primary age-related tauopathy, we compared rates of decline in the sum of boxes score from the CDR® Dementia Staging Instrument and in five cognitive domains (episodic memory, attention/working memory, executive function, language/semantic memory, and global composite) using z-scores for neuropsychological tests that were calculated based on scores for participants with normal cognition. The differences in rates of change were tested using linear mixed-effects models accounting for clinical centre clustering and repeated measures by individual. Models were adjusted for sex, age, education, baseline test score, Braak stage, apolipoprotein ε4 (APOE ε4) carrier status, family history of cognitive impairment, and history of stroke, hypertension, or diabetes. We identified 578 participants with a global CDR of 0.5 (i.e. mild cognitive impairment) at baseline, 126 with primary age-related tauopathy and 452 with Alzheimer's disease. Examining the difference in rates of change in CDR sum of boxes and in all domain scores, participants with Alzheimer's disease had a significantly steeper decline after becoming clinically symptomatic than those with primary age-related tauopathy. This remained true after adjusting for covariates. The results of this analysis corroborate previous studies showing that primary age-related tauopathy has slower cognitive decline than Alzheimer's disease across multiple neuropsychological domains, thus adding to the understanding of the neuropsychological burden in primary age-related tauopathy. The study provides further evidence to support the hypothesis that primary age-related tauopathy has distinct neuropathological and clinical features compared to Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner. [ABSTRACT FROM AUTHOR]

Introduction: Sexual minority discrimination might lead to a higher risk of mild cognitive impairment (MCI) and dementia. The aim of this study was to assess the risk of MCI and dementia between older adults in same-sex relationships (SSR) and opposite-sex relationships (OSR).Methods: We analyzed longitudinal data from the National Alzheimer's Coordinating Center up to September 2017. Analyses included cognitively normal individuals 55+ at baseline who had a spouse, partner, or companion as study partner at any assessment. Associations were calculated using survival analysis adjusting for demographics and APOE-e4 carrier status.Results: Hazard ratios of MCI and dementia did not differ statistically between SSR and OSR individuals in the total sample nor stratified by sex.Conclusion: The lack of association between SSR and MCI and dementia warrants future research into their potential resilience mechanisms and the inclusion of sexual minority status questions in research and surveillance studies. The potential recruitment bias caused by nonprobabilistic sampling of the cohort and the reporting and ascertainment bias caused by using SSR to infer sexual minority status may have influenced our findings. [ABSTRACT FROM AUTHOR]

Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-β protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 non-demented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = − 0.03, p = 4.25 × 10−8; β = 0.03, p = 3.97 × 10−8) than males (β = − 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture. [ABSTRACT FROM AUTHOR]

Age-related changes in memory are not uniform, even in the absence of dementia. Characterization of non-disease associated cognitive changes is crucial to gain a more complete understanding of brain aging. Episodic memory was investigated in 13,037 ethnically diverse elderly (ages 72 to 85 years) with two to 15 years of follow-up, and with known dementia status, age, sex, education, and APOE genotypes. Adjusted trajectories of episodic memory performance over time were estimated using Latent Class Mixed Models. Analysis was conducted using two samples at baseline evaluation: i) non-cognitively impaired individuals, and ii) all individuals regardless of dementia status. We calculated the age-specific annual incidence rates of dementia in the non-demented elderly (n = 10,220). Two major episodic memory trajectories were estimated: 1) Stable—consisting of individuals exhibiting a constant or improved memory function, and 2) Decliner—consisting of individuals whose memory function declined. The majority of the study participants maintain their memory performance over time. Compared to those with Stable trajectory, individuals characterized as Decliners were more likely to have non-white ethnic background, fewer years of education, a higher frequency of ε4 allele at APOE gene and five times more likely to develop dementia. The steepest decline in episodic memory was observed in Caribbean-Hispanics compared to non-Hispanic whites (p = 4.3 x 10−15). The highest incident rates of dementia were observed in the oldest age group, among those of Caribbean-Hispanics ancestry and among Decliners who exhibited rates five times higher than those with Stable trajectories (11 per 100 person-years versus 3 per 100 person-years. Age, education, ethnic background and APOE genotype influence the maintenance of episodic memory. Declining memory is one of the strongest predictors of incident dementia. [ABSTRACT FROM AUTHOR]

