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The brain signature concept aims to characterize brain regions most strongly associated with an outcome of interest. Brain signatures derive their power from data-driven searches that select features based solely on performance metrics of prediction or classification. This approach has important potential to delineate biologically relevant brain substrates for prediction or classification of future trajectories. Recent work has used exploratory voxel-wise or atlas-based searches, with some using machine learning techniques to define salient features. These have shown undoubted usefulness, but two issues remain. The preponderance of recent work has been aimed at categorical rather than continuous outcomes, and it is rare for non-atlas reliant voxel-based signatures to be reported that would be useful for modelling and hypothesis testing. We describe a cross-validated signature region model for structural brain components associated with baseline and longitudinal episodic memory across cognitively heterogeneous populations including normal, mild impairment and dementia. We used three non-overlapping cohorts of older participants: from the UC Davis Aging and Diversity cohort (n = 255; mean age 75.3 ± 7.1 years; 128 cognitively normal, 97 mild cognitive impairment, 30 demented and seven unclassified); from Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1 (n = 379; mean age 75.1 ± 7.2; 82 cognitively normal, 176 mild cognitive impairment, 121 Alzheimer’s dementia); and from ADNI2/GO (n = 680; mean age 72.5 ± 7.1; 220 cognitively normal, 381 mild cognitive impairment and 79 Alzheimer’s dementia). We used voxel-wise regression analysis, correcting for multiple comparisons, to generate an array of regional masks corresponding to different association strength levels of cortical grey matter with baseline memory and brain atrophy with memory change. Cognitive measures were episodic memory using Spanish and English Neuropsychological Assessment Scales instruments for UC Davis and ADNI-Mem for ADNI 1 and ADNI2/GO. Performance metric was the adjusted R2 coefficient of determination of each model explaining outcomes in two cohorts other than where it was computed. We compared within-cohort performances of signature models against each other and against other recent signature models of episodic memory. Findings were: (i) two independently generated signature region of interest models performed similarly in a third separate cohort; (ii) a signature region of interest generated in one imaging cohort replicated its performance level when explaining cognitive outcomes in each of other, separate cohorts; and (iii) this approach better explained baseline and longitudinal memory than other recent theory-driven and data-driven models. This suggests our approach can generate signatures that may be easily and robustly applied for modelling and hypothesis testing in mixed cognition cohorts.

Background: Higher glucose levels are associated with dementia risk in people with and without diabetes. However, little is known about how this association might vary by hypertension status and antihypertensive treatment. Most studies on modifiable dementia risk factors consider each factor in isolation. Objective: To test the hypothesis that hypertension and antihypertensive treatments may modify associations between glucose levels and dementia. Methods: Analyses of data generated from a research study and clinical care of participants from a prospective cohort of dementia-free older adults, including glucose measures, diabetes and antihypertensive treatments, and blood pressure data. We defined groups based on blood pressure (hypertensive versus not, ≥140/90 mmHg versus

BACKGROUND: Evidence links fine particulate matter (PM(2.5)) to Alzheimer’s Disease (AD), but no community-based prospective cohort studies in older adults have evaluated the association between long-term exposure to PM(2.5) and markers of AD neuropathology at autopsy. OBJECTIVE: Using a well-established autopsy cohort and new spatiotemporal predictions of air pollution, we evaluated associations of 10-year PM(2.5) exposure prior to death with Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC score). METHODS: We used autopsy specimens (N=832) from the Adult Changes in Thought (ACT) study, with enrollment ongoing since 1994. We assigned long-term exposure at residential address based on two-week average concentrations from a newly developed spatiotemporal model. To account for potential selection bias, we conducted inverse probability weighting (IPW). Adjusting for covariates with tiered models, we performed ordinal regression for Braak and CERAD and logistic regression for dichotomized ABC score. RESULTS: 10-year average (SD) PM(2.5) from death across the autopsy cohort was 8.2 (1.9) μg/m(3). Average (SD) age at death was 89 (7) years. Each 1 μg/m(3) increase in 10-year average PM(2.5) prior to death was associated with a suggestive increase in the odds of worse neuropathology as indicated by CERAD score (OR: 1.35 (0.90, 1.90)) but a suggestive decreased odds of neuropathology as defined by the ABC score (OR: 0.79 (0.49, 1.19)). There was no association with Braak stage (OR: 0.99 (0.64, 1.47)). CONCLUSIONS: We report inconclusive associations between PM(2.5) and AD neuropathology at autopsy among a cohort where 94% of individuals experienced 10-year exposures below the current EPA standard. Prior studies of AD risk factors and AD neuropathology are similarly inconclusive, suggesting alternative mechanistic pathways for disease or residual confounding.

ObjectiveTo assess whether angiotensin II–stimulating antihypertensives (thiazides, dihydropyridine calcium channel blockers, and angiotensin I receptor blockers) convey a lower risk of incident dementia compared to angiotensin II–inhibiting antihypertensives (angiotensin-converting enzyme inhibitors, β-blockers, and nondihydropyridine calcium channel blockers), in accordance with the “angiotensin hypothesis.”MethodsWe performed Cox regression analyses of incident dementia (or mortality as competing risk) during 6–8 years of follow-up in a population sample of 1,909 community-dwelling individuals (54% women) without dementia, aged 70–78 (mean 74.5 ± 2.5) years.ResultsAfter a median of 6.7 years of follow-up, dementia status was available for 1,870 (98%) and mortality for 1,904 (>99%) participants. Dementia incidence was 5.6% (27/480) in angiotensin II–stimulating, 8.2% (59/721) in angiotensin II–inhibiting, and 6.9% (46/669) in both antihypertensive type users. Adjusted for dementia risk factors including blood pressure and medical history, angiotensin II–stimulating antihypertensive users had a 45% lower incident dementia rate (hazard ratio [HR], 0.55; 95% CI, 0.34–0.89) without excess mortality (HR, 0.86; 95% CI, 0.64–1.16), and individuals using both types had a nonsignificant 20% lower dementia rate (HR, 0.80; 95% CI,0.53–1.20) without excess mortality (HR, 0.97; 95% CI, 0.76–1.24), compared to angiotensin II–inhibiting antihypertensive users. Results were consistent for subgroups based on diabetes and stroke history, but may be specific for individuals without a history of cardiovascular disease.ConclusionsUsers of angiotensin II–stimulating antihypertensives had lower dementia rates compared to angiotensin II–inhibiting antihypertensive users, supporting the angiotensin hypothesis. Confounding by indication must be examined further, although subanalyses suggest this did not influence results. If replicated, dementia prevention could become a compelling indication for older individuals receiving antihypertensive treatment.

