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Background and Objectives: Previous randomized controlled trials and longitudinal studies have indicated that ongoing antihypertensive use in late life reduces all-cause dementia risk, but the specific impact on Alzheimer dementia (AD) and non-AD risk remains unclear. This study investigates whether previous hypertension or antihypertensive use modifies AD or non-AD risk in late life and the ideal blood pressure (BP) for risk reduction in a diverse consortium of cohort studies., Methods: This individual participant data meta-analysis included community-based longitudinal studies of aging from a preexisting consortium. The main outcomes were risk of developing AD and non-AD. The main exposures were hypertension history/antihypertensive use and baseline systolic BP/diastolic BP. Mixed-effects Cox proportional hazards models were used to assess risk and natural splines were applied to model the relationship between BP and the dementia outcomes. The main model controlled for age, age 2 , sex, education, ethnoracial group, and study cohort. Supplementary analyses included a fully adjusted model, an analysis restricting to those with >5 years of follow-up and models that examined the moderating effect of age, sex, and ethnoracial group., Results: There were 31,250 participants from 14 nations in the analysis (41% male) with a mean baseline age of 72 (SD 7.5, range 60-110) years. Participants with untreated hypertension had a 36% (hazard ratio [HR] 1.36, 95% CI 1.01-1.83, p = 0.0406) and 42% (HR 1.42, 95% CI 1.08-1.87, p = 0.0135) increased risk of AD compared with "healthy controls" and those with treated hypertension, respectively. Compared with "healthy controls" both those with treated (HR 1.29, 95% CI 1.03-1.60, p = 0.0267) and untreated hypertension (HR 1.69, 95% CI 1.19-2.40, p = 0.0032) had greater non-AD risk, but there was no difference between the treated and untreated groups. Baseline diastolic BP had a significant U-shaped relationship ( p = 0.0227) with non-AD risk in an analysis restricted to those with 5-year follow-up, but otherwise there was no significant relationship between baseline BP and either AD or non-AD risk., Discussion: Antihypertensive use was associated with decreased AD but not non-AD risk throughout late life. This suggests that treating hypertension throughout late life continues to be crucial in AD risk mitigation. A single measure of BP was not associated with AD risk, but DBP may have a U-shaped relationship with non-AD risk over longer periods in late life.

Introduction: The LIfestyle for BRAin Health (LIBRA) index yields a dementia risk score based on modifiable lifestyle factors and is validated in Western samples. We investigated whether the association between LIBRA scores and incident dementia is moderated by geographical location or sociodemographic characteristics., Methods: We combined data from 21 prospective cohorts across six continents (N = 31,680) and conducted cohort-specific Cox proportional hazard regression analyses in a two-step individual participant data meta-analysis., Results: A one-standard-deviation increase in LIBRA score was associated with a 21% higher risk for dementia. The association was stronger for Asian cohorts compared to European cohorts, and for individuals aged ≤75 years (vs older), though only within the first 5 years of follow-up. No interactions with sex, education, or socioeconomic position were observed., Discussion: Modifiable risk and protective factors appear relevant for dementia risk reduction across diverse geographical and sociodemographic groups., Highlights: A two-step individual participant data meta-analysis was conducted. This was done at a global scale using data from 21 ethno-regionally diverse cohorts. The association between a modifiable dementia risk score and dementia was examined. The association was modified by geographical region and age at baseline. Yet, modifiable dementia risk and protective factors appear relevant in all investigated groups and regions., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Motoric cognitive risk syndrome (MCR) is a predementia condition that combines slow gait speed and subjective cognitive concerns (SCC). The SCC criterion is presently unstandardized, possibly limiting risk detection. We sought to (a) characterize SCC practices through MCR literature review; (b) investigate the ability of SCC in slow gait individuals in predicting the likelihood of cognitive impairment in a demographically diverse sample of community-dwelling, nondemented older adults., Methods: First, we comprehensively reviewed the MCR literature, extracting information regarding SCC measures, items, sources, and cognitive domain. Next, Einstein Aging Study (EAS) participants (N = 278, Mage = 77.22 ± 4.74, %female = 67, Meducation = 15 ± 3.61, %non-Hispanic White = 46.3) completed gait, Clinical Dementia Rating Scale (CDR), and SCC assessment at baseline and annual follow-up (Mfollow-up = 3.5). Forty-two participants met slow gait criteria at baseline. Generalized linear mixed-effects models examined baseline SCC to predict cognitive impairment on CDR over follow-up., Results: We reviewed all published MCR studies (N = 106) and documented ambiguity in SCC criteria, with a prevalent approach being use of a single self-reported memory item. In EAS, high SCC endorsement on a comprehensive, validated screen significantly affected the rate of cognitive impairment (CDR; βinteraction = 0.039, p = .018) in slow gait individuals., Conclusions: An assessment approach that queries across numerous SCC domains was found to predict future decline in clinical dementia status in slow gait older adults. Current SCC practices in MCR, which tend to utilize a single-memory item, may not be the optimal approach. We discuss the implications of SCC criteria validation and standardization to enhance early dementia detection in MCR., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The extent to which the Big Five personality traits and subjective well-being (SWB) are discriminatory predictors of clinical manifestation of dementia versus dementia-related neuropathology is unclear., Methods: Using data from eight independent studies (N total = 44,531; N dementia = 1703; baseline M age = 49 to 81 years, 26 to 61% female; M follow-up range = 3.53 to 21.00 years), Bayesian multilevel models tested whether personality traits and SWB differentially predicted neuropsychological and neuropathological characteristics of dementia., Results: Synthesized and individual study results indicate that high neuroticism and negative affect and low conscientiousness, extraversion, and positive affect were associated with increased risk of long-term dementia diagnosis. There were no consistent associations with neuropathology., Discussion: This multistudy project provides robust, conceptually replicated and extended evidence that psychosocial factors are strong predictors of dementia diagnosis but not consistently associated with neuropathology at autopsy., Highlights: N(+), C(-), E(-), PA(-), and NA(+) were associated with incident diagnosis. Results were consistent despite self-report versus clinical diagnosis of dementia. Psychological factors were not associated with neuropathology at autopsy. Individuals with higher conscientiousness and no diagnosis had less neuropathology. High C individuals may withstand neuropathology for longer before death., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Importance: The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested., Objectives: To assess the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (age >60 years) with dementia and the moderating factors of age, sex, and racial group., Data Source and Study Selection: Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries (US, Brazil, Australia, China, Korea, Singapore, Central African Republic, Republic of Congo, Nigeria, Germany, Spain, Italy, France, Sweden, and Greece)., Data Extraction and Synthesis: Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data reporting guidelines., Main Outcomes and Measures: The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group., Results: The analysis included 17 studies with 34 519 community dwelling older adults (20 160 [58.4%] female) with a mean (SD) age of 72.5 (7.5) years and a mean (SD) follow-up of 4.3 (4.3) years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio [HR], 1.42; 95% CI 1.15-1.76; P = .001) and 26% increased risk compared with individuals with treated hypertension (HR, 1.26; 95% CI, 1.03-1.53; P = .02). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls (HR, 1.13; 95% CI, 0.99-1.28; P = .07). The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses., Conclusions and Relevance: This individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