Preliminary studies suggest that neighborhood social and built environment (BE) characteristics may affect cognition in older adults. Older adults are particularly vulnerable to the neighborhood environment due to a decreasing range of routine travel with increasing age. We examined if multiple neighborhood BE characteristics are cross-sectionally associated with cognition in a diverse sample of older adults, and if the BE-cognition associations vary by individual-level demographics. The sample included 4539 participants from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to examine the associations between five BE measures and four cognitive measures, and effect modification by individual-level education and race/ethnicity. In the overall sample, increasing social destination density, walking destination density, and intersection density were associated with worse overall cognition, whereas increasing proportion of land dedicated to retail was associated with better processing speed. Effect modification results suggest that the association between urban density and worse cognition may be limited to or strongest in those of non-white race/ethnicity. Although an increase in neighborhood retail destinations was associated with better cognition in the overall sample, these results suggest that certain BE characteristics in dense urban environments may have a disproportionately negative association with cognition in vulnerable populations. However, our findings must be replicated in longitudinal studies and other regional samples. [ABSTRACT FROM AUTHOR]

Objective: Alzheimer's disease (AD) is a neurodegenerative disease, manifesting in clinically observable deficits in memory, thinking, and behavior that disproportionately affects older adults. Susceptibility genes, such as apolipoprotein ε4, have long been associated with an increased risk of AD diagnosis. Studies have shown associations between depression and increased risk of AD development. Furthermore, findings from previous investigations suggest mixed effects in the use of psychotropic medication in older adults. The hypothesis for this study is that antidepressant use modifies the increased hazard of depression or such that a non-significant hazard will result with respect to eventual AD development.Methods: Utilizing data from the National Alzheimer's Coordinating Center, we examined evaluations of 11,443 cognitively intact participants. Survival analysis was used to explore relationships between depression, apolipoprotein E, AD diagnosis, and antidepressant use.Results: An analytical sample of 8732 participants with normal cognition was examined. Among users of antidepressant medication, the hazard, in most cases, was no longer statistically significant. One generic medication showed protective benefits for users (p < 0.001). In addition, there was a statistically significant relationship between recent depression (n = 2083; p < 0.001), lifetime depression (n = 2068; p < 0.05), and ε4 carrier status (n = 2470; p < 0.001) and AD development.Conclusions: The findings suggest that a mechanism related to antidepressant use may reduce the hazard of eventual AD. Furthermore, the findings reinforce the association between depression, apolipoprotein E (APOE) ε4, and AD diagnosis. This study contributes to the emerging literature exploring interventions aimed at decreasing the risk of AD by targeting potentially modifiable psychosocial risk factors such as depression. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Identifying asymptomatic older individuals at elevated risk for developing Alzheimer disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE ɛ4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high Consortium to Establish a Registry for Alzheimer's Disease (amyloid) and Braak (tau) scores at autopsy, even among APOE ɛ4 noncarriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimer neurodegeneration. Ann Neurol 2017;82:484-488. [ABSTRACT FROM AUTHOR]

Context: Some evidence suggests that treating vascular risk factors and performing mentally stimulating activities may delay cognitive impairment onset in older adults. Exposure to a complex neighborhood environment may be one mechanism to help delay cognitive decline.Evidence Acquisition: PubMed, Web of Science, and ProQuest Dissertation and Theses Global database were systematically reviewed, identifying 25 studies published from February 1, 1989 to March 5, 2016 (data synthesized, May 3, 2015 to October 7, 2016). The review was restricted to quantitative studies focused on: (1) neighborhood social and built environment and cognition; and (2) community-dwelling adults aged ≥45 years.Evidence Synthesis: The majority of studies were cross-sectional, U.S.-based, and found at least one significant association. The diversity of measures and neighborhood definitions limited the synthesis of findings in many instances. Evidence was moderately strong for an association between neighborhood SES and cognition, and modest for associations between neighborhood demographics, design, and destination accessibility and cognition. Most studies examining effect modification found significant associations, with some evidence for effect modification of the neighborhood SES-cognition association by individual-level SES. No studies had low risk of bias and many tested multiple associations that increased the chance of a statistically significant finding. Considering the studies to date, the evidence for an association between neighborhood characteristics and cognition is modest.Conclusions: Future studies should include longitudinal measures of neighborhood characteristics and cognition; examine potential effect modifiers, such as sex and disability; and study mediators that may help elucidate the biological mechanisms linking neighborhood environment and cognition. [ABSTRACT FROM AUTHOR]