We assessed acceptability/usability of tablet-based patient-reported outcome (PRO) assessments among patients in HIV care, and relationships with health outcomes using a modified version of the 6-item Acceptability E-Scale (AES) within a self-administered PRO assessment. Using multivariable linear regression, we measured associations between patient characteristics and continuous combined AES score. Among 786 patients (median age=48; 91% male; 49% white; 17% Spanish-speaking) overall mean score was 26/30 points (SD: 4.4). Mean scores per dimension (max 5, 1=lowest acceptability, 5=highest): ease of use 4.7, understandability 4.7, time burden 4.3, overall satisfaction 4.3, helpfulness describing symptoms/behaviors 4.2, and enjoyability 3.8. Higher overall score was associated with race/ethnicity (+1.3 points/African-American patients (95%CI:0.3-2.3); +1.6 points/Latino patients (95%CI:0.9-2.3) compared to white patients). Patients completing PROs in Spanish scored +2.4 points on average (95%CI:1.6-3.3). Higher acceptability was associated with better quality of life (0.3 points (95%CI:0.2-0.5)) and adherence (0.4 points (95%CI:0.2-0.6)). Lower acceptability was associated with: higher depression symptoms (−0.9 points (95%CI:-1.4 to −0.4)); recent illicit opioid use (−2.0 points (95%CI:-3.9 to −0.2)); multiple recent sex partners (−0.8 points (95%CI:−1.5 to −0.1)). While patients endorsing depression symptoms, recent opioid use, condomless sex, or multiple sex partners found PROs to be less acceptable, overall, patients found self-administered, tablet-based PRO assessments to be highly acceptable and easy to use.

Background Few studies characterize older adult physical activity and sitting patterns using accurate accelerometer and concurrent posture measures. In this descriptive paper, we report accelerometer data collection protocols, consent rates, and physical behavior measures from a population-based cohort study (Adult Changes in Thought, ACT). Methods The ACT study holds enrollment steady at approximately 2000 members of Kaiser Permanente Washington aged 65+ without dementia undergoing detailed biennial assessments. In 2016 the ACT-Activity Monitor (ACT-AM) sub-study was initiated to obtain data from wearing activPAL and ActiGraph devices for 7 days following regular biennial visits. We describe the methods protocol of ACT-AM and present characteristics of people who did and did not consent to wear devices. We compute inverse probability of response weights and incorporate these weights in linear regression models to estimate means and 95% confidence intervals (CI) of device-based pattern metrics, adjusted for wear time and demographic factors, and weighted to account for potential selection bias due to device-wear consent. Results Among 1885 eligible ACT participants, 56% agreed to wear both devices (mean age 77 years, 56% female, 89% non-Hispanic white, 91% with post-secondary education). On average, those who agreed to wear devices were younger and healthier. Estimated mean (95% CI) activPAL-derived sitting, standing, and stepping times were 10.2 h/day (603–618 min/day), 3.9 h/day (226–239 min/day), and 1.4 h/day (79–84 min/day), respectively. Estimated mean ActiGraph derived sedentary (Vector Magnitude [VM] 518 counts/15 s) physical activity durations were 9.5 h/day (565–577 min/day), 4.5 h/day (267–276 min/day), and 1.0 h/day (59–64 min/day). Participants who were older, had chronic conditions, and were unable to walk a half-mile had higher sedentary time and less physical activity. Conclusions Our recruitment rate demonstrates the feasibility of cohort participants to wear two devices that measure sedentary time and physical activity. Data indicate high levels of sitting time in older adults but also high levels of physical activity using cut-points developed for older adults. These data will help researchers test hypotheses related to physical behavior and health in older adults in the future.

BACKGROUND Although one third of Medicare beneficiaries are enrolled in Medicare Advantage (MA) plans, there is limited information about the cost of treating Alzheimer disease and related dementias (ADRD) in these settings. OBJECTIVE The objective of this study was to estimate direct health care costs attributable to ADRD among older adults within a large MA plan. RESEARCH DESIGN A retrospective cohort design was used to estimate direct total, outpatient, inpatient, ambulatory pharmacy, and nursing home costs for 3 years before and after an incident ADRD diagnosis for 927 individuals diagnosed with ADRD relative to a sex-matched and birth year-matched set of 2945 controls. SUBJECT Adults, 65 years of age and older enrolled in the Kaiser Permanente Washington MA plan and the Adult Changes in Thought (ACT) Study, a prospective longitudinal cohort study of ADRD and brain aging. MEASURES Data on monthly health service use obtained from health system electronic medical records for the period 1992-2012. RESULTS Total monthly health care costs for individuals with ADRD are statistically greater (P

Background American Indians have excess risk of depression, which can contribute to cerebrovascular and cognitive disability, with effects on memory, processing speed, executive function, and visuospatial ability. However, studies examining depression and cognition in American Indians are limited; this study aims to report associations of depression with general cognition, verbal fluency and memory, and processing speed. Design Cohort study. Setting The Cerebrovascular Disease and its Consequences in American Indians study was an ancillary examination of Strong Heart Study participants from 3 U.S. regions. Participants All eligible were included in this analysis (N=818). Measurements Participants completed evaluations for depressive symptomology, cognition, and physical function-including Center for Epidemiologic Studies Depression (CESD), Modified Mini-Mental State Examination (3MSE), Wechsler Adult Intelligence Scale-Fourth Edition coding (WAIS), Controlled Oral Word Association (COWA), California Verbal and Learning Test, Halstead finger tapping, grip strength, and Short Physical Performance Battery (SPPB) tests. Linear mixed models were adjusted for site, age, sex, education, income, marital status, alcohol, smoking, diabetes, hypertension, obesity, cholesterol, stroke, infarct, and hemorrhage. Results Symptoms of depression were common, with 20% (N=138) endorsing CES-D scores of 16+. More depressive symptoms were associated with older age, female sex, lower education, lower income, non-married status, not using alcohol, not smoking, hypertension, diabetes, and stroke. In adjusted analyses, processing speed (WAIS: β -0.13, 95%CI -0.25, -0.03), general cognition (3MSE: β -0.10, 95%CI -0.17, -0.03), verbal fluency (COWA: β -0.10, 95%CI -0.19, -0.01), and motor function (SPPB: β -0.05, 95%CI -0.07, -0.03) were significantly associated with more symptoms of depression. Conclusion These findings maybe informative for health disparities populations, especially those with depressive risk. Clinicians may require particular training in cultural humility. Future studies should validate use of the CES-D scale in this population; longitudinal studies may focus on causal mechanisms and potential secondary prevention, such as social support. J Am Geriatr Soc 68:1739-1747, 2020.