Introduction: Sex differences in dementia risk, and risk factor (RF) associations with dementia, remain uncertain across diverse ethno-regional groups., Methods: A total of 29,850 participants (58% women) from 21 cohorts across six continents were included in an individual participant data meta-analysis. Sex-specific hazard ratios (HRs), and women-to-men ratio of hazard ratios (RHRs) for associations between RFs and all-cause dementia were derived from mixed-effect Cox models., Results: Incident dementia occurred in 2089 (66% women) participants over 4.6 years (median). Women had higher dementia risk (HR, 1.12 [1.02, 1.23]) than men, particularly in low- and lower-middle-income economies. Associations between longer education and former alcohol use with dementia risk (RHR, 1.01 [1.00, 1.03] per year, and 0.55 [0.38, 0.79], respectively) were stronger for men than women; otherwise, there were no discernible sex differences in other RFs., Discussion: Dementia risk was higher in women than men, with possible variations by country-level income settings, but most RFs appear to work similarly in women and men., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Aim: To synthesize international findings on the alcohol-dementia relationship, including representation from low- and middle-income countries., Methods: Individual participant data meta-analysis of 15 prospective epidemiological cohort studies from countries situated in six continents. Cox regression investigated the dementia risk associated with alcohol use in older adults aged over 60 years. Additional analyses assessed the alcohol-dementia relationship in the sample stratified by sex and by continent. Participants included 24 478 community dwelling individuals without a history of dementia at baseline and at least one follow-up dementia assessment. The main outcome measure was all-cause dementia as determined by clinical interview., Results: At baseline, the mean age across studies was 71.8 (standard deviation = 7.5, range = 60-102 years), 14 260 (58.3%) were female and 13 269 (54.2%) were current drinkers. During 151 636 person-years of follow-up, there were 2124 incident cases of dementia (14.0 per 1000 person-years). When compared with abstainers, the risk for dementia was lower in occasional [hazard ratio (HR) = 0.78; 95% confidence interval (CI) = 0.68-0.89], light-moderate (HR = 0.78; 95% CI = 0.70-0.87) and moderate-heavy drinkers (HR = 0.62; 95% CI = 0.51-0.77). There was no evidence of differences between life-time abstainers and former drinkers in terms of dementia risk (HR = 0.98; 95% CI = 0.81-1.18). In dose-response analyses, moderate drinking up to 40 g/day was associated with a lower risk of dementia when compared with lif-time abstaining. Among current drinkers, there was no consistent evidence for differences in terms of dementia risk. Results were similar when the sample was stratified by sex. When analysed at the continent level, there was considerable heterogeneity in the alcohol-dementia relationship., Conclusions: Abstinence from alcohol appears to be associated with an increased risk for all-cause dementia. Among current drinkers, there appears to be no consistent evidence to suggest that the amount of alcohol consumed in later life is associated with dementia risk., (© 2022 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Introduction: Though consistent evidence suggests that physical activity may delay dementia onset, the duration and amount of activity required remains unclear., Methods: We harmonized longitudinal data of 11,988 participants from 10 cohorts in eight countries to examine the dose-response relationship between late-life physical activity and incident dementia among older adults., Results: Using no physical activity as a reference, dementia risk decreased with duration of physical activity up to 3.1 to 6.0 hours/week (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.67 to 1.15 for 0.1 to 3.0 hours/week; HR 0.68, 95% CI 0.52 to 0.89 for 3.1 to 6.0 hours/week), but plateaued with higher duration. For the amount of physical activity, a similar pattern of dose-response curve was observed, with an inflection point of 9.1 to 18.0 metabolic equivalent value (MET)-hours/week (HR 0.92, 95% CI 0.70 to 1.22 for 0.1 to 9.0 MET-hours/week; HR 0.70, 95% CI 0.53 to 0.93 for 9.1 to 18.0 MET-hours/week)., Discussion: This cross-national analysis suggests that performing 3.1 to 6.0 hours of physical activity and expending 9.1 to 18.0/MET-hours of energy per week may reduce dementia risk., (© 2022 the Alzheimer's Association.)

Background: falls share risk factors with cognitive decline but whether falls predict cognitive decline, pre-dementia syndromes and dementia is poorly understood., Objectives: this study aimed to examine if falls are associated with cognitive decline in specific domains and the risk of Motoric Cognitive Risk (MCR) syndrome and dementia., Design: cross-sectional study., Methods: in older people (age 80.6 ± 5.3 years) free of dementia at baseline, the number of falls (none, one or multiple) during the year before enrolment and the first year of follow-up (exposure) were recorded. Decline in specific cognitive functions (global cognition, episodic verbal memory, verbal fluency, working memory, response inhibition and processing speed-attention), incident MCR and incident dementia were outcome measures. Linear mixed effects models were used to examine the associations between falls and cognitive decline, adjusting for confounders. Cox proportional hazards models were used to determine if falls predicted risk of incident MCR or dementia., Results: of 522 eligible participants, 140 had a single fall and 70 had multiple falls. Multiple falls were associated with a greater decline in global cognition, episodic memory, verbal fluency and processing speed-attention compared to those with no falls (P < 0.05). Over a median follow-up of 1.0 years 36 participants developed MCR and 43 participants developed dementia. Those with multiple falls had a two-fold increased risk of MCR compared to those with no falls, but no increased risk of developing dementia., Conclusions: multiple falls may be an important marker to identify older people at greater risk of future cognitive decline and incident MCR., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Education and occupational complexity are main sources of mental engagement during early life and adulthood respectively, but research findings are not conclusive regarding protective effects of these factors against late-life dementia., Objective: This project aimed to examine the unique contributions of education and occupational complexity to incident dementia, and to assess the mediating effects of occupational complexity on the association between education and dementia across diverse cohorts., Method: We used data from 10,195 participants (median baseline age = 74.1, range = 58∼103), representing 9 international datasets from 6 countries over 4 continents. Using a coordinated analysis approach, the accelerated failure time model was applied to each dataset, followed by meta-analysis. In addition, causal mediation analyses were performed., Result: The meta-analytic results indicated that both education and occupational complexity were independently associated with increased dementia-free survival time, with 28%of the effect of education mediated by occupational complexity. There was evidence of threshold effects for education, with increased dementia-free survival time associated with 'high school completion' or 'above high school' compared to 'middle school completion or below'., Conclusion: Using datasets from a wide range of geographical regions, we found that both early life education and adulthood occupational complexity were independently predictive of dementia. Education and occupational experiences occur during early life and adulthood respectively, and dementia prevention efforts could thus be made at different stages of the life course.

Background: Population-based studies typically rely on self-reported medical diagnosis (SRMD) of mild cognitive impairment (MCI)/dementia; however, links to objective neurocognitive function have not been established., Objective: Examine the association between SRMD of MCI/dementia and objective neurocognitive function among Hispanic/Latino adults., Methods: We conducted a case-control study using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) baseline data and its ancillary SOL-Investigation of Neurocognitive Aging (SOL-INCA) at visit 2. Hispanic/Latino adults aged 50 years and older (n = 593) were administered neurocognitive tests: the Six-Item Screener (SIS), Brief-Spanish English Verbal Learning Test (B-SVELT Sum), B-SVELT Recall, Word Fluency Test (WF), Digit Symbol Substitution Test (DSS), and Trail Making Test A and B. Individual and global neurocognitive function scores were used for analyses. Propensity matching techniques and survey generalized linear regression models were used to compare SRMD of MCI/dementia with demographic, psychological, and cardiovascular risk matched controls. Complex survey design methods were applied., Results: There were 121 cases of SRMD of MCI/dementia and 472 propensity matched controls. At baseline, compared to matched controls, cases showed no differences in neurocognitive function (p > 0.05). At SOL-INCA visit 2, cases had poorer scores in global neurocognitive function (p < 0.05), B-SEVLT Sum, B-SEVLT Recall, WF, DSS, and Trail A (p < 0.01)., Conclusion: Observed differences in neurocognitive test scores between SRMD of MCI/dementia cases and matched controls were present at visit 2, but not at baseline in middle-aged and older Hispanic/Latino adults. These findings present initial evidence of the potential utility of SRMD of MCI/dementia in epidemiologic studies, where obtaining confirmation of diagnosis may not be feasible.

Objectives: Although personality change is typically considered a symptom of dementia, some studies suggest that personality change may be an early indication of dementia. One prospective study found increases in neuroticism preceding dementia diagnosis (Yoneda, T., Rush, J., Berg, A. I., Johansson, B., & Piccinin, A. M. (2017). Trajectories of personality traits preceding dementia diagnosis. The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences, 72, 922-931. doi:10.1093/geronb/gbw006). This study extends this research by examining trajectories of personality traits in additional longitudinal studies of aging., Methods: Three independent series of latent growth curve models were fitted to data from the Longitudinal Aging Study Amsterdam and Einstein Aging Study to estimate trajectories of personality traits in individuals with incident dementia diagnosis (total N = 210), in individuals with incident Mild Cognitive Impairment (N = 135), and in individuals who did not receive a diagnosis during follow-up periods (total N = 1740)., Results: Controlling for sex, age, education, depressive symptoms, and the interaction between age and education, growth curve analyses consistently revealed significant linear increases in neuroticism preceding dementia diagnosis in both datasets and in individuals with mild cognitive impairment. Analyses examining individuals without a diagnosis revealed nonsignificant change in neuroticism overtime., Discussion: Replication of our previous work in 2 additional datasets provides compelling evidence that increases in neuroticism may be early indication of dementia, which can facilitate development of screening assessments., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Engaging in mentally challenging activities may protect against dementia in late life. However, little is known whether the association between mentally challenging activities and dementia risk varies with race/ethnicity., Objective: The current study investigates whether having jobs with higher mental stimulation is differentially associated with a decreased risk of dementia between African Americans (AAs) and non-Hispanic Whites (nHWs)., Methods: The sample consisted of 1,079 individuals (66% nHWs, 28% AAs; age = 78.6±5.3) from the longitudinal Einstein Aging Study. Occupation information of each participant was collected retrospectively at baseline and was linked to the substantive complexity of work score from the Dictionary of Occupational Titles. Cox proportional hazards models were used to evaluate the associations of occupational complexity with risk of dementia., Results: Individuals whose jobs had moderate-to-high levels of complexity, compared to those with the lowest complexity, were at modestly decreased risk for incident dementia. When stratified by race, moderate-to-high levels of occupational complexity were significantly associated with lower risk of developing dementia for AAs (HR = 0.35). When risk of dementia was evaluated based on the combinations of race×occupational complexity, AAs with lowest occupational complexity showed the highest risk of developing dementia, while other combinations exhibited lower risk of developing dementia (HRs = 0.36~0.43)., Conclusion: Our results suggest that moderate-to-high levels of complexity at work are associated with a decreased risk of incident dementia in AAs. Understanding the differential effects of mentally challenging occupations across race/ethnicity may suggest important intervention strategies that could mitigate racial disparities in dementia rates.