We examined the relationships between Alzheimer's disease neuropathologic change (ADNC), Lewy body disease (LBD), and vascular brain injury (VBI) in 2 large autopsy samples. Because findings may differ between study populations, data came from U.S. Alzheimer's Disease Centers contributing to the National Alzheimer's Coordinating Center (n = 2742) and from the population-based Adult Changes in Thought study (n = 499). Regardless of study population, over 50% of participants with ADNC had co-occurring LBD or VBI; the majority of whom had a clinical AD dementia diagnosis prior to death. Overlap of pathologies was similar between studies, especially after standardizing to the distribution of age and dementia status in the Adult Changes in Thought population. LBD, but not VBI, was positively associated with ADNC in both studies. Interestingly, cortical LBD was more common in those with intermediate ADNC compared to low or high ADNC, especially in the National Alzheimer's Coordinating Center ( p < 0.001). High prevalence of co-occurring neuropathologies among older adults with dementia has implications for accurate diagnosis of dementia etiologies and development of disease-modifying strategies. [ABSTRACT FROM AUTHOR]

Background: Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction.Methods and Findings: Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10-5). We then integrated these AD-associated SNPs into a Cox proportional hazard model using genotype data from a subset of 6,409 AD patients and 9,386 older controls from Phase 1 of the Alzheimer's Disease Genetics Consortium (ADGC), providing a polygenic hazard score (PHS) for each participant. By combining population-based incidence rates and the genotype-derived PHS for each individual, we derived estimates of instantaneous risk for developing AD, based on genotype and age, and tested replication in multiple independent cohorts (ADGC Phase 2, National Institute on Aging Alzheimer's Disease Center [NIA ADC], and Alzheimer's Disease Neuroimaging Initiative [ADNI], total n = 20,680). Within the ADGC Phase 1 cohort, individuals in the highest PHS quartile developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE ε3/3 individuals, the PHS modified expected age of AD onset by more than 10 y between the lowest and highest deciles (hazard ratio 3.34, 95% CI 2.62-4.24, p = 1.0 × 10-22). In independent cohorts, the PHS strongly predicted empirical age of AD onset (ADGC Phase 2, r = 0.90, p = 1.1 × 10-26) and longitudinal progression from normal aging to AD (NIA ADC, Cochran-Armitage trend test, p = 1.5 × 10-10), and was associated with neuropathology (NIA ADC, Braak stage of neurofibrillary tangles, p = 3.9 × 10-6, and Consortium to Establish a Registry for Alzheimer's Disease score for neuritic plaques, p = 6.8 × 10-6) and in vivo markers of AD neurodegeneration (ADNI, volume loss within the entorhinal cortex, p = 6.3 × 10-6, and hippocampus, p = 7.9 × 10-5). Additional prospective validation of these results in non-US, non-white, and prospective community-based cohorts is necessary before clinical use.Conclusions: We have developed a PHS for quantifying individual differences in age-specific genetic risk for AD. Within the cohorts studied here, polygenic architecture plays an important role in modifying AD risk beyond APOE. With thorough validation, quantification of inherited genetic variation may prove useful for stratifying AD risk and as an enrichment strategy in therapeutic trials. [ABSTRACT FROM AUTHOR]

Background: Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies.Methods: In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging-Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex.Findings: On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β -4·0, 95% CI -5·5 to -2·6; p<0·0001; R2 0·22, p<0·0001) and with survival (-2·0, -3·2 to -0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates.Interpretation: Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology.Funding: US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke). [ABSTRACT FROM AUTHOR]