Introduction: Harmonized neuropsychological assessment for neurocognitive disorders, an international priority for valid and reliable diagnostic procedures, has been achieved only in specific countries or research contexts.Methods: To harmonize the assessment of mild cognitive impairment in Europe, a workshop (Geneva, May 2018) convened stakeholders, methodologists, academic, and non-academic clinicians and experts from European, US, and Australian harmonization initiatives.Results: With formal presentations and thematic working-groups we defined a standard battery consistent with the U.S. Uniform DataSet, version 3, and homogeneous methodology to obtain consistent normative data across tests and languages. Adaptations consist of including two tests specific to typical Alzheimer's disease and behavioral variant frontotemporal dementia. The methodology for harmonized normative data includes consensus definition of cognitively normal controls, classification of confounding factors (age, sex, and education), and calculation of minimum sample sizes.Discussion: This expert consensus allows harmonizing the diagnosis of neurocognitive disorders across European countries and possibly beyond.

Background Central nervous system (CNS)-active medication use is an important modifiable risk factor for falls in older adults. A fall-related injury should prompt providers to evaluate and reduce CNS-active medications to prevent recurrent falls. We evaluated change in CNS-active medications up to 12 months following a fall-related injury in community-dwelling older adults compared with a matched cohort without fall-related injury. Methods Participants were from the Adult Changes in Thought study conducted at Kaiser Permanente Washington. Fall-related injury codes between 1994 and 2014 defined index encounters in participants with no evidence of such injuries in the preceding year. We matched each fall-related injury index encounter with up to five randomly selected clinical encounters from participants without injury. Using automated pharmacy data, we estimated the average change in CNS-active medication use at 3, 6, and 12 months post-index according to the presence or absence of CNS-active medication use before index. Results One thousand five hundred sixteen participants with fall-related injury index encounters (449 CNS-active users, 1067 nonusers) were matched to 7014 index encounters from people without fall-related injuries (1751 users, 5236 nonusers). Among CNS-active users at the index encounter, those with fall-related injury had an average decrease in standard daily doses (SDDs) at 12 months (-0.43; 95% CI: -0.63 to -0.23), and those without injury had a greater (p = 0.047) average decrease (-0.66; 95% CI: -0.78 to -0.55). Among nonusers at index, those with fall-related injury had a smaller increase than those without injury (+0.17, 95% CI: +0.13 to +0.21, vs. +0.24, 95% CI: +0.20 to +0.28, p = 0.005). Conclusions The differences in CNS-active medication use change over 12 months between those with and without fall-related injury were small and unlikely to be clinically significant. These results suggest that fall risk-increasing drug use is not reduced following a fall-related injury, thus opportunities exist to reduce CNS-active medications, a potentially modifiable risk factor for falls.

Introduction Alzheimer's disease (AD) neuropathological subtypes (limbic predominant [lpAD], hippocampal sparing [HpSpAD], and typical [tAD]), defined by relative neurofibrillary tangle (NFT) burden in limbic and cortical regions, have not been studied in prospectively characterized epidemiological cohorts with robust cognitive assessments. Methods Two hundred ninety‐two participants with neuropathologically confirmed AD from the Religious Orders Study and Memory and Aging Project were categorized by neuropathological subtype based on previously specified diagnostic criteria using quantitative regional NFT counts. Rates of cognitive decline were compared across subtypes using linear mixed‐effects models that included subtype, time, and a subtype–time interaction as predictors and four cognitive domain factor scores (memory, executive function, language, visuospatial) and a global score as outcomes. To assess if memory was relatively preserved in HpSpAD, non‐memory factor scores were included as covariates in the mixed‐effects model with memory as the outcome. Results There were 57 (20%) with lpAD, 22 (8%) with HpSpAD and 213 (73%) with tAD. LpAD died significantly later than the participants with tAD (2.4 years, P = .01) and with HpSpAD (3.8 years, P = .03). Compared to tAD, HpSpAD, but not lpAD, performed significantly worse in all cognitive domains at the time of initial impairment and declined significantly faster in memory, language, and globally. HpSpAD did not have relatively preserved memory performance at any time point. Conclusion The relative frequencies of AD neuropathological subtypes in an epidemiological sample were consistent with a previous report in a convenience sample. People with HpSpAD decline rapidly, but may not have a memory‐sparing clinical syndrome. Cohort‐specific differences in regional tau burden and comorbid neuropathology may explain the lack of clinicopathological correlation.

Importance Multiple polygenic risk scores (PRSs) for breast cancer have been developed from large research consortia; however, their generalizability to diverse clinical settings is unknown. Objective To examine the performance of previously developed breast cancer PRSs in a clinical setting for women of European, African, and Latinx ancestry. Design, Setting, and Participants This cohort study using the Electronic Medical Records and Genomics (eMERGE) network data set included 39 591 women from 9 contributing medical centers in the US that had electronic medical records (EMR) linked to genotype data. Breast cancer cases and controls were identified through a validated EMR phenotyping algorithm. Main Outcomes and Measures Multivariable logistic regression was used to assess the association between breast cancer risk and 7 previously developed PRSs, adjusting for age, study site, breast cancer family history, and first 3 ancestry informative principal components. Results This study included 39 591 women: 33 594 with European, 3801 with African, and 2196 with Latinx ancestry. The mean (SD) age at breast cancer diagnosis was 60.7 (13.0), 58.8 (12.5), and 60.1 (13.0) years for women with European, African, and Latinx ancestry, respectively. PRSs derived from women with European ancestry were associated with breast cancer risk in women with European ancestry (highest odds ratio [OR] per 1-SD increase, 1.46; 95% CI, 1.41-1.51), women with Latinx ancestry (highest OR, 1.31; 95% CI, 1.09-1.58), and women with African ancestry (OR, 1.19; 95% CI, 1.05-1.35). For women with European ancestry, this association with breast cancer risk was largest in the extremes of the PRS distribution, with ORs ranging from 2.19 (95% CI, 1.84-2.53) to 2.48 (95% CI, 1.89-3.25) for the 3 different PRSs examined for those in the highest 1% of the PRS compared with those in the middle quantile. Among women with Latinx and African ancestries at the extremes of the PRS distribution, there were no statistically significant associations. Conclusions and Relevance This cohort study found that PRS models derived from women with European ancestry for breast cancer risk generalized well for women with European, Latinx, and African ancestries across different clinical settings, although the effect sizes for women with African ancestry were smaller, likely because of differences in risk allele frequencies and linkage disequilibrium patterns. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.