Introduction: To report clinical predictors of transition to dementia in motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by cognitive complaints and slow gait., Methods: We examined if cognitive or motoric impairments predicted transition to dementia in 610 older adults with MCR from three cohorts. Association of cognitive (logical memory, clinical dementia rating, cognitive complaint severity, and Mini-Mental State Examination) and motoric factors (gait velocity) with dementia risk was computed using Cox models., Results: There were 156 incident dementias (134 Alzheimer's disease). In the pooled sample, logical memory (adjusted hazard ratio [aHR] 0.91), cognitive complaint severity (aHR 1.53), and Mini-Mental State Examination (aHR 0.75) predicted transition of MCR to dementia. Clinical dementia rating score ≥0.5 predicted dementia (aHR 3.18) in one cohort. Gait velocity did not predict dementia., Discussion: While MCR is a motoric-based predementia syndrome, severity of cognitive but not motoric impairments predicts conversion to dementia., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: We hypothesized that higher quality of life would be associated with better cognitive function and a reduced risk of incident all cause dementia and Alzheimer disease (AD) in older adults., Materials and Methods: Participants included 1183 older adults with an average age of 78.2 (SD=5.3) from Einstein Aging Study. The 36-Item Short-Form Health Survey was used to measure health-related quality of life (HRQoL). We investigated baseline associations between the cognitive domains of memory, executive function, and general fluid ability with 8 subscales of the 36-Item Short-Form Health Survey (physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, social functioning, role limitations due to emotional problems, vitality, and general mental health) and the 2 component summary scores of physical component summary (PCS) and mental component summary (MCS). Next, we used Cox proportional hazard models to assess the predictive validity of HRQoL subscales for the onset of incident dementia and incident AD., Results: At baseline, higher scores (better HRQoL) on MCS and its 4 subscales (social functioning, role limitations due to emotional problems, vitality, and general mental health) were associated with higher performance on both memory and executive function domains. Higher scores in role limitation due to physical problems, role limitation due to emotional problems, and general mental health subscales were associated with reduced risk of incident dementia. Higher MCS, but not PCS, predicted a reduced incident of all-cause dementia and AD., Conclusions: These findings suggest that diminution of HRQoL precedes the onset of diagnosable dementia and may be useful in the prediction of dementia onset.

Background: In a previous report, we used latent class analysis (LCA) to identify natural subgroups of older adults in the Einstein Aging Study (EAS) based on neuropsychological performance. These subgroups differed in demographics, genetic profile, and prognosis. Herein, we assess the generalizability of these findings to an independent sample, the Rush Memory and Aging Project (MAP), which used an overlapping, but distinct neuropsychological battery., Objective: Our aim was to identify the association of natural subgroups based on neuropsychological performance in the MAP cohort with incident dementia and compare them with the associations identified in the EAS., Methods: MAP is a community-dwelling cohort of older adults living in the northeastern Illinois, Chicago. Latent class models were applied to baseline scores of 10 neuropsychological measures across 1,662 dementia-free MAP participants. Results were compared to prior findings from the EAS., Results: LCA resulted in a 5-class model: Mixed-Domain Impairment (n = 71, 4.3%), Memory-specific-Impairment (n = 274, 16.5%), Average (n = 767, 46.1%), Frontal Impairment (n = 222, 13.4%), and a class of Superior Cognition (n = 328, 19.7%). Similar to the EAS, the Mixed-Domain Impairment, the Memory-Specific Impairment, and the Frontal Impairment classes had higher risk of incident Alzheimer's disease when compared to the Average class. By contrast, the Superior Cognition had a lower risk of Alzheimer's disease when compared to the Average class., Conclusions: Natural cognitive subgroups in MAP are similar to those identified in EAS. These similarities, despite study differences in geography, sampling strategy, and cognitive tests, suggest that LCA is capable of identifying classes that are not limited to a single sample or a set of cognitive tests.

Background: Chronic pain is common among older adults and is associated with cognitive dysfunction based on cross-sectional studies. However, the longitudinal association between chronic pain and incident dementia in community-based samples is unknown., Objective: We aimed to evaluate the association of pain intensity and pain interference with incident dementia in a community-based sample of older adults., Methods: Participants were 1,114 individuals 70 years of age or older from Einstein Aging Study (EAS), a longitudinal cohort study of community-dwelling older adults in the Bronx County, NY. The primary outcome measure was incident dementia, diagnosed using DSM-IV criteria. Pain intensity and interference in the month prior to first annual visit were measured using items from the SF-36 questionnaire. Pain intensity and pain interference were assessed as predictors of time to incident dementia using Cox proportionate hazards models while controlling for potential confounders., Results: Among participants, 114 individuals developed dementia over an average 4.4 years (SD=3.1) of follow-up. Models showed that pain intensity had no significant effect on time to developing dementia, whereas higher levels of pain interference were associated with a higher risk of dementia. In the model that included both pain intensity and interference as predictors of incident dementia, pain interference had a significant effect on incident dementia, and pain intensity remained non-significant., Conclusion: As a potential remediable risk factor, the mechanisms linking pain interference to cognitive decline merit further exploration., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The Memory Binding Test (MBT) demonstrated good cross-sectional discriminative validity and predicted incident aMCI., Objective: To assess whether the MBT predicts incident dementia better than a conventional list learning test in a longitudinal community-based study., Methods: As a sub-study in the Einstein Aging Study, 309 participants age≥70 initially free of dementia were administered the MBT and followed annually for incident dementia for up to 13 years. Based on previous work, poor memory binding was defined using an optimal empirical cut-score of≤17 on the binding measure of the MBT, Total Items in the Paired condition (TIP). Cox proportional hazards models were used to assess predictive validity adjusting for covariates. We compared the predictive validity of MBT TIP to that of the free and cued selective reminding test free recall score (FCSRT-FR; cut-score:≤24) and the single list recall measure of the MBT, Cued Recalled from List 1 (CR-L1; cut-score:≤12)., Results: Thirty-five of 309 participants developed incident dementia. When assessing each test alone, the hazard ratio (HR) for dementia was significant for MBT TIP (HR = 8.58, 95% CI: (3.58, 20.58), p < 0.0001), FCSRT-FR (HR = 4.19, 95% CI: (1.94, 9.04), p = 0.0003) and MBT CR-L1 (HR = 2.91, 95% CI: (1.37, 6.18), p = 0.006). MBT TIP remained a significant predictor of dementia (p = 0.0002) when adjusting for FCSRT-FR or CR-L1., Conclusions: Older adults with poor memory binding as measured by the MBT TIP were at increased risk for incident dementia. This measure outperforms conventional episodic memory measures of free and cued recall, supporting the memory binding hypothesis.

Importance: Trends in dementia incidence rates have important implications for planning and prevention. To better understand incidence trends over time requires separation of age and cohort effects, and few prior studies have used this approach., Objectives: To examine trends in dementia incidence and concomitant trends in cardiovascular comorbidities among individuals aged 70 years or older who were enrolled in the Einstein Aging Study between 1993 and 2015., Design, Setting, and Participants: In this birth cohort analysis of all-cause dementia incidence in persons enrolled in the Einstein Aging Study from October 20, 1993, through November 17, 2015, a systematically recruited, population-based sample of 1348 participants from Bronx County, New York, who were 70 years or older without dementia at enrollment and at least one annual follow-up was studied. Poisson regression was used to model dementia incidence as a function of age, sex, educational level, race, and birth cohort, with profile likelihood used to identify the timing of significant increases or decreases in incidence., Exposures: Birth year and age., Main Outcomes and Measures: Incident dementia defined by consensus case conference based on annual, standardized neuropsychological and neurologic examination findings, using criteria from the DSM-IV., Results: Among 1348 individuals (mean [SD] baseline age, 78.5 [5.4] years; 830 [61.6%] female; 915 [67.9%] non-Hispanic white), 150 incident dementia cases developed during 5932 person-years (mean [SD] follow-up, 4.4 [3.4] years). Dementia incidence decreased in successive birth cohorts. Incidence per 100 person-years was 5.09 in birth cohorts before 1920, 3.11 in the 1920 through 1924 birth cohorts, 1.73 in the 1925 through 1929 birth cohorts, and 0.23 in cohorts born after 1929. Change point analyses identified a significant decrease in dementia incidence among those born after July 1929 (95% CI, June 1929 to January 1930). The relative rate for birth cohorts before July 1929 vs after was 0.13 (95% CI, 0.04-0.41). Prevalence of stroke and myocardial infarction decreased across successive birth cohorts, whereas diabetes prevalence increased. Adjustment for these cardiovascular comorbidities did not explain the decreased dementia incidence rates for more recent birth cohorts., Conclusions and Relevance: Analyses confirm decreasing dementia incidence in this population-based sample. Whether decreasing incidence will contribute to reduced burden of dementia given the aging of the population is not known.