Risk factors and cognitive sequelae of brain arteriolosclerosis pathology are not fully understood. To address this, we used multimodal data from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative data sets. Previous studies showed evidence of distinct neurodegenerative disease outcomes and clinical-pathological correlations in the "oldest-old" compared to younger cohorts. Therefore, using the National Alzheimer's Coordinating Center data set, we analyzed clinical and neuropathological data from two groups according to ages at death: < 80 years (n = 1008) and ≥80 years (n = 1382). In both age groups, severe brain arteriolosclerosis was associated with worse performances on global cognition tests. Hypertension (but not diabetes) was a brain arteriolosclerosis risk factor in the younger group. In the ≥80 years age at death group, an ABCC9 gene variant (rs704180), previously associated with aging-related hippocampal sclerosis, was also associated with brain arteriolosclerosis. A post-hoc arterial spin labeling neuroimaging experiment indicated that ABCC9 genotype is associated with cerebral blood flow impairment; in a convenience sample from Alzheimer's Disease Neuroimaging Initiative (n = 15, homozygous individuals), non-risk genotype carriers showed higher global cerebral blood flow compared to risk genotype carriers. We conclude that brain arteriolosclerosis is associated with altered cognitive status and a novel vascular genetic risk factor. [ABSTRACT FROM AUTHOR]

We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer's neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer's Coordinating Center/Alzheimer's Disease Genetic Consortium data; n = 2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer's Disease Neuroimaging Initiative data; n = 1239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically, because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases ( p < 0.04 in two separately analyzed groups), but not in Alzheimer's disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker. [ABSTRACT FROM AUTHOR]

Objective The ε4 allele of apolipoprotein E ( APOE) is the strongest known common genetic risk factor for Alzheimer's disease (AD) and alters age of onset in retrospective studies. Here, we longitudinally test the effects of APOE ε4 genotype and age during progression from normal cognition to AD. Methods Using data from 5381 cognitively normal older individuals and Cox proportional hazards models, we longitudinally tested the effects of APOE genotype on progression from normal cognition to mild cognitive impairment (MCI) or AD in four age strata (<60, 60-70, 70-80, 80 + ) and with a sliding window approach between ages 60 and 85. Results We found that APOE ε4 carrier status and dosage significantly influenced progression to MCI or AD in all four age groups and that APOE ε4-associated progression risk peaked between ages 70 and 75. We confirmed APOE ε4-associated progression risk in a subset of the cohort with pathologically proven diagnoses. Interpretation Our findings indicate that in clinically normal individuals, APOE ε4 status significantly predicts progression to MCI or AD across older adulthood and that this risk varies with age. This information will be useful as therapeutic interventions become available and clinical decisions can be individually tailored based on age and genetic data. [ABSTRACT FROM AUTHOR]

The classic pathologic hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with "AD-type" (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer's disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans—e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as AD-related were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P < 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies. • A subset of AD-type dementia gene variants were associated with plaques & tangles (ADNC). • Other gene variants linked to dementia were associated with non-ADNC pathologies. • Gene variants in TNIP1 and WNT3 were associated with hippocampal sclerosis. • A SORL1 variant showed a trend for association with LATE-NC + ADNC. • In non-Europeans, there was a trend for an ABCA7 variant to be associated with ADNC. [ABSTRACT FROM AUTHOR]

Objective Alzheimer’s disease (AD) is the result of neurodegeneration, which manifests clinically as deficits in memory, thinking, and behavior. It was hypothesized that neuropsychiatric symptoms and the apolipoprotein E genotype increase the likelihood of Alzheimer’s disease development. Methods Utilizing data from the National Alzheimer’s Coordinating Center, information from evaluations of 11,453 cognitively intact participants was analyzed. Survival analysis was used to explore relationships between individual neuropsychiatric symptoms as determined by the Neuropsychiatric Inventory Questionnaire, apolipoprotein E, and eventual AD diagnosis. Cox proportional hazard models were utilized to explore the main effects and synergistic (additive and multiplicative) interactions. Results This study provided evidence for an increased hazard of developing AD among participants with any of the symptoms assessed by the NPI-Q. The hazard of developing AD was almost thirteen times higher for ε 4 carriers with delusions and eleven times greater for those with apathy and disinhibition. Statistically significant hazards ( p > 0.001) were also realized by ε 4 carriers with hallucinations; agitation; depression; anxiety; elation; apathy; irritability; and motor, sleep, and appetite disturbances. Conclusions Findings suggest that neuropsychiatric symptoms are associated with eventual AD diagnosis among a group of cognitively asymptomatic participants at baseline. Many studies begin with a group of participants already impacted by AD diagnosis. The longitudinal analysis of a group of participants who, at baseline, demonstrated no observable signs of AD was a strength of this study. This investigation contributes to the literature exploring an increased hazard of AD due to potential modifiable risk factors and genetic biomarkers such as apolipoprotein E. [ABSTRACT FROM AUTHOR]