Background: Air pollution may be associated with elevated dementia risk. Prior research has limitations that may affect reliability, and no studies have evaluated this question in a population-based cohort of men and women in the United States. Objectives: We evaluated the association between time-varying, 10-y average fine particulate matter (PM2.5) exposure and hazard of all-cause dementia. An additional goal was to understand how to adequately control for age and calendar-time-related confounding through choice of the time axis and covariate adjustment. Methods: Using the Adult Changes in Thought (ACT) population-based prospective cohort study in Seattle, we linked spatiotemporal model-based PM2.5 exposures to participant addresses from 1978 to 2018. Dementia diagnoses were made using high-quality, standardized, consensus-based protocols at biennial follow-ups. We conducted multivariable Cox proportional hazards regression to evaluate the association between time-varying, 10-y average PM2.5 exposure and time to event in a model with age as the time axis, stratified by apolipoprotein E (APOE) genotype, and adjusted for sex, education, race, neighborhood median household income, and calendar time. Alternative models used calendar time as the time axis. Results: We report 1,136 cases of incident dementia among 4,166 individuals with nonmissing APOE status. Mean [mean ± standard deviation (SD)] 10-y average PM2.5 was 10.1 (±2.9) μg/m3. Each 1-μg/m3 increase in the moving average of 10-y PM2.5 was associated with a 16% greater hazard of all-cause dementia [1.16 (95% confidence interval: 1.03, 1.31)]. Results using calendar time as the time axis were similar. Discussion: In this prospective cohort study with extensive exposure data and consensus-based outcome ascertainment, elevated long-term exposure to PM2.5 was associated with increased hazard of all-cause dementia. We found that optimal control of age and time confounding could be achieved through use of either age or calendar time as the time axis in our study. Our results strengthen evidence on the neurodegenerative effects of PM2.5. https://doi.org/10.1289/EHP9018

Evidence suggests priorities differ between patients in HIV care and their providers regarding topics most important to address in care. At five U.S. sites, we asked patients and providers to prioritize 25 potential topic areas to address during routine visits, and invited patients to discuss selection rationale. Patients (n = 206) and providers (n = 17) showed high discordance in rank order priorities (X2 (24, 223) = 71.12; p

BACKGROUND: The extent to which obesity and genetics determine post-operative complications is incompletely understood. METHODS: We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990-2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records & Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score (GRS) was constructed from 97 obesity-risk single nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk for obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components. RESULTS: Individuals with overweight or obese BMI (≥25 kg/m(2)) had increased risk for incisional hernia (Odds ratio [OR] 1.7-5.5, p

Purpose Antihypertensives may have effects on the brain beyond blood pressure lowering. Ongoing clinical trials aim to evaluate the effectiveness of approved antihypertensives in preventing dementia, including patients with and without hypertension. In order for a dementia prevention strategy using antihypertensives to be effective, it is critical to understand patient concerns about this strategy in both users and non-users of antihypertensives. Thus, this study examined the association between current use of antihypertensive and having concerns about using an antihypertensive as a dementia prevention strategy, as well as sociodemographic factors associated with concerns. Patients and methods Cross-sectional, self-administered, web-based survey was conducted among 1661 patients in a large health system in January 2018. Participants reported whether they were currently taking an antihypertensive (yes/no), and what types of hypothetical concerns they have about the idea of taking an antihypertensive to prevent dementia (yes/no, for each of 7 concerns). Associations between the two variables were assessed via logistic regression, and odds ratios with 95% confidence intervals were calculated. Results Most respondents were female (77%), 51-70 years of age (64%), and white (89%), with 30% reporting current antihypertensive use. Compared to current users, non-users were more likely to report the five following concerns: side effects from the medication, hassle to take medications, lack of evidence, not wanting to use medications, and already having normal/low blood pressure. Non-users were also less likely to report having no concerns (adjusted OR = 0.3; 95% CI = 0.2-0.4) compared to current users. Younger age and lower income were associated with having more concerns. Conclusion Patients not currently using an antihypertensive are more likely to have concerns about using an antihypertensive for dementia prevention, compared to current antihypertensive users. Patient perspectives are important to consider for the implementation of dementia prevention strategies.

BACKGROUND: There is considerable heterogeneity in clinical presentation among people with late-onset Alzheimer’s disease (LOAD). We have categorized people with LOAD into subgroups based on relative impairments across cognitive domains. These 6 groups are people with no relatively impaired domains (AD-No Domains), 4 groups with one relatively impaired domain (AD-Memory, AD-Executive, AD-Language, and AD-Visuospatial), and a group with multiple relatively impaired domains (AD-Multiple Domains). Our previous analysis demonstrated that genetic factors vary across cognitively-defined LOAD groups. OBJECTIVE: To determine whether risks associated with depression and traumatic brain injury with loss of consciousness (TBI) for cognitively defined LOAD subgroups are similar. METHODS: We used cognitive data at LOAD diagnosis from three prospective cohort studies to determine cognitively-defined subgroups. We compared subgroups in endorsement of items from the Centers for Epidemiological Studies Depression (CES-D) scale and history of TBI. RESULTS: Among 1505 people with LOAD from the three studies, there were substantial differences across subgroups in total CES-D score, with lower scores (less depression) for people with AD with relative impairments in memory (AD-Memory) compared to those in other groups. Differences were noteworthy for the sleep-related item of the CES-D, as people with AD-Memory were less likely to report restless sleep than people in other groups. There were no differences in TBI history across groups. CONCLUSIONS: Differences in risk factor associations across subgroups such as differences in endorsement of depression symptoms and restless sleep provide support for the hypothesis that there are biologically coherent subgroups of Alzheimer’s disease.

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.

Low perceived social support negatively impacts health outcomes. HIV-related stigma may hinder social support. We developed a measure of perceived social support for use in HIV care. We developed a pool of legacy social support items based on literature review. We categorized items similar in content and winnowed items within each of these categories to the strongest alternatives using a qualitative item review process. We designed an interview guide representative of content areas, conducted concept elicitation interviews with patients in English/Spanish, and coded transcripts to match item pool content. We developed new items for salient unrepresented content. In focus groups, patients prioritized highly matched items. We performed cognitive interviews with patients on resulting high-priority items. We performed validity testing on final items against two legacy social support measures. From concept elicitation interviews (n=32), we matched the following concepts: sense of belonging/inclusion (e.g., feeling part of a community/group); communication (e.g., sharing thoughts/feelings with others, and vice-versa); emotional support (feeling loved/liked/cared about); feeling accepted by others as a person; companionship (e.g., fun with others); practical support (e.g., feeling that others in your life would offer tangible support). We identified a new concept: feeling supported by friends/family in remaining healthy. Focus groups (n=23) prioritized highly emotional support, communication, and support to remain healthy. Cognitive interviews (n=30) found most items were well-understood; we revised or omitted those that were not. The final 8-item measure performed well when administered to patients (n=708), with good construct validity. We used an Item Response Theory program to create a 3-item Short Form version of the measure, which captures 96% of patients indicating low social support. We developed the Multifactoral Assessment of Perceived Social Support (MAPSS) and Short Form (MAPSS-SF), which are brief, clinically relevant, sufficiently unidimensional measures of social support for use with patients living with HIV.