Objective: We aimed to assess reliability and cross-sectional discriminative validity of the Memory Binding Test (MBT) to distinguish persons with amnestic cognitive impairment (aMCI) and dementia from cognitively normal elderly controls., Method: The MBT was administered to 20 participants with dementia, 31 with aMCI and 246 controls, who received the first administration of the MBT from May 2003 to December 2007, as a substudy of the community-based Einstein Aging Study (age range: 70+). The optimal index resulted from comparing the partial area under the receiver operating characteristic curves (ROC AUC) of four major MBT indices for specificities ≥0.70. Optimal cut-score of the optimal index was selected by maximizing the sum of sensitivity and specificity. Age and education effects were assessed using stratified cut-scores and adjusted logistic regression. Reliability was computed as intraclass correlation between scores at baseline and 1-year follow-up for participants who remained cognitively normal., Results: Total number of Items recalled in the Paired condition (TIP) was elected the optimal index. TIP cut-score was ≤22 for differentiating aMCI alone (sensitivity = 0.74, specificity = 0.73) and aMCI and dementia combined (sensitivity = 0.84, specificity = 0.73) from controls. It was ≤17 for differentiating dementia from aMCI and controls (sensitivity = 0.95, specificity = 0.87). Age and education adjustments did not materially improve discriminative validity. The reliability of TIP was 0.77., Conclusions: MBT achieved moderate to good reliability. TIP had superior cross-sectional discriminative validity than the other MBT indices. We recommend using the empirical cut-score of TIP ≤22 for discriminating aMCI and dementia and ≤17 for discriminating dementia alone., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The Perceived Stress Scale (PSS) is made up of two subscales but is typically used as a single summary measure. However, research has shown that the two subscales may have differential properties in older adults., Objective: To evaluate the internal consistency, test-retest reliability, and the concurrent and predictive validity for development of amnestic mild cognitive impairment (aMCI) of the positively-worded (PSS-PW) and negatively-worded (PSS-NW) subscale scores of the PSS in older adults., Methods: We recruited community residing older adults free of dementia from the Einstein Aging Study. Reliability of the PSS-PW and PSS-NW was assessed using Cronbach's alpha for internal consistency and intraclass correlation for one year test-retest reliability. Concurrent validity was evaluated by examining the relationship between the PSS subscales and depression, anxiety, neuroticism, and positive and negative affect. Predictive validity was assessed using multivariate Cox regression analyses to examine the relationship between baseline PSS-PW and PSS-NW score and subsequent onset of aMCI., Results: Both PSS-PW and PSS-NW showed adequate internal consistency and retest reliabilities. Both the PSS-PW and PSS-NW were associated with depression, neuroticism, and negative affect. The PSS-NW was uniquely associated with anxiety while the PSS-PW was uniquely associated with positive affect. Only the PSS-PW was associated with a statistically significant increased risk of incident aMCI (HR = 1.27; 95% CI: 1.06-1.51 for every 5-point increase in PSS-PW)., Conclusions: Evaluating the separate effects of the two PSS subscales may reveal more information than simply using a single summation score. Future research should investigate the PSS-PW and PSS-NW as separate subscales.

Objective: The objective was to compare two screening strategies for dementia in an urban primary care clinic, serving a low-education, minority community composed largely of Latino and African American patients., Method: Two hundred and fifty-seven patients underwent two-stage patient-based screening (PBS) and informant-based screening (IBS) followed by a diagnostic evaluation. In the first stage, PBS included brief tests of episodic memory (Memory Impairment Screen), semantic memory (Animal Fluency), and executive function (Reciting Months Backwards). For IBS, the first stage consisted of the short Informant Questionnaire on Cognitive Decline in the Elderly, administered to a family member or friend. Patients who screened positive in the first stage of either strategy underwent testing with the picture version of the Free and Cued Selective Reminding Test with Immediate Recall to identify memory impairment. Sensitivity, specificity, and positive and negative predictive values were computed for various cutoffs of each test and combination of tests. Dementia was diagnosed using Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria without access to the screening test results., Results: We identified 66 patients (25.7%) with previously undiagnosed dementia. Sensitivity was the same (77%) for both strategies but specificity was higher for IBS than for PBS (92% versus 83%). IBS's higher specificity makes it the preferred strategy if a knowledgeable informant is available., Conclusion: Unrecognized dementia is common in primary care. Case-finding can be improved using either PBS or IBS two-stage screening strategies.

Individuals with chronic kidney disease (CKD), especially older adults, are at more risk of experiencing cognitive impairment, possibly leading to mild cognitive impairment and/or dementia. Studies report associations between CKD and cognitive impairment; although unclear, there seems to be a graded association between stage of CKD and affected cognitive domains, with executive function being affected earlier in the process than episodic memory and global ability. In CKD, dysexecutive mild cognitive impairment and vascular dementia are also more prominent than other subtypes. Explanations are directed toward traditional and nontraditional vascular factors, which may also explain or mediate the association between CKD and type of cognitive impairment. Future research is urged to focus on the longitudinal association between specific domains of cognitive function, including executive function and memory and CKD; to develop screening tools fit for every CKD stage in elderly individuals, and lastly, to use imaging methods that may help clarify the underlying mechanisms connecting the kidney and the brain.

Objective: To contrast four approaches to norming two widely used memory tests in older adults for the purpose of detecting preclinical dementia., Method: The study sample included participants from the Einstein Aging Study who were over age 70, were free of dementia at baseline, and were followed for at least 5 years. Norms were derived from a conventional sample (excluding individuals with dementia at baseline but not those who developed dementia during follow-up) and a robust normative sample (excluding persons with dementia at baseline as well as those who developed dementia over 5 years of follow-up). Both normative samples were examined with and without adjustment for age and education. We contrasted the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT+IR) and the Logical Memory (LM) test for their ability to identify persons with preclinical dementia, operationally defined by the development of diagnosable dementia over 5 years of follow-up, using these four approaches to developing norms for detecting preclinical dementia., Results: Of 418 participants included in the conventional normative sample, the mean age was 78.2 years, and 59% were female. There were 78 incident cases of dementia over 5 years leaving 340 participants in the robust normative sample. Means and standard deviations were defined for both the conventional and robust normative samples, and cut-scores with and without adjustment were set at 1.5 standard deviations below the mean of each test. As predicted, in comparison with the conventional sample, the robust sample had higher cut-scores, which provided higher sensitivity for detecting preclinical dementia. This effect persisted regardless of adjustment. The pFCSRT+IR was more sensitive than LM in detecting incident dementia cases., Conclusion: When using cognitive test norms to identify preclinical dementia, robust norming procedures improves detection using both the pFCSRT+IR and LM.

The purpose was to compare the Spanish language picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT+IR) and the Mini Mental State Exam (MMSE) in identifying very mild dementia among Spanish speaking Latino patients. The tests and an independent diagnostic assessment were administered to 112 Latino patients free of medically diagnosed dementia from an urban primary care clinic. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to examine differences in the operating characteristics of the pFCSRT+IR and the MMSE. Cut scores were manipulated to equate sensitivities (specificities) at clinically relevant values to compare differences in specificities (sensitivities) using the Pearson Chi Square test. Youden's index was used to select the optimal cut scores. Twenty-four of the 112 primary care patients (21%) received a research dementia diagnosis, indicating a substantial burden of unrecognized dementia. MMSE scores but not free recall scores were associated with years of education in patients free of dementia. AUC was significantly higher for free recall than for MMSE. Free recall performed significantly better than the MMSE in sensitivity and in specificity. Using optimal cut scores, patients with impaired free recall were 10 times more likely to have dementia than patients with intact recall, and patients with impaired MMSE scores were 4.5 times more likely to have dementia than patients with intact scores. These results suggest that the Spanish language pFCSRT+IR may be an effective tool for dementia screening in educationally diverse Latino primary care populations.