Introduction: No known studies have compared longitudinal characteristics between individuals with incident mild cognitive impairment due to Parkinson's disease (PD-MCI) versus Alzheimer's Disease (AD-MCI).Methods: We used longitudinal data from the National Alzheimer's Coordinating Center's Uniform Data Set to compare 41 PD-MCI and 191 AD-MCI participants according to their demographics, presence of ≥1 APOE e4 allele, and baseline and change over time in clinical characteristics, neuropsychological test scores, and Clinical Dementia Rating sum of boxes (CDR-SB). Multivariable linear regression models with generalized estimating equations were used to account for clustered data and to test for baseline and longitudinal differences in neuropsychological test scores.Results: PD-MCI and AD-MCI participants differed by many demographic and clinical characteristics. Significantly fewer PD-MCI participants developed dementia over one year. Compared to AD-MCI participants, PD-MCI participants performed better at baseline and over time on a global measure of cognition (Mini Mental State Exam), memory measures (immediate and delayed Logical Memory), and a language measure (Boston Naming Test), and additionally performed better over time on an attention measure (Digit Span Forward), a language measure (Vegetable List), a processing speed measure (Digit Symbol), and an overall measure of memory and functional impairment (CDR-SB).Conclusion: Our study provides further evidence that PD-MCI is clinically distinct from AD-MCI and requires different tools for diagnosis and monitoring clinical progression. More importantly, this study suggests that PD-MCI takes longer to convert into dementia than AD-MCI, findings that require replication by other studies. [ABSTRACT FROM AUTHOR]

We examined the relationship between cerebral amyloid angiopathy (CAA), Alzheimer's disease neuropathologic changes, other vascular brain pathologies, and cognition in a large multicenter autopsy sample. Data were obtained from the National Alzheimer's Coordinating Center on autopsied subjects ( N = 3976) who died between 2002 and 2012. Descriptive statistics and multivariable regression models estimated the associations between CAA and other pathologies, and between CAA severity and cognitive test scores proximal to death. CAA tended to co-occur with Alzheimer's disease neuropathologic changes but a minority of cases were discrepant. CAA was absent in 22% ( n = 520) of subjects with frequent neuritic plaques but present in 20.9% ( n = 91) of subjects with no neuritic plaques. In subjects with no/sparse neuritic plaques, nonhemorrhagic brain infarcts were more common in those with CAA pathology than without ( p = 0.007). In subjects without the APOE ε4 allele, CAA severity was associated with lower cognition proximal to death, factoring in other pathologies. The presence of CAA in patients without Alzheimer's disease may indicate a distinct cerebrovascular condition. [ABSTRACT FROM AUTHOR]

Diagnosing behavioral variant frontotemporal dementia (bvFTD) in patients with prior history of stroke or with silent brain infarcts on neuroimaging studies can be challenging. Vascular changes in patients with bvFTD are not unusual, but bvFTD tends to be ruled out in the presence of cerebrovascular disease. We aimed to identify the clinical, cognitive, and risk factor profile of bvFTD with coexistent cerebrovascular disease (V-bvFTD). We compared demographic data, clinical diagnoses, vascular risk factors, functional status, and normalized neuropsychological z-scores between patients with V-bvFTD versus bvFTD without concomitant cerebrovascular disease (NV-bvFTD) from the National Alzheimer's Coordinating Centre database. We included 391 neuropathologically-diagnosed cases of frontotemporal lobe degeneration. We excluded patients that were diagnosed with aphasic variants of frontotemporal dementia before death. Patients with V-bvFTD (n = 62) were older at the time of onset of cognitive decline (71.6 vs. 62.5 years, p < 0.001) and death (78.7 vs. 69.6, p < 0.001), more likely to be hypertensive (75.8% vs. 45.7%, p = 0.002) and to have a history of stroke (21.2% vs. 6.1%, p = 0.007) than those with NV-bvFTD (n = 329). V-bvFTD was often underdiagnosed, affected elderly patients, and had a similar cognitive profile as NV-bvFTD despite the presence of brain infarcts. In the whole cohort, we observed enhanced cognitive performance with increasing age quintiles despite larger proportions of cerebrovascular disease pathology, likely meaning that frontotemporal lobe degeneration–related primary neurodegeneration exerts a stronger impact on cognition than cerebrovascular disease. Coexisting cerebrovascular disease should not preclude the diagnosis of bvFTD. [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 ( ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance ( p = 1.4 × 10), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 ( GRN) and OR = 1.22 rs1990622 ( TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database ( n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology ( p = 0.03). Thus, we describe a novel and targetable dementia risk factor. [ABSTRACT FROM AUTHOR]