Alzheimer’s disease neuropathologic change (ADNC) is defined by progressive accumulation of β-amyloid plaques and hyperphosphorylated tau (pTau) neurofibrillary tangles across diverse regions of brain. Non-demented individuals who reach advanced age without significant ADNC are considered to be resistant to AD, while those burdened with ADNC are considered to be resilient. Understanding mechanisms underlying ADNC resistance and resilience may provide important clues to treating and/or preventing AD associated dementia. ADNC criteria for resistance and resilience are not well-defined, so we developed stringent pathologic cutoffs for non-demented subjects to eliminate cases of borderline pathology. We identified 14 resistant (85+ years old, non-demented, Braak stage ≤ III, CERAD absent) and 7 resilient (non-demented, Braak stage VI, CERAD frequent) individuals out of 684 autopsies from the Adult Changes in Thought study, a long-standing community-based cohort. We matched each resistant or resilient subject to a subject with dementia and severe ADNC (Braak stage VI, CERAD frequent) by age, sex, year of death, and post-mortem interval. We expanded the neuropathologic evaluation to include quantitative approaches to assess neuropathology and found that resilient participants had lower neocortical pTau burden despite fulfilling criteria for Braak stage VI. Moreover, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) was robustly associated with clinical dementia and was more prevalent in cases with high pTau burden, supporting the notion that resilience to ADNC may depend, in part, on resistance to pTDP-43 pathology. To probe for interactions between tau and TDP-43, we developed a C. elegans model of combined human (h) Tau and TDP-43 proteotoxicity, which exhibited a severe degenerative phenotype most compatible with a synergistic, rather than simply additive, interaction between hTau and hTDP-43 neurodegeneration. Pathways that underlie this synergy may present novel therapeutic targets for the prevention and treatment of AD.

Objective The Automated Neuropsychological Assessment Metrics (Version 4) Traumatic Brain Injury Military (ANAM4 TBI-MIL) is commonly administered among U.S. service members both pre-deployment and following TBI. The current study used the ANAM4 TBI-MIL to develop a cognition summary score for TBI research and clinical trials, comparing eight composite scores based on their distributions and sensitivity/specificity when differentiating between service members with and without mild TBI (MTBI). Method Male service members with MTBI (n = 56; Mdn = 11 days-since-injury) or no self-reported TBI history (n = 733) completed eight ANAM4 TBI-MIL tests. Their throughput scores (correct responses/minute) were used to calculate eight composite scores: the overall test battery mean (OTBM); global deficit score (GDS); neuropsychological deficit score-weighted (NDS-W); low score composite (LSC); number of scores Results The OTBM and ACS were normally distributed. Other composites had skewed, zero-inflated distributions (62.9% had GDS = 0). All composites differed significantly between participants with and without MTBI (p < .001), with deficit scores showing the largest effect sizes (d = 1.32–1.47). The Area Under the Curve (AUC) was lowest for number of scores ≤5th percentile (AUC = 0.653) and highest for the LSC, OTBM, ACS, and NDS-W (AUC = 0.709–0.713). Conclusions The ANAM4 TBI-MIL has no well-validated composite score. The current study examined multiple candidate composite scores, finding that deficit scores showed larger group differences than the OTBM, but similar AUC values. The deficit scores were highly correlated. Future studies are needed to determine whether these scores show less redundancy among participants with more severe TBIs.

Lack of a unitary operational definition of mild cognitive impairment (MCI) has resulted in mixed prevalence rates and unclear predictive validity regarding conversion to dementia and likelihood of reversion. We examined 1,721 nondemented participants aged 65 and older from the Adult Changes in Thought (ACT) community-based cohort. Participants were followed longitudinally through biennial visits (average years assessed = 5.38). Categorization of MCI was based on: 1) deviation of neuropsychological test scores from a benchmark based on either standard or individualized expectations of a participant's mean premorbid cognitive ability, and 2) cutoff for impairment (1.0 versus 1.5 standard deviations [sd] below benchmark). MCI prevalence ranged from 56-92%; using individualized benchmarks and less stringent cutoffs produced higher rates. During follow-up, 17% of the cohort developed dementia. Examination of sensitivity, specificity, and predictive validity revealed that the criterion of 1.5 sd from the standardized benchmark was optimal, but still had limited predictive validity. Participants meeting this criterion at their first visit were three times more likely to develop dementia and this increased to seven times if participants had this diagnosis at the second timepoint as well. Those who did not have an MCI diagnosis at their first visit, but did at their second, had a significant increase of risk (but to a lesser extent than those diagnosed at both visits), while those who had an MCI diagnosis at their first visit, but not their second, did not have a significantly increased risk. These results highlight how assessing MCI stability greatly improves prediction of risk.

Objectives To examine the association between central nervous system (CNS)-active medication use and the risk of fall-related injury in community-dwelling older adults following dementia onset. Further, to evaluate increased risk at higher doses or with a greater number of CNS-active medication classes. Methods Participants included community-dwelling older adults aged 65 years and older with a dementia diagnosis participating in the Adult Changes in Thought Study. From automated pharmacy data, a time-varying composite measure of CNS-active medication use was created. Central nervous system-active medication use was classified as current (use within prior 30 days), recent (prior 31-90 days), past (prior 91-365 days), and nonuse (no exposure in prior year). For current users, standardized daily doses (SDDs) were calculated for each CNS-active medication and summed across medications, and the number of CNS-active medication classes used was also measured. The outcome was fall-related injury based on emergency department, inpatient, and outpatient International Classification of Diseases, Ninth Revision (ICD-9) and external cause of injury (E) codes. Results Among 793 subjects, 303 fall-related injuries occurred over a mean follow-up of 3.7 years (2907 total person-years). Relative to nonuse, fall risk was significantly higher for current use (adjusted hazard ratio [HR] 1.59, 95% confidence internal [CI] 1.19-2.12) but not for past or recent use. Among current users, increased risk was seen across SDD levels: HRs (95% CI): 1.77 (1.19-2.62), 1.79 (1.25-2.56), and 1.35 (0.96-1.92) for less than 1 SDD, 1 to less than 2 SDDs, and 2 or more SDDs, respectively (trend test, p=0.14). A trend was seen for increasing risk with a greater number of CNS-active medication classes; however, this was not statistically significant (trend test, p=0.084). Conclusions Current use of CNS-active medications was associated with fall-related injury in community-dwelling older adults followed from time of dementia onset, with increased risk even with use of low doses.