Background: A large number of longitudinal studies of population-based ageing cohorts are in progress internationally, but the insights from these studies into the risk and protective factors for cognitive ageing and conditions like mild cognitive impairment and dementia have been inconsistent. Some of the problems confounding this research can be reduced by harmonising and pooling data across studies. COSMIC (Cohort Studies of Memory in an International Consortium) aims to harmonise data from international cohort studies of cognitive ageing, in order to better understand the determinants of cognitive ageing and neurocognitive disorders., Methods/design: Longitudinal studies of cognitive ageing and dementia with at least 500 individuals aged 60 years or over are eligible and invited to be members of COSMIC. There are currently 17 member studies, from regions that include Asia, Australia, Europe, and North America. A Research Steering Committee has been established, two meetings of study leaders held, and a website developed. The initial attempts at harmonising key variables like neuropsychological test scores are in progress., Discussion: The challenges of international consortia like COSMIC include efficient communication among members, extended use of resources, and data harmonisation. Successful harmonisation will facilitate projects investigating rates of cognitive decline, risk and protective factors for mild cognitive impairment, and biomarkers of mild cognitive impairment and dementia. Extended implications of COSMIC could include standardised ways of collecting and reporting data, and a rich cognitive ageing database being made available to other researchers. COSMIC could potentially transform our understanding of the epidemiology of cognitive ageing, and have a world-wide impact on promoting successful ageing.

Background: Despite growing evidence of links between gait and cognition in aging, cognitive risk assessments that incorporate motoric signs have not been examined. We sought to validate a new Motoric Cognitive Risk (MCR) syndrome to identify individuals at high risk of developing dementia., Methods: We evaluated 997 community residing individuals aged 70 and older participating in the Einstein Aging Study over a median follow-up time of 36.9 months. MCR syndrome was defined as presence of cognitive complaints and slow gait (one standard deviation below age- and sex-specific gait speed means) in nondemented individuals. Cox models were used to evaluate the effect of MCR syndrome on the risk of developing dementia and subtypes., Results: Fifty-two participants met criteria for MCR syndrome at baseline with a prevalence of 7% (95% CI: 5-9%). Prevalence of MCR increased with age. Participants with MCR were at higher risk of developing dementia (hazard ratio [HR] adjusted for age, sex, and education: 3.27, 95% CI: 1.55-6.90) and vascular dementia (adjusted HR: 12.81, 95% CI: 4.98-32.97). The association of MCR with risk of dementia or vascular dementia remained significant even after accounting for other confounders and diagnostic overlap with "cognitive" mild cognitive impairment syndrome subtypes., Conclusions: A motor-based MCR syndrome provides a clinical approach to identify individuals at high risk for dementia, especially vascular dementia, to target for further investigations and who may benefit from preventive interventions.

Cognitive reserve is invoked to explain the protective effects of education and cognitively-stimulating activities against all-cause dementia and Alzheimer's disease (AD). For non-native English speakers (n-NES), speaking English may be a cognitive activity associated with lower dementia risk. We hypothesized that n-NES have lower risk of incident dementia/AD and that educational level might modify this relationship. Participants took part in the Einstein Aging Study (Bronx, NY), a longitudinal study of aging and dementia. All (n = 1779) spoke fluent English and self-reported birthplace and whether English was their first language. n-NES additionally reported mother tongue, age of English acquisition, and current percentile-use of a non-English language. Nested Cox proportional hazards models progressively adjusted for gender, race, education, and immigrant and marital status estimated hazard ratios (HR) for incident dementia/AD as a function of n-NES status. 390 (22%) participants were n-NES. 126 incident dementia cases occurred during 4174 person-years of follow-up (median 1.44; range 0-16); 101 individuals met criteria for probable/possible AD. There was no statistically-significant association between n-NES status and incident dementia in the fully-adjusted model (HR 1.26; 95% CI 0.76-2.09; p = 0.36). Results were similar for AD. Stratification of education into three groups revealed increased risk of dementia for n-NES with ≥ 16 years of education (HR 3.97; 95% CI 1.62-9.75; p = 0.003). We conclude that n-NES status does not appear to have an independent protective effect against incident dementia/AD, and that n-NES status may contribute to risk of dementia in an education-dependent manner.

Participation in cognitively stimulating leisure activities such as crossword puzzles may delay onset of the memory decline in the preclinical stages of dementia, possibly via its effect on improving cognitive reserve. We followed 488 initially cognitively intact community residing individuals with clinical and cognitive assessments every 12-18 months in the Bronx Aging Study. We assessed the influence of crossword puzzle participation on the onset of accelerated memory decline as measured by the Buschke Selective Reminding Test in 101 individuals who developed incident dementia using a change point model. Crossword puzzle participation at baseline delayed onset of accelerated memory decline by 2.54 years. Inclusion of education or participation in other cognitively stimulating activities did not significantly add to the fit of the model beyond the effect of puzzles. Our findings show that late life crossword puzzle participation, independent of education, was associated with delayed onset of memory decline in persons who developed dementia. Given the wide availability and accessibility of crossword puzzles, their role in preventing cognitive decline should be validated in future clinical trials.

Context: Polymorphisms in the cholesteryl ester transfer protein (CETP) gene have been associated with exceptional longevity and lower cardiovascular risk, but associations with memory decline and dementia risk are unclear., Objective: To test the hypothesis that a single-nucleotide polymorphism (SNP) at CETP codon 405 (isoleucine to valine V405; SNP rs5882) is associated with a lower rate of memory decline and lower risk of incident dementia, including Alzheimer disease (AD)., Design, Setting, and Participants: Prospective cohort study comprising 608 community-dwelling adults without dementia aged 70 years or older from the Einstein Aging Study with CETP genotype available. Fifteen participants with prevalent dementia were excluded, and 70 without follow-up--63 lost to follow-up and 7 new to the study--were excluded from the Cox proportional hazards model, which included 523 participants in the analysis. Standardized neuropsychological and neurological measures were administered annually from 1994-2009. Linear mixed-effects models adjusted for sex, education, race, medical comorbidities, and apolipoprotein (APOE) epsilon4 examined associations of V405 genotype with longitudinal performance on cognitive tests of episodic memory (Free and Cued Selective Reminding Test [FCSRT], possible scores of 0-48), attention (Digit Span), and psychomotor speed (Digit Symbol Substitution). The V405 genotype was the main predictor of incident dementia or AD in similarly adjusted Cox proportional hazards models with age as the time scale., Main Outcome Measures: Memory decline and incident dementia., Results: Valine allele frequency was 43.5%. A total of 40 cases of incident dementia occurred during follow-up (mean [(SD], 4.3 [3.1] years). Compared with isoleucine homozygotes, valine homozygotes had significantly slower memory decline on the FCSRT (0.43 points per year of age for isoleucine; 95% confidence interval [CI], -0.58 to -0.29 vs 0.21 points per year of age for valine; 95% CI, -0.39 to -0.04; difference in linear age slope, 0.22; 95% CI, 0.02 to 0.41; P = .03) and no significant differences on the Digit Span or Digit Symbol Substitution tests. Valine homozygotes also had lower risk of dementia (hazard ratio, 0.28; 95% CI, 0.10-0.85; P = .02) and AD (hazard ratio, 0.31; 95% CI, 0.10-0.95; P = .04)., Conclusion: This preliminary report suggests that CETP V405 valine homozygosity is associated with slower memory decline and lower incident dementia and AD risk.

Context: Neuropsychological tests are used to predict and diagnose dementia. However, to our knowledge, no studies to date have examined whether within-person across-neuropsychological test variability predicts dementia., Objective: To examine whether within-person across-neuropsychological test variability predicts future dementia., Design: The Einstein Aging Study (EAS) is a population-based longitudinal study of aging and dementia located in Bronx County, New York. We used Cox proportional hazards models using age as the time scale to estimate hazard ratios (HRs) for performance on individual neuropsychological tests (Free and Cued Selective Reminding Test, Digit Symbol Substitution subtest of the Wechsler Adult Intelligence Scale Revised, and the Vocabulary subtest of the Wechsler Adult Intelligence Scale Revised) and for within-person across-neuropsychological test variability as predictors of incident dementia. Analyses were stratified by sex, and controlled for education and medical illness., Setting and Participants: A total of 1797 participants (age > or = 70 years) enrolled in the EAS between October 1993 and December 2007. Participants seen for the baseline visit only (n = 750), prevalent dementia cases (n = 72), and those with missing follow-up information (n = 78) were excluded. A total of 897 individuals were included in this investigation. Participants had follow-up visits every 12 to 18 months., Main Outcome Measure: Incident dementia., Results: Sixty-one cases of incident dementia were identified during follow-up (mean [SD], 3.3 [2.4] years), of which 26 were in the highest quartile of within-person across-neuropsychological test variability. Adjusting for sex, education, and medical illness, variability was associated with incident dementia (HR for 1-point difference in variability, 3.93 [95% confidence interval {CI}, 2.04-7.56]). The association persisted even after adjusting for level of performance on individual neuropsychological tests (HR for 1-point difference in variability, 2.10 [95% CI, 1.04-4.23]). Comparing Cox models using neuropsychological tests with and without within-person across-neuropsychological test variability showed that the former improved the prediction of dementia. Sensitivity in a model predicting dementia at 1 year also improved when neuropsychological test variability was included., Conclusions: In this population, within-person across-neuropsychological test variability was associated with development of incident dementia independent of neuropsychological test performance. This finding needs to be confirmed in future studies.