Abstract: Background: Apolipoprotein (APOE) e4 allele status has been linked to clinical presentation and progression in Alzheimer's disease; however, evidence for a role of APOE e4 in Parkinson's disease (PD) remains largely inconclusive. In this analysis we explored potential significant associations between APOE e4 allele status and characteristics of clinical presentation in patients with PD. Methods: Data came from 424 subjects evaluated using the Uniform Data Set (UDS) assessment collected by the National Alzheimer's Coordinating Center. Subjects had a known year of diagnosis of PD and experienced change in motor function prior to any change in cognition. Linear and logistic regression were used to model the association between APOE e4 carrier status and clinical characteristics including measures of cognitive decline and motor and neuropsychiatric symptoms. Amyloid burden was also evaluated for a subset of patients who died and consented to autopsy. Results: Odds of dementia were higher in APOE e4 carriers (OR = 5.15), and, on average, APOE e4 carriers scored two points worse on tests of episodic memory and the Clinical Dementia Rating Sum of Boxes assessment. There was little evidence to support an association between e4 carrier status and severity of motor features, and, of the four neuropsychiatric symptoms evaluated, only presence of hallucinations was significantly associated with APOE e4 carrier status (OR = 5.29). Neuropathology data revealed higher frequencies of neuritic and diffuse amyloid plaques in APOE e4 carriers compared to non-carriers. Conclusions: APOE e4 allele status is associated with dementia and severity of Alzheimer's disease pathologic features in PD. [Copyright &y& Elsevier]