Background The aging eye offers unique opportunities to study and understand the aging brain, in particular related to Alzheimer's disease (AD) and dementia. However, little is known about relationships between eye diseases and dementia-related neurodegeneration. Objective To determine the potential association between three age-related eye diseases and AD and dementia-related neuropathology. Methods We reviewed autopsy data from the prospective longitudinal Adult Changes in Thought (ACT) cohort. ICD-9 codes were used to identify diagnoses of diabetic retinopathy, glaucoma, and age-related macular degeneration. Multivariate regression models were used to determine odds ratios (OR) of neuropathology features associated with dementia, including Braak stage, Consortium to Establish a Registry for AD (CERAD score), Lewy bodies, hippocampal sclerosis, and microvascular brain injury, in addition to quantitative paired helical filament (PHF)-tau levels for people with and without each eye condition. We also evaluated interactions between eye conditions and dementia related neuropathologic findings were evaluated. Results 676 autopsies were included. Diabetic retinopathy was significantly associated with increased risk of deep cerebral microinfarcts (OR = 1.91 [95% confidence interval (CI) 1.11, 3.27], p = 0.02). No other significant association or interaction between eye diseases and neuropathology was found. When PHF-tau quantity was evaluated in 124 decedents, the OR for the association between PHF-tau in the occipital cortex and glaucoma was 1.36 (95% CI 0.91, 2.03, p = 0.13). No statistical correction was made for multiple comparisons. Conclusion Increased risk of deep cerebral microinfarcts was found in participants diagnosed with diabetic retinopathy. Eye diseases such as glaucoma may increase susceptibility to neurofibrillary tangles in the occipital cortex.

Introduction As the number of U.S. veterans over age 65 has increased, interest in whether military service affects late-life health outcomes has grown. Whether military employment is associated with increased risk of cognitive decline and dementia remains unclear. Materials and Methods We used data from 4,370 participants of the longitudinal Adult Changes in Thought (ACT) cohort study, enrolled at age 65 or older, to examine whether military employment was associated with greater cognitive decline or higher risk of incident dementia in late life. We classified persons as having military employment if their first or second-longest occupation was with the military. Cognitive status was assessed at each biennial Adult Changes in Thought study visit using the Cognitive Abilities Screening Instrument, scored using item response theory (CASI-IRT). Participants meeting screening criteria were referred for dementia ascertainment involving clinical examination and additional cognitive testing. Primary analyses were adjusted for sociodemographic characteristics and APOE genotype. Secondary analyses additionally adjusted for indicators of early-life socioeconomic status and considered effect modification by age, gender, and prior traumatic brain injury with loss of consciousness TBI with LOC. Results Overall, 6% of participants had military employment; of these, 76% were males. Military employment was not significantly associated with cognitive change (difference in modeled 10-year cognitive change in CASI-IRT scores in SD units (95% confidence interval [CI]): −0.042 (−0.19, 0.11), risk of dementia (hazard ratio [HR] [95% CI]: 0.92 [0.71, 1.18]), or risk of Alzheimer’s disease dementia (HR [95% CI]: 0.93 [0.70, 1.23]). These results were robust to additional adjustment and sensitivity analyses. There was no evidence of effect modification by age, gender, or traumatic brain injury with loss of consciousness. Conclusions Among members of the Adult Changes in Thought cohort, military employment was not associated with increased risk of cognitive decline or dementia. Nevertheless, military veterans face the same high risks for cognitive decline and dementia as other aging adults.

The AT(N) research framework categorizes eight biomarker profiles using amyloid (A), tauopathy (T), and neurodegeneration (N), regardless of dementia status. We evaluated associations with dementia risk in a community-based cohort by approximating AT(N) profiles using autopsy-based neuropathology correlates, and considered cost implications for clinical trials for secondary prevention of dementia based on AT(N) profiles. We used Consortium to Establish a Registry for Alzheimer's Disease (moderate/frequent) to approximate A+, Braak stage (IV-VI) for T+, and temporal pole lateral ventricular dilation for (N)+. Outcomes included dementia prevalence at death and incidence in the last 5 years of life. A+T+(N)+ was the most common profile (31%). Dementia prevalence ranged from 14% (A-T-[N]-) to 79% (A+T+[N]+). Between 8% (A+T-[N]-) and 68% (A+T+[N]-) of decedents developed incident dementia in the last 5 years of life. Clinical trials would incur substantial expense to characterize AT(N). Many people with biomarker-defined preclinical Alzheimer's disease will never develop clinical dementia during life, highlighting resilience to clinical expression of AD neuropathologic changes and the need for improved tools for prediction beyond current AT(N) biomarkers.

People who have Alzheimer's disease neuropathologic change (ADNC) typically associated with dementia but not the associated cognitive decline can be considered to be “resilient” to the effects of ADNC. We have previously reported lower neocortical levels of hyperphosphorylated tau (pTau) and less limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) in the resilient participants compared to those with dementia and similar ADNC as determined by current NIA‐AA recommendations using traditional semi‐quantitative assessments of amyloid β and pathological tau burden. To better understand differences between AD‐dementia and resilient participants, we developed and applied a deep learning approach to analyze the neuropathology of 14 brain donors from the Adult Changes in Thought study, including seven stringently defined resilient participants and seven age‐matched AD‐dementia controls. We created two novel, fully automated deep learning algorithms to quantify the level of phosphorylated TDP‐43 (pTDP‐43) and pTau in whole slide imaging. The models performed better than traditional techniques for quantifying pTDP‐43 and pTau. The second model was able to segment lesions staining for pTau into neurofibrillary tangles (NFTs) and tau neurites (neuronal processes positive for pTau). Both groups had similar quantities of pTau localizing to neurites, but the pTau burden associated with NFTs in the resilient group was significantly lower compared to the group with dementia. These results validate use of deep learning approaches to quantify clinically relevant microscopic characteristics from neuropathology workups. These results also suggest that the burden of NFTs is more strongly associated with cognitive impairment than the more diffuse neuritic tau commonly seen with tangle pathology and suggest that additional factors may underlie resilience mechanisms defined by traditional means., To better understand the neuropathology of individuals with Alzheimer's disease (AD) dementia and "resilient" individuals who have AD pathology but are cognitively normal, we developed deep learning algorithms to quantify the level of phosphorylated TDP‐43 and pTau in whole slide imaging. The models performed better than traditional techniques for quantifying pTDP‐43 and pTau, and the pTau model was able to segment pTau lesions into neurofibrillary tangles (NFTs) and tau neurites (neuronal processes positive for pTau). While both groups had similar quantities of pTau localizing to neurites, the resilient group had significantly less pTau burden associated with NFTs compared to the group with dementia.