Objectives: To determine whether the Alzheimer's Disease Screen for Primary Care (ADS-PC) is more sensitive to early dementia than the Mini-Mental State Examination (MMSE) and whether it has as high a misclassification rate in minority patients and patients with limited education., Design: Cross-sectional validation study., Setting: Urban geriatric primary care practice., Participants: Three hundred sixteen African-American and Caucasian patients, including 55 patients with early dementia (Clinical Demential Rating of 0.5)., Measurements: The ADS-PC is a two-stage strategy for identifying early dementia that consists of a brief high-sensitivity dementia screen, applied to all patients aged 65 and older, and a second stage to identify memory impairment, applied to patients who fail the first stage. Differences in the sensitivities or specificities of the ADS-PC and the MMSE were evaluated using the McNemar test., Results: Receiver operating characteristic curves were used to examine differences in the operating characteristics of the ADS-PC across a range of cutscores. When the specificities of both tests were equated (0.90), the sensitivities were significantly different (ADS-PC, 0.75; MMSE, 0.56). The MMSE failed to identify five times as many cases of dementia as the ADS-PC. When the sensitivities were equated, the specificities differed significantly (ADS-PC, 0.95; MMSE, 0.73). The MMSE misclassified five times as many noncases as the ADS-PC. This pattern of significantly higher sensitivity and specificity for the ADS-PC than for the MMSE was repeated in the results according to race and for individuals with high school or more education but not in individuals with less education., Conclusion: The ADS-PC outperformed the MMSE in identifying early dementia in a racially and educationally diverse primary care cohort.

As new and more effective treatments for Alzheimer's disease (AD) emerge, the development of efficient screening strategies in educationally and racially diverse primary care settings has increased in importance. A set of candidate screening tests and an independent diagnostic assessment were administered to a sample of 318 patients treated at a geriatric primary care center. Fifty-six subjects met criteria for dementia. Exploratory analysis led to the development of three two-stage screening strategies that differed in the composition of the first stage or Rapid Dementia Screen, which is applied to all patients over the age of 65. The second stage, applied to those patients who screen positively for dementia, is accomplished with the Free and Cued Selective Reminding Test to detect memory impairment. Using clinical diagnosis as a gold standard, the strategies had high sensitivity and specificity for identifying dementia and performed better for identifying AD than non-AD dementias. Sensitivity and specificity did not differ by race or education. The strategies provide an efficient approach to screening for early dementia.

Background: Identifying quantitative gait markers of preclinical dementia may lead to new insights into early disease stages, improve diagnostic assessments and identify new preventive strategies., Objective: To examine the relationship of quantitative gait parameters to decline in specific cognitive domains as well as the risk of developing dementia in older adults., Methods: We conducted a prospective cohort study nested within a community based ageing study. Of the 427 subjects aged 70 years and older with quantitative gait assessments, 399 were dementia-free at baseline., Results: Over 5 years of follow-up (median 2 years), 33 subjects developed dementia. Factor analysis was used to reduce eight baseline quantitative gait parameters to three independent factors representing pace, rhythm and variability. In linear models, a 1 point increase on the rhythm factor was associated with further memory decline (by 107%), whereas the pace factor was associated with decline on executive function measured by the digit symbol substitution (by 29%) and letter fluency (by 92%) tests. In Cox models adjusted for age, sex and education, a 1 point increase on baseline rhythm (hazard ratio (HR) 1.48; 95% CI 1.03 to 2.14) and variability factor scores (HR 1.37; 95% CI 1.05 to 1.78) was associated with increased risk of dementia. The pace factor predicted the risk of developing vascular dementia (HR 1.60; 95% CI 1.06 to 2.41)., Conclusion: Our findings indicate that quantitative gait measures predict future risk of cognitive decline and dementia in initially non-demented older adults.

Mutations in leucine-rich repeat kinase 2 gene (LRRK2) have been associated with idiopathic Parkinson's disease (PD), as well as pleomorphic neurodegenerative pathology, including Alzheimer's disease. One specific LRRK2 mutation, G2019S, was reported in 18% of people with PD of Ashkenazi descent, supporting a founder effect in this population. To determine if this mutation is also associated with dementia in the Ashkenazim, we screened 192 elderly Ashkenazi Jewish (AJ) individuals in a longitudinal aging and cognition study, of whom 49 (25.5%) had dementia. Two non-demented individuals harbored the mutation (2/143, 1.4%), but no individuals with dementia. Neither person with the mutation had Parkinson's disease. Therefore, the LRRK2 mutation has a relatively high frequency in the AJ population, is not fully penetrant for parkinsonism in the elderly, and does not appear to be commonly associated with late-onset dementia.

This longitudinal study examined memory loss in a sample of 391 initially nondemented older adults. Analyses decomposed observed memory loss into decline associated with preclinical dementia, study attrition, terminal decline, and chronological age. Measuring memory as a function of only chronological age failed to provide an adequate representation of cognitive change. Disease progression accounted for virtually all of the memory loss in the 25% of the sample that developed diagnosable dementia. In the remainder of the sample, both chronological age and study attrition contributed to observed memory loss. These results suggest that much of memory loss in aging adults may be attributable to the progression of preclinical dementia and other nonnormative aging processes that are not captured by chronological age.

Background: Participation in leisure activities has been associated with a lower risk of dementia. It is unclear whether increased participation in leisure activities lowers the risk of dementia or participation in leisure activities declines during the preclinical phase of dementia., Methods: We examined the relation between leisure activities and the risk of dementia in a prospective cohort of 469 subjects older than 75 years of age who resided in the community and did not have dementia at base line. We examined the frequency of participation in leisure activities at enrollment and derived cognitive-activity and physical-activity scales in which the units of measure were activity-days per week. Cox proportional-hazards analysis was used to evaluate the risk of dementia according to the base-line level of participation in leisure activities, with adjustment for age, sex, educational level, presence or absence of chronic medical illnesses, and base-line cognitive status., Results: Over a median follow-up period of 5.1 years, dementia developed in 124 subjects (Alzheimer's disease in 61 subjects, vascular dementia in 30, mixed dementia in 25, and other types of dementia in 8). Among leisure activities, reading, playing board games, playing musical instruments, and dancing were associated with a reduced risk of dementia. A one-point increment in the cognitive-activity score was significantly associated with a reduced risk of dementia (hazard ratio, 0.93 [95 percent confidence interval, 0.90 to 0.97]), but a one-point increment in the physical-activity score was not (hazard ratio, 1.00). The association with the cognitive-activity score persisted after the exclusion of the subjects with possible preclinical dementia at base line. Results were similar for Alzheimer's disease and vascular dementia. In linear mixed models, increased participation in cognitive activities at base line was associated with reduced rates of decline in memory., Conclusions: Participation in leisure activities is associated with a reduced risk of dementia, even after adjustment for base-line cognitive status and after the exclusion of subjects with possible preclinical dementia. Controlled trials are needed to assess the protective effect of cognitive leisure activities on the risk of dementia., (Copyright 2003 Massachusetts Medical Society)

Background: Neurologic abnormalities affecting gait occur early in several types of non-Alzheimer's dementias, but their value in predicting the development of dementia is uncertain., Methods: We analyzed the relation between neurologic gait status at base line and the development of dementia in a prospective study involving 422 subjects older than 75 years of age who lived in the community and did not have dementia at base line. Cox proportional-hazards regression analysis was used to calculate hazard ratios with adjustment for potential confounding demographic, medical, and cognitive variables., Results: At enrollment, 85 subjects had neurologic gait abnormalities of the following types: unsteady gait (in 31 subjects), frontal gait (in 12 subjects), hemiparetic gait (in 11 subjects), neuropathic gait (in 11 subjects), ataxic gait (in 10 subjects), parkinsonian gait (in 8 subjects), and spastic gait (in 2 subjects). During follow-up (median duration, 6.6 years), there were 125 newly diagnosed cases of dementia, 70 of them cases of Alzheimer's disease and 55 cases of non-Alzheimer's dementia (47 of which involved vascular dementia and 8 of which involved other types of dementia). Subjects with neurologic gait abnormalities had a greater risk of development of dementia (hazard ratio, 1.96 [95 percent confidence interval, 1.30 to 2.96]). These subjects had an increased risk of non-Alzheimer's dementia (hazard ratio, 3.51 [95 percent confidence interval, 1.98 to 6.24]), but not of Alzheimer's dementia (hazard ratio, 1.07 [95 percent confidence interval, 0.57 to 2.02]). Of non-Alzheimer's dementias, abnormal gait predicted the development of vascular dementia (hazard ratio, 3.46 [95 percent confidence interval, 1.86 to 6.42]). Among the types of abnormal gait, unsteady gait predicted vascular dementia (hazard ratio, 2.61), as did frontal gait (hazard ratio, 4.32) and hemiparetic gait (hazard ratio, 13.13)., Conclusions: The presence of neurologic gait abnormalities in elderly persons without dementia at base line is a significant predictor of the risk of development of dementia, especially non-Alzheimer's dementia., (Copyright 2002 Massachusetts Medical Society)