Hippocampal sclerosis of aging (HS-Aging) neuropathology was observed in more than 15% of aged individuals in prior studies. However, much remains unknown about the clinical correlates of HS-Aging pathology or the association(s) between HS-Aging, Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) pathology. Clinical and comorbid pathological features linked to HS-Aging pathology were analyzed using National Alzheimer's Coordinating Center (NACC) data. From autopsy data extending back to 1990 (n = 9,817 participants), the neuropathological diagnoses were evaluated from American AD Centers (ADCs). Among participants who died between 2005-2012 (n = 1,422), additional analyses identified clinical and pathological features associated with HS-Aging pathology. We also compared cognitive testing and longevity outcomes between HS-Aging cases and a subsample with non-tauopathy FTLD (n = 210). Reporting of HS-Aging pathology increased dramatically among ADCs in recent years, to nearly 20% of autopsies in 2012. Participants with relatively 'pure' HS-Aging pathology were often diagnosed clinically as having probable (68%) or possible (15%) AD. However, the co-occurrence of HS-Aging pathology and AD neuropathology (AD-NP) did not indicate any pattern of correlation between the two pathologies. Compared with other pathologies, participants with HS-Aging pathology had higher overall cognitive/functional ability (versus AD-NP) and verbal fluency (versus both AD-NP and FTLD) but similar episodic memory impairment at one clinic visit 2-5 years prior to death. Patients with HS-Aging live considerably longer than patients with non-tauopathy FTLD. We conclude that the manifestations of HS-Aging, increasingly recognized in recent years, probably indicate a separate disease process of direct relevance to patient care, dementia research, and clinical trials. [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis of aging (HS-Aging) neuropathology was observed in more than 15% of aged individuals in prior studies. However, much remains unknown about the clinical correlates of HS-Aging pathology or the association(s) between HS-Aging, Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) pathology. Clinical and comorbid pathological features linked to HS-Aging pathology were analyzed using National Alzheimer's Coordinating Center (NACC) data. From autopsy data extending back to 1990 (n = 9,817 participants), the neuropathological diagnoses were evaluated from American AD Centers (ADCs). Among participants who died between 2005-2012 (n = 1,422), additional analyses identified clinical and pathological features associated with HS-Aging pathology. We also compared cognitive testing and longevity outcomes between HS-Aging cases and a subsample with non-tauopathy FTLD (n = 210). Reporting of HS-Aging pathology increased dramatically among ADCs in recent years, to nearly 20% of autopsies in 2012. Participants with relatively "pure" HS-Aging pathology were often diagnosed clinically as having probable (68%) or possible (15%) AD. However, the co-occurrence of HS-Aging pathology and AD neuropathology (AD-NP) did not indicate any pattern of correlation between the two pathologies. Compared with other pathologies, participants with HS-Aging pathology had higher overall cognitive/functional ability (versus AD-NP) and verbal fluency (versus both AD-NP and FTLD) but similar episodic memory impairment at one clinic visit 2-5 years prior to death. Patients with HS-Aging live considerably longer than patients with non-tauopathy FTLD. We conclude that the manifestations of HS-Aging, increasingly recognized in recent years, probably indicate a separate disease process of direct relevance to patient care, dementia research, and clinical trials. [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis of ageing is a prevalent brain disease that afflicts older persons and has been linked with cerebrovascular pathology. Arteriolosclerosis is a subtype of cerebrovascular pathology characterized by concentrically thickened arterioles. Here we report data from multiple large autopsy series (University of Kentucky Alzheimer’s Disease Centre, Nun Study, and National Alzheimer’s Coordinating Centre) showing a specific association between hippocampal sclerosis of ageing pathology and arteriolosclerosis. The present analyses incorporate 226 cases of autopsy-proven hippocampal sclerosis of ageing and 1792 controls. Case–control comparisons were performed including digital pathological assessments for detailed analyses of blood vessel morphology. We found no evidence of associations between hippocampal sclerosis of ageing pathology and lacunar infarcts, large infarcts, Circle of Willis atherosclerosis, or cerebral amyloid angiopathy. Individuals with hippocampal sclerosis of ageing pathology did not show increased rates of clinically documented hypertension, diabetes, or other cardiac risk factors. The correlation between arteriolosclerosis and hippocampal sclerosis of ageing pathology was strong in multiple brain regions outside of the hippocampus. For example, the presence of arteriolosclerosis in the frontal cortex (Brodmann area 9) was strongly associated with hippocampal sclerosis of ageing pathology (P < 0.001). This enables informative evaluation of anatomical regions outside of the hippocampus. To assess the morphology of brain microvasculature far more rigorously than what is possible using semi-quantitative pathological scoring, we applied digital pathological (Aperio ScanScope) methods on a subsample of frontal cortex sections from hippocampal sclerosis of ageing (n = 15) and control (n = 42) cases. Following technical studies to optimize immunostaining methods for small blood vessel visualization, our analyses focused on sections immunostained for smooth muscle actin (a marker of arterioles) and CD34 (an endothelial marker), with separate analyses on grey and white matter. A total of 43 834 smooth muscle actin-positive vascular profiles and 603 798 CD34-positive vascular profiles were evaluated. In frontal cortex of cases with hippocampal sclerosis of ageing, smooth muscle actin-immunoreactive arterioles had thicker walls (P < 0.05), larger perimeters (P < 0.03), and larger vessel areas (P < 0.03) than controls. Unlike the arterioles, CD34-immunoreactive capillaries had dimensions that were unchanged in cases with hippocampal sclerosis of ageing versus controls. Arteriolosclerosis appears specific to hippocampal sclerosis of ageing brains, because brains with Alzheimer’s disease pathology did not show the same morphological alterations. We conclude that there may be a pathogenetic change in aged human brain arterioles that impacts multiple brain areas and contributes to hippocampal sclerosis of ageing. [ABSTRACT FROM PUBLISHER]