Background Research supports that moderate-to-vigorous intensity physical activity (MVPA) is key to prolonged health and function. Among older adults, substantial changes to MVPA may be infeasible, thus a growing literature suggests a shift in focus to whole-day activity patterns. Methods With data from 795 older adults aged 65–100 in the Adult Changes in Thought Activity Monitoring study, we used linear regression to estimate associations between ActiGraph and activPAL measured activity patterns – including light intensity physical activity, steps, standing, and sedentary behaviors – and physical function as measured by a short Performance-based Physical Function (sPPF) score (range 0–12), a composite score based on three standardized physical performance tasks: gait speed, timed chair stands, and grip strength. We examined whether relationships persisted when controlling for MVPA or differed across age, gender, or quartiles of MVPA. Results In models unadjusted for MVPA, a 1-standard deviation (SD) increment of daily sitting (1.9 h more), mean sitting bout duration (8 min longer average), or time spent in sedentary activity (1.6 h more) was associated with ~ 0.3–0.4 points lower mean sPPF score (all p Conclusions We found associations between function and activity metrics other than MVPA in key subgroups, findings that support research on broader activity patterns and may offer ideas regarding practical intervention opportunities for improving function in older adults.

Background: Vascular disease is a risk factor for Alzheimer’s disease (AD) and related dementia in older adults. Retinal artery/vein occlusion (RAVO) is an ophthalmic complication of systemic vascular pathology. Whether there are associations between RAVO and dementia risk is unknown. Objective: To determine whether RAVOs are associated with an increased risk of developing vascular dementia or AD. Methods: Data from Adult Changes in Thought (ACT) study participants were analyzed. This prospective, population-based cohort study followed older adults (age ≥65 years) who were dementia-free at enrollment for development of vascular dementia or AD based on research criteria. RAVO diagnoses were extracted from electronic medical records. Cox-regression survival analyses were stratified by APOE ɛ4 genotype and adjusted for demographic and clinical factors. Results: On review of 41,216 person-years (4,743 participants), 266 (5.6%) experienced RAVO. APOE ɛ4 carriers who developed RAVO had greater than four-fold higher risk for developing vascular dementia (Hazard Ratio [HR] 4.54, 95% Confidence Interval [CI] 1.86, 11.10, p = 0.001). When including other cerebrovascular disease (history of carotid endarterectomy or transient ischemic attack) in the model, the risk was three-fold higher (HR 3.06, 95% CI 1.23, 7.62). No other conditions evaluated in the secondary analyses were found to confound this relationship. There was no effect in non-APOE ɛ4 carriers (HR 1.03, 95% CI 0.37, 2.80). There were no significant associations between RAVO and AD in either APOE group. Conclusion: Older dementia-free patients who present with RAVO and carry the APOE ɛ4 allele appear to be at higher risk for vascular dementia.

To determine associations of traumatic brain injury (TBI) and military employment with activities of daily living (ADL) in late life.Population-based prospective cohort study with biennial follow-up and censoring at the time of dementia diagnosis.Community-based integrated health care delivery system.Participants (N=4953) were men (n=2066) and women (n=2887) aged ≥65 years who were dementia free.Not applicable.ADL difficulties at baseline and accumulation during follow-up.TBI with loss of consciousness (LOC) before the age of 40 years was associated with slightly higher ADL difficulty at baseline for women (rate ratio [RR], 1.44; 95% confidence interval [CI], 1.08-1.93; P=.01). For men, TBI with LOC at any age was associated with greater ADL difficulty at baseline (age40y: RR, 1.58; 95% CI, 1.20-2.08; P=.001; age ≥40y: RR, 2.14; 95% CI, 1.24-3.68; P=.006). TBI with LOC was not associated with the rate of accumulation of ADL difficulties over time in men or women. There was no evidence of an association between military employment and either outcome, nor of an interaction between military employment and TBI with LOC. Findings were consistent across a variety of sensitivity analyses.Further investigation into factors underlying greater late life functional impairment among survivors of TBI is warranted.

The late neuropathological effects of traumatic brain injury have yet to be fully elucidated, particularly with respect to community-based cohorts. To contribute to this critical gap in knowledge, we designed a multimodal neuropathological study, integrating traditional and quantitative approaches to detect pathologic changes in 532 consecutive brain autopsies from participants in the Adult Changes in Thought (ACT) study. Diagnostic evaluation including assessment for chronic traumatic encephalopathy (CTE) and quantitative immunoassay-based methods were deployed to examine levels of pathological (hyperphosphorylated) tau (pTau) and amyloid (A) β in brains from ACT participants with (n = 107) and without (n = 425) history of remote TBI with loss of consciousness (w/LOC). Further neuropathological assessments included immunohistochemistry for α-synuclein and phospho-TDP-43 pathology and astro- (GFAP) and micro- (Iba1) gliosis, mass spectrometry analysis of free radical injury, and gene expression evaluation (RNA sequencing) in a smaller sub-cohort of matched samples (49 cases with TBI and 49 non-exposed matched controls). Out of 532 cases, only 3 (0.6%–none with TBI w/LOC history) showed evidence of the neuropathologic signature of chronic traumatic encephalopathy (CTE). Across the entire cohort, the levels of pTau and Aβ showed expected differences for brain region (higher levels in temporal cortex), neuropathological diagnosis (higher in participants with Alzheimer's disease), and APOE genotype (higher in participants with one or more APOE ε4 allele). However, no differences in PHF-tau or Aβ1−42 were identified by Histelide with respect to the history of TBI w/LOC. In a subset of TBI cases with more carefully matched control samples and more extensive analysis, those with TBI w/LOC history had higher levels of hippocampal pTau but no significant differences in Aβ, α-synuclein, pTDP-43, GFAP, Iba1, or free radical injury. RNA-sequencing also did not reveal significant gene expression associated with any measure of TBI exposure. Combined, these findings suggest long term neuropathological changes associated with TBI w/LOC may be subtle, involve non-traditional pathways of neurotoxicity and neurodegeneration, and/or differ from those in autopsy cohorts specifically selected for neurotrauma exposure.

Background There is concern that the Patient Health Questionnaire-9 (PHQ-9) depression scale may be impacted by the presence of somatic symptoms (differential item functioning (DIF)) in patients with neurological conditions. We evaluated the PHQ-9 for the presence and impact of DIF in large clinical samples of neurological patients. Methods We conducted a cross-sectional study of patients seen at the Cleveland Clinic Cerebrovascular, Headache, Movement Disorder, and Neuromuscular clinics who completed the PHQ-9 and patient-reported disease severity measures as part of standard care between 7/29/2008-2/21/2013. We evaluated PHQ-9 items for DIF with respect to disease-specific severity for each condition. Salient DIF impact was characterized as a difference between DIF-adjusted and unadjusted PHQ-9 scores. Results Included in the study were 2,112 patients with stroke, 8,221 with migraine, 440 with amyotrophic lateral sclerosis (ALS), and 5,022 with Parkinson's disease (PD). Several PHQ-9 items demonstrated DIF with respect to disease-specific severity, although salient DIF was present in very few patients (stroke (n=0); migraine (n=1); ALS (n=13); PD (n=1)). Conclusions PHQ-9 items function consistently across disease severity, with salient levels of DIF impact found only for a very small proportion of people. These results suggest that the PHQ-9 provides a consistent measure of depression severity among people with neurological conditions associated with somatic symptoms that overlap with depression.

