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Objectives To examine the circumstances and needs of older adults who were “kinless,” defined as having no living spouse or children, when they developed dementia. Methods We conducted a secondary analysis of information from the Adult Changes in Thought study. Among 848 participants diagnosed with dementia between 1994 and 2016, we identified 64 who had no living spouse or child at dementia onset. We then conducted a qualitative analysis of administrative documents pertaining to these participants: handwritten comments recorded after each study visit, and medical history documents containing clinical chart notes from participants’ medical records. Results In this community-dwelling cohort of older adults diagnosed with dementia, 8.4% were kinless at dementia onset. Participants in this sample had an average age of 87 years old, half lived alone, and one third lived with unrelated persons. Through inductive content analysis, we identified 4 themes that describe their circumstances and needs: (1) life trajectories, (2) caregiving resources, (3) care needs and gaps, and (4) turning points in caregiving arrangements. Discussion Our qualitative analysis reveals that the life trajectories that led members of the analytic cohort to be kinless at dementia onset were quite varied. This research highlights the importance of nonfamily caregivers and participants’ own roles as caregivers. Our findings suggest that clinicians and health systems may need to work with other parties to directly provide dementia caregiving support rather than rely on family, and address factors such as neighborhood affordability that particularly affect older adults who have limited family support.

Objectives Telephone-administered cognitive assessments are a cost-effective and sometimes necessary alternative to face-to-face assessments. There is limited information in large studies concerning mode effects, or differences in cognition attributable to the assessment method, as a potential measurement threat. We evaluated mode effects on cognitive scores using a population-based sample of community-living older adults. Methods We used data from participants aged 65–79 in the 2014 Health and Retirement Study for whom the interview mode was randomized (n = 6,825). We assessed mode differences in test means, whether mode modifies associations of cognition with criterion variables, and formal measurement invariance testing. Results Relative to face-to-face assessment, telephone assessment was associated with higher scores for memory and calculation (0.06 to 0.013 standard deviations [SD]) and lower scores for nonmemory items (−0.09 to −0.01 SD). Cognition was significantly differentially related to instrumental activities of daily living difficulty depending on assessment mode. Measurement invariance testing identified evidence of mode differences in certain tests as a function of mode: adjusting for underlying cognition, the largest mode differences in memory and attention: immediate noun recall, delayed word recall, and serial-7s scores were higher given telephone administration. Discussion Differences by mode of administration are apparent in cognitive measurement in older adults, albeit to a small degree in our study, and most pronounced for tests of memory and attention. The importance of accounting for mode differences ultimately depends on one’s research question and study sample: not all associations may be affected by mode differences, and such modification may only be apparent among those with lower cognitive functioning.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer’s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer’s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer’s disease. It is well established that there are sex differences in response to Alzheimer’s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20–25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15–44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10−09, β (males) = −0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10−04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer’s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer’s disease may be personalized based on their biological sex and genetic context.

Background Identification of novel risk factors for dementia in older adults could facilitate development of methods to identify patients most at risk and improve their cognitive outcomes. We aimed to determine whether lower appendicular lean mass (ALM), assessed by dual-energy x-ray absorptiometry (DXA), and lower grip strength are associated with a greater likelihood of incident dementia among older adults in the Health Aging and Body Composition Study (Health ABC). Methods Health ABC data from 1997 to 2008 were analyzed (n = 2 704). Baseline ALM to body mass index (BMI) ratio (ALMBMI) was assessed by DXA. Baseline grip strength was assessed by hand-held dynamometry. Incident dementia diagnosis was defined as either (i) dementia-related hospitalization plus a Modified Mini-Mental State Examination (3MS) score of ≤ 90; or (ii) record of prescription for anti-dementia medication; or (iii) decline of at least 1.5 SDs on the 3MS score compared to baseline. Cox proportional hazard models estimated associations of ALMBMI and grip strength with incident dementia over follow-up with and without adjusting for covariates, stratified by sex. Results Among older men, each standard deviation decrement in ALMBMI (adjusted hazard ratio [aHR]: 1.33; 95% confidence interval [CI]: 1.07, 1.65) or grip strength (aHR 1.22; 95% CI: 1.06, 1.41) was associated with increased likelihood of incident dementia. Conclusions Lower ALMBMI and grip strength may be important risk factors for the development of dementia among older men. How these factors may belong to a causal pathway of dementia must be elucidated in future work.

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.

Objectives To characterize the extent to which brief cognitive assessments administered in the population-representative U.S. Health and Retirement Study (HRS) and its International Partner Studies can be considered to be measuring a single, unidimensional latent cognitive function construct. Methods Cognitive function assessments were administered in face-to-face interviews in 12 studies in 26 countries (N = 155,690), including the U.S. HRS and selected International Partner Studies. We used the time point of the first cognitive assessment for each study to minimize differential practice effects across studies and documented cognitive test item coverage across studies. Using confirmatory factor analysis models, we estimated single-factor general cognitive function models and bifactor models representing memory-specific and nonmemory-specific cognitive domains for each study. We evaluated model fits and factor loadings across studies. Results Despite relatively sparse and inconsistent cognitive item coverage across studies, all studies had some cognitive test items in common with other studies. In all studies, the bifactor models with a memory-specific domain fit better than single-factor general cognitive function models. The data fit the models at reasonable thresholds for single-factor models in 6 of the 12 studies and for the bifactor models in all 12 of the 12 studies. Discussion The cognitive assessments in the U.S. HRS and its International Partner Studies reflect comparable underlying cognitive constructs. We discuss the assumptions underlying our methods, present alternatives, and future directions for cross-national harmonization of cognitive aging data.

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.

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.

Patient-specific stem cell technology from skin and other biopsy sources has transformed in vitro models of neurodegenerative disease, permitting interrogation of