Cerebrovascular disease and vascular risk factors are associated with Alzheimer's disease, but the evidence for their association with other neurodegenerative disorders is limited. Therefore, we compared the prevalence of cerebrovascular disease, vascular pathology and vascular risk factors in a wide range of neurodegenerative diseases and correlate them with dementia severity. Presence of cerebrovascular disease, vascular pathology and vascular risk factors was studied in 5715 cases of the National Alzheimer's Coordinating Centre database with a single neurodegenerative disease diagnosis (Alzheimer's disease, frontotemporal lobar degeneration due to tau, and TAR DNA-binding protein 43 immunoreactive deposits, α-synucleinopathies, hippocampal sclerosis and prion disease) based on a neuropathological examination with or without cerebrovascular disease, defined neuropathologically. In addition, 210 'unremarkable brain' cases without cognitive impairment, and 280 cases with pure cerebrovascular disease were included for comparison. Cases with cerebrovascular disease were older than those without cerebrovascular disease in all the groups except for those with hippocampal sclerosis. After controlling for age and gender as fixed effects and centre as a random effect, we observed that α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease showed a lower prevalence of coincident cerebrovascular disease than patients with Alzheimer's disease, and this was more significant in younger subjects. When cerebrovascular disease was also present, patients with Alzheimer's disease and patients with α-synucleinopathy showed relatively lower burdens of their respective lesions than those without cerebrovascular disease in the context of comparable severity of dementia at time of death. Concurrent cerebrovascular disease is a common neuropathological finding in aged subjects with dementia, is more common in Alzheimer's disease than in other neurodegenerative disorders, especially in younger subjects, and lowers the threshold for dementia due to Alzheimer's disease and α-synucleinopathies, which suggests that these disorders should be targeted by treatments for cerebrovascular disease. [ABSTRACT FROM AUTHOR]

Cerebrovascular disease and vascular risk factors are associated with Alzheimer’s disease, but the evidence for their association with other neurodegenerative disorders is limited. Therefore, we compared the prevalence of cerebrovascular disease, vascular pathology and vascular risk factors in a wide range of neurodegenerative diseases and correlate them with dementia severity. Presence of cerebrovascular disease, vascular pathology and vascular risk factors was studied in 5715 cases of the National Alzheimer’s Coordinating Centre database with a single neurodegenerative disease diagnosis (Alzheimer’s disease, frontotemporal lobar degeneration due to tau, and TAR DNA-binding protein 43 immunoreactive deposits, α-synucleinopathies, hippocampal sclerosis and prion disease) based on a neuropathological examination with or without cerebrovascular disease, defined neuropathologically. In addition, 210 ‘unremarkable brain’ cases without cognitive impairment, and 280 cases with pure cerebrovascular disease were included for comparison. Cases with cerebrovascular disease were older than those without cerebrovascular disease in all the groups except for those with hippocampal sclerosis. After controlling for age and gender as fixed effects and centre as a random effect, we observed that α-synucleinopathies, frontotemporal lobar degeneration due to tau and TAR DNA-binding protein 43, and prion disease showed a lower prevalence of coincident cerebrovascular disease than patients with Alzheimer’s disease, and this was more significant in younger subjects. When cerebrovascular disease was also present, patients with Alzheimer’s disease and patients with α-synucleinopathy showed relatively lower burdens of their respective lesions than those without cerebrovascular disease in the context of comparable severity of dementia at time of death. Concurrent cerebrovascular disease is a common neuropathological finding in aged subjects with dementia, is more common in Alzheimer’s disease than in other neurodegenerative disorders, especially in younger subjects, and lowers the threshold for dementia due to Alzheimer’s disease and α-synucleinopathies, which suggests that these disorders should be targeted by treatments for cerebrovascular disease. [ABSTRACT FROM PUBLISHER]

The feasibility of using imperfectly phenotyped “silver standard” samples identified from electronic medical record diagnoses is considered in genetic association studies when these samples might be combined with an existing set of samples phenotyped with a gold standard technique. An analytic expression is derived for the power of a chi-square test of independence using either research-quality case/control samples alone, or augmented with silver standard data. The subset of the parameter space where inclusion of silver standard samples increases statistical power is identified. A case study of dementia subjects identified from electronic medical records from the Electronic Medical Records and Genomics (eMERGE) network, combined with subjects from two studies specifically targeting dementia, verifies these results. [ABSTRACT FROM AUTHOR]

Abstract: Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia. [Copyright &y& Elsevier]