Social support (SS) predicts health outcomes among patients living with HIV. Systematic assessment of SS in routine HIV care is rare. We administered a brief, validated measure of SS, the Multifactoral Assessment of Perceived Social Support, within a patient-reported outcomes assessment of several health domains in routine HIV care at 4 U.S. clinics in English and Spanish (n=708). In univariate analysis, low SS was associated with poorer engagement in care, antiretroviral adherence, and health-related quality of life (HRQL); current methamphetamine/crystal use, depression, anxiety, and HIV stigma (all p

The clinical presentation of Alzheimer’s disease (AD) varies widely across individuals but the neurobiological mechanisms underlying this heterogeneity are largely unknown. Here, we compared regional gray matter (GM) volumes and associated gene expression profiles between cognitively-defined subgroups of amyloid-β positive individuals clinically diagnosed with AD dementia (age: 66 ± 7, 47% male, MMSE: 21 ± 5). All participants underwent neuropsychological assessment with tests covering memory, executive-functioning, language and visuospatial-functioning domains. Subgroup classification was achieved using a psychometric framework that assesses which cognitive domain shows substantial relative impairment compared to the intra-individual average across domains, which yielded the following subgroups in our sample; AD-Memory (n = 41), AD-Executive (n = 117), AD-Language (n = 33), AD-Visuospatial (n = 171). We performed voxel-wise contrasts of GM volumes derived from 3Tesla structural MRI between subgroups and controls (n = 127, age 58 ± 9, 42% male, MMSE 29 ± 1), and observed that differences in regional GM volumes compared to controls closely matched the respective cognitive profiles. Specifically, we detected lower medial temporal lobe GM volumes in AD-Memory, lower fronto-parietal GM volumes in AD-Executive, asymmetric GM volumes in the temporal lobe (left < right) in AD-Language, and lower GM volumes in posterior areas in AD-Visuospatial. In order to examine possible biological drivers of these differences in regional GM volumes, we correlated subgroup-specific regional GM volumes to brain-wide gene expression profiles based on a stereotactic characterization of the transcriptional architecture of the human brain as provided by the Allen human brain atlas. Gene-set enrichment analyses revealed that variations in regional expression of genes involved in processes like mitochondrial respiration and metabolism of proteins were associated with patterns of regional GM volume across multiple subgroups. Other gene expression vs GM volume-associations were only detected in particular subgroups, e.g., genes involved in the cell cycle for AD-Memory, specific sets of genes related to protein metabolism in AD-Language, and genes associated with modification of gene expression in AD-Visuospatial. We conclude that cognitively-defined AD subgroups show neurobiological differences, and distinct biological pathways may be involved in the emergence of these differences., This work was supported by R01 AG 029672 (Paul K Crane, PI). Wiesje van der Flier is recipient of JPND-funded E-DADS (ZonMW project #733051106). Michel J Grothe is supported by the “Miguel Servet” program [CP19/00031] of the Spanish Instituto de Salud Carlos III (ISCIII-FEDER). Frederik Barkhof is supported by the NIHR biomedical research center at UCLH. Jesse Mez is supported by P30AG13846 and K23AG046377.

Background Traumatic brain injury (TBI) and military service are common lifetime exposures among current older adults that may affect late-life mental health. The objective of the present study was to evaluate the association between TBI with loss of consciousness (LOC) and military employment and late-life depressive symptom severity trajectory. Methods 1445 males and 2096 females adults at least 65 years old without dementia or recent TBI were enrolled and followed biennially for up to 10 years in the Adult Changes in Thought study from Kaiser Permanente Washington in Seattle, Washington. Results Using group-based trajectory modeling, we documented four distinct depressive symptom severity trajectories that followed a similar course in males and females (Minimal, Decreasing, Increasing, and Persistent). In multinomial regression analyses, TBI with LOC in males was associated with greater likelihood of Persistent versus Minimal depressive symptom severity compared to individuals without TBI (OR = 1.51, 95% CI: 1.01, 2.27; p=0.046). Males reporting past military employment had greater likelihood of Decreasing versus Minimal depressive symptom severity compared to individuals without past military employment (OR = 1.54, 95% CI: 1.03, 2.31; p=0.035). There was no association between TBI or military employment and depression trajectories in females, and no evidence of effect modification by age or between exposures. Limitations Lifetime history of TBI was ascertained retrospectively and may be subject to recall bias. Also, past military employment does not presuppose combat exposure. Conclusions Remote TBI and past military employment are relevant to late-life trajectories of depressive symptom severity in dementia-free older males.

BackgroundThis study was aimed to determine whether incident dementia and HbA1c levels are associated with increased rates of potentially preventable hospitalizations (PPHs) in persons with diabetes.MethodA total of 565 adults aged 65+ ever treated for diabetes were enrolled from Adult Changes in Thought study. PPHs were from principal discharge diagnoses and included diabetes PPH (dPPH), respiratory PPH (rPPH), urinovolemic PPH (uPPH), cardiovascular PPH, and other PPH. Poisson generalized estimating equations estimated rate ratios (RRs) and 95% confidence intervals (CIs) for the associations between dementia or HbA1c measures and rate of PPHs.ResultsA total of 562 individuals contributed 3 602 dementia-free years, and 132 individuals contributed 511 dementia follow-up years. One hundred twenty-eight (23%) dementia-free individuals had 210 PPH admissions and a crude rate of 58 per 1 000 person-years, while 55 (42%) individuals with dementia had 93 PPH admissions and a crude rate of 182 per 1 000 person-years. The adjusted RR (95% CI) comparing rates between dementia and dementia-free groups were 2.27 (1.60, 3.21) for overall PPH; 5.90 (2.70, 12.88) for dPPH; 5.17 (2.49, 10.73) for uPPH; and 2.01 (1.06, 3.83) for rPPH. Compared with HbA1c of 7%–8% and adjusted for dementia, the RR (95% CI) for overall PPH was 1.43 (1.00, 2.06) for >8% HbA1c and 1.18 (0.85, 1.65) for 8% and ConclusionIncident dementia is associated with higher rates of PPHs among people with diabetes, especially PPHs due to diabetes, urinary tract infection (UTI), and dehydration. Potential evidence suggested that HbA1c levels of >8% versus lower levels are associated with higher rates of overall PPHs and UTI- and dehydration-related PPHs.