The Hispanic/Latino population is one of the largest and most diverse ethnoracial groups in the United States at high risk for dementia. We examined cognitive constructs and associations with subsequent hippocampal volume (HV) and white matter hyperintensity volume (WMHV). Participants were from the Hispanic Community Health Study/Study of Latinos-Magnetic Resonance Imaging Study (n = 2029). We examined confirmatory factor analysis and longitudinal invariance using neurocognitive scores at Visits 1 (2008-2011) and 2 (2014-2018) and path analyses. We obtained a longitudinally invariant two-factor episodic memory (EM) and working memory (WM) construct. Lower EM profile at both visits was associated with greater WMHV and smaller HV at Visit 2. Lower WM profile at both visits was associated with larger WMHV and smaller HV at Visit 2. Neurocognitive profiles were associated with subsequent neurodegeneration in a sample of Hispanics/Latinos. Identifying neurocognitive risk profiles may lead to early detection and intervention, and significantly impact the course of neurodegeneration.HighlightsCognitive profiles predict brain integrity up to 10 years later.We observed two-factor latent memory constructs and longitudinal invariance.These findings were observed in a Hispanic/Latino cohort.

ObjectiveHispanic/Latino individuals in the U.S. have the highest prevalence of undiagnosed and untreated diabetes and are at increased risk for cognitive impairment. In this study, we examine glycemic control in relation to cognitive aging and impairment in a large prospective cohort of middle-aged and older Hispanic/Latino individuals of diverse heritages.Research design and methodsStudy of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) is a Hispanic Community Health Study/Study of Latinos (HCHS/SOL) ancillary study. HCHS/SOL is a multisite (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA), probability sampled prospective cohort study. SOL-INCA enrolled 6,377 diverse Hispanic/Latino individuals aged 50 years and older (2016-2018). The primary outcomes were cognitive function, 7-year cognitive decline, and mild cognitive impairment (MCI). The primary glycemia exposure variables were measured from fasting blood samples collected at HCHS/SOL visit 1 (2008-2011).ResultsVisit 1 mean age was 56.5 years ± 8.2 SD, and the average glycosylated hemoglobin A1C (HbA1c) was 6.12% (43.5 ± 14.6 mmol/mol). After covariate adjustment, higher HbA1c was associated with accelerated 7-year global (b = -0.045; 95% CI -0.070; -0.021; in z score units) and executive cognitive decline and a higher prevalence of MCI (odds ratio 1.20; 95% CI 1.11; 1.29).ConclusionsElevated HbA1c levels were associated with 7-year executive cognitive decline and increased MCI risk among diverse middle-aged and older Hispanic/Latino individuals. Our findings indicate that poor glycemic control in midlife may pose significant risks for cognitive decline and MCI later in life among Hispanic/Latino individuals of diverse heritages.

IntroductionReproductive health history may contribute to cognitive aging and risk for Alzheimer's disease, but this is understudied among Hispanic/Latina women.MethodsParticipants included 2126 Hispanic/Latina postmenopausal women (44 to 75 years) from the Study of Latinos-Investigation of Neurocognitive Aging. Survey linear regressions separately modeled the associations between reproductive health measures (age at menarche, history of oral contraceptive use, number of pregnancies, number of live births, age at menopause, female hormone use at Visit 1, and reproductive span) with cognitive outcomes at Visit 2 (performance, 7-year change, and mild cognitive impairment [MCI] prevalence).ResultsYounger age at menarche, oral contraceptive use, lower pregnancies, lower live births, and older age at menopause were associated with better cognitive performance. Older age at menarche was protective against cognitive change. Hormone use was linked to lower MCI prevalence.DiscussionSeveral aspects of reproductive health appear to impact cognitive aging among Hispanic/Latina women.

IntroductionThe extent to which the Big Five personality traits and subjective well-being (SWB) are discriminatory predictors of clinical manifestation of dementia versus dementia-related neuropathology is unclear.MethodsUsing data from eight independent studies (Ntotal = 44,531; Ndementia = 1703; baseline Mage = 49 to 81 years, 26 to 61% female; Mfollow-up range = 3.53 to 21.00 years), Bayesian multilevel models tested whether personality traits and SWB differentially predicted neuropsychological and neuropathological characteristics of dementia.ResultsSynthesized and individual study results indicate that high neuroticism and negative affect and low conscientiousness, extraversion, and positive affect were associated with increased risk of long-term dementia diagnosis. There were no consistent associations with neuropathology.DiscussionThis multistudy project provides robust, conceptually replicated and extended evidence that psychosocial factors are strong predictors of dementia diagnosis but not consistently associated with neuropathology at autopsy.HighlightsN(+), C(-), E(-), PA(-), and NA(+) were associated with incident diagnosis. Results were consistent despite self-report versus clinical diagnosis of dementia. Psychological factors were not associated with neuropathology at autopsy. Individuals with higher conscientiousness and no diagnosis had less neuropathology. High C individuals may withstand neuropathology for longer before death.

Hispanic/Latino adults are a growing segment of the older U.S. population yet are underrepresented in brain aging research. We aimed to characterize brain aging among diverse Hispanic/Latino individuals. Hispanic/Latino individuals (unweighted n = 2273 ages 35-85 years; 56% female) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) population-based study underwent magnetic resonance imaging (MRI) as part of the SOL- Investigation of Neurocognitive Aging MRI (SOL-INCA-MRI) ancillary study (2018-2022). We performed linear regressions to calculate age associations with brain volumes for each outcome (total (global) brain, hippocampal, lateral ventricle, total white matter hyperintensity (WMH), individual cortical lobar, and total cortical gray matter) and tested modification by sex. Older age was associated with smaller gray matter volumes and larger lateral ventricle and WMH volumes. Age-related differences in global brain volumes and gray matter volumes in specific regions (i.e., the hippocampus and temporal and occipital lobes) were less pronounced among women. Our findings warrant further investigation into sex-specific mechanisms of brain aging using longitudinal studies.

Background and objectivesIncreasing evidence indicates that a subset of cognitively normal individuals has subtle cognitive impairment at baseline. We sought to identify them using the Stages of Objective Memory Impairment (SOMI) system. Symptomatic cognitive impairment was operationalized by a Clinical Dementia Rating (CDR) ≥0.5. We hypothesized that incident impairment would be higher for participants with subtle retrieval impairment (SOMI-1), higher still for those with moderate retrieval impairment (SOMI-2), and highest for those with storage impairment (SOMI-3/4) after adjusting for demographics and APOE ε4 status. A secondary objective was to determine whether including biomarkers of β-amyloid, tau pathology, and neurodegeneration in the models affect prediction. We hypothesized that even after adjusting for in vivo biomarkers, SOMI would remain a significant predictor of time to incident symptomatic cognitive impairment.MethodsAmong 969 cognitively normal participants, defined by a CDR = 0, from the Knight Alzheimer Disease Research Center, SOMI stage was determined from their baseline Free and Cued Selective Reminding Test scores, 555 had CSF and structural MRI measures and comprised the biomarker subgroup, and 144 of them were amyloid positive. Cox proportional hazards models tested associations of SOMI stages at baseline and biomarkers with time to incident cognitive impairment defined as the transition to CDR ≥0.5.ResultsAmong all participants, the mean age was 69.35 years, 59.6% were female, and mean follow-up was 6.36 years. Participants in SOMI-1-4 had elevated hazard ratios for the transition from normal to impaired cognition in comparison with those who were SOMI-0 (no memory impairment). Individuals in SOMI-1 (mildly impaired retrieval) and SOMI-2 (moderately impaired retrieval) were at nearly double the risk of clinical progression compared with persons with no memory problems. When memory storage impairment emerges (SOMI-3/4), the hazard ratio for clinical progression increased approximately 3 times. SOMI stage remained an independent predictor of incident cognitive impairment after adjusting for all biomarkers.DiscussionSOMI predicts the transition from normal cognition to incident symptomatic cognitive impairment (CDR ≥0.5). The results support the use of SOMI to identify those cognitively normal participants most likely to develop incident cognitive impairment who can then be referred for biomarker screening.

This study examined the relationship between endogenous hormones and cognitive function in nondemented, ethnically-diverse community-dwelling older men enrolled in the Einstein Aging Study (EAS). All eligible participants (185 men, mean age = 81 years) received neuropsychological assessment (Free and Cued Selective Reminding Test (FCSRT), Logical Memory (LM), Trail Making Test B (TMTB), block design (BD)) and provided blood samples for hormonal assays (total estradiol, total testosterone, calculated free testosterone index). Linear regression analysis adjusted for age, education, body mass index, and cardiovascular comorbidities indicated that men with high levels of total estradiol demonstrated better FCSRT verbal memory performance ([beta] = 0.17, p less than 0.02) compared to men with lower levels of total estradiol. The results remained unchanged when the model was further adjusted for ethnicity. We did not detect an association between testosterone and cognitive performance. These findings indicate that high levels of total estradiol in older men are associated with better performance on a cue-based, controlled learning test of verbal memory that is a sensitive predictor of dementia.

IntroductionPolygenic Risk Scores (PRSs) are summaries of genetic risk alleles for an outcome.MethodsWe used summary statistics from five GWASs of AD to construct PRSs in 4,189 diverse Hispanics/Latinos (mean age 63 years) from the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA). We assessed the PRS associations with MCI in the combined set of people and in diverse subgroups, and when including and excluding the APOE gene region. We also assessed PRS associations with MCI in an independent dataset from the Mass General Brigham Biobank.ResultsA simple sum of 5 PRSs ("PRSsum"), each constructed based on a different AD GWAS, was associated with MCI (OR = 1.28, 95% CI [1.14, 1.41]) in a model adjusted for counts of the APOE-[Formula: see text] and APOE-[Formula: see text] alleles. Associations of single-GWAS PRSs were weaker. When removing SNPs from the APOE region from the PRSs, the association of PRSsum with MCI was weaker (OR = 1.17, 95% CI [1.04,1.31] with adjustment for APOE alleles). In all association analyses, APOE-[Formula: see text] and APOE-[Formula: see text] alleles were not associated with MCI.DiscussionA sum of AD PRSs is associated with MCI in Hispanic/Latino older adults. Despite no association of APOE-[Formula: see text] and APOE-[Formula: see text] alleles with MCI, the association of the AD PRS with MCI is stronger when including the APOE region. Thus, APOE variants different than the classic APOE alleles may be important predictors of MCI in Hispanic/Latino adults.

APOE-ɛ4 risk on Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) differs between race/ethnic groups, presumably due to ancestral genomic background surrounding the APOE locus. We studied whether African and Amerindian ancestry-enriched genetic variants in the APOE region modify the effect of the APOE-ɛ4 alleles on Mild Cognitive Impairment (MCI) in Hispanics/Latinos. We defined African and Amerindian ancestry-enriched variants as those common in one Hispanic/Latino parental ancestry and rare in the other two. We identified such variants in the APOE region with a predicted moderate impact based on the SnpEff tool. We tested their interaction with APOE-ɛ4 on MCI in the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) population and African Americans from the Atherosclerosis Risk In Communities (ARIC) study. We identified 5 Amerindian and 14 African enriched variants with an expected moderate effect. A suggestive significant interaction (p-value = 0.01) was found for one African-enriched variant, rs8112679, located in the ZNF222 gene fourth exon. Our results suggest there are no ancestry-enriched variants with large effect sizes of interaction effects with APOE-ɛ4 on MCI in the APOE region in the Hispanic/Latino population. Further studies are needed in larger datasets to identify potential interactions with smaller effect sizes.

Background and objectivesThe goal of this work was to investigate the neuroimaging correlates of the Stages of Objective Memory Impairment (SOMI) system operationalized with the Free and Cued Selective Reminding Test (FCSRT), a widely used episodic memory measure.MethodsThe FCSRT begins with a study phase in which items (e.g., grapes) are identified in response to unique semantic cues (e.g., fruit) that are used in the test phase to prompt recall of items not retrieved by free recall. There are 3 test trials of the 16 items (maximum 48). Data from 4,484 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were used. All participants had amyloid PET imaging, and a subset of 1,262 β-amyloid (Aβ)-positive had structural MRIs. We compared the Aβ mean cortical standardized uptake value ratio (SUVR) and volumetric measures of hippocampus, parahippocampal gyrus, entorhinal cortex, and inferior temporal cortex between the 5 SOMI stages.ResultsParticipants had a mean age of 71.3 (SD 4.6) years; 40.6% were male; and 34.6% were APOE ε4 positive. Half had no memory impairment; the other half had retrieval deficits, storage limitations, or both. Analysis of covariance in the entire sample while controlling for age, sex, education, and APOE ε4 showed that individuals in higher SOMI stages had higher global amyloid SUVR (p < 0.001). Both SOMI-4 and -3 subgroups had higher amyloid SUVR than SOMI-0 and SOMI-1 subgroups. Individuals in higher SOMI stages had smaller hippocampal volume (p = 0.003), entorhinal cortex (p < 0.05), and inferior temporal lobes (p < 0.05), but there was no difference between parahippocampal gyrus volume of different SOMI stages. Pairwise comparison of SOMI subgroups showed that the SOMI-4, -3, and -2 subgroups had smaller hippocampal volume than the SOMI-0 and -1 subgroup. The SOMI-4 subgroup had significantly smaller entorhinal cortex and smaller inferior temporal lobe compared to all other groups.DiscussionPresence of Alzheimer disease pathology is closely related to memory impairment according to SOMI stages in the cognitively unimpaired sample of A4. Results from structural MRIs suggest that memory storage impairment (SOMI-3 and -4) is present when there is widespread medial temporal lobe atrophy.Trial registration informationClinicalTrials.gov identifier: NCT02008357.Classification of evidenceThis study provides Class I evidence that, in normal older individuals, higher stages of memory impairment assessed with FCSRT were associated with higher amyloid imaging burden and lower volume of hippocampus, entorhinal cortex, and inferior temporal lobes.

ObjectiveTo compare the predictive validity of learning and retention measures from the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT + IR) for identifying incident mild cognitive impairment (MCI).MethodsLearning was defined by the sum of free recall (FR) and retention by delayed free recall (DFR) tested 15-20 min later. Totally, 1422 Baltimore Longitudinal Study of Aging (BLSA) participants (mean age 69.6 years, 54% male, mean 16.7 years of education) without dementia or MCI received the pFCSRT + IR at baseline and were followed longitudinally. Cox proportional hazards models were used to evaluate the effect of baseline learning and retention on risk of MCI.ResultsIn total, 187 participants developed MCI over a median of 8.1 years of follow-up. FR and DFR each predicted incident MCI adjusting for age, sex, and education. Also, each independently predicted incident MCI in the presence of the other with similar effect sizes: around 20% decrease in the hazard of MCI corresponding to one standard deviation increase in FR or DFR.ConclusionThe practice of preferring retention over learning to predict incident MCI should be reconsidered. The decision to include retention should be guided by time constraints and patient burden.

BackgroundThe ideal participants for Alzheimer's disease (AD) clinical trials would show cognitive decline in the absence of treatment (i.e., placebo arm) and would also respond to the therapeutic intervention.ObjectiveTo investigate if predictive models can be an effective tool for identifying and excluding people unlikely to show cognitive decline as an enrichment strategy in AD trials.MethodWe used data from the placebo arms of two phase 3, double-blind trials, EXPEDITION and EXPEDITION2. Patients had 18 months of follow-up. Based on the longitudinal data from the placebo arm, we classified participants into two groups: one showed cognitive decline (any negative slope) and the other showed no cognitive decline (slope is zero or positive) on the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog). We used baseline data for EXPEDITION to train regression-based classifiers and machine learning classifiers to estimate probability of cognitive decline. Models were applied to EXPEDITION2 data to assess predicted performance in an independent sample. Features used in predictive models included baseline demographics, apolipoprotein E ε4 genotype, neuropsychological scores, functional scores, and volumetric magnetic resonance imaging.ResultIn EXPEDITION, 46.3% of placebo-treated patients showed no cognitive decline and the proportion was similar in EXPEDITION2 (45.6%). Models had high sensitivity and modest specificity in both the training (EXPEDITION) and replication samples (EXPEDITION2) for detecting the stable group. Positive predictive value of models was higher than the base prevalence of cognitive decline, and negative predictive value of models were higher than the base rate of participants who had stable cognition.ConclusionExcluding persons with AD unlikely to decline from the active and placebo arms of clinical trials using predictive models may boost the power of AD trials through selective inclusion of participants expected to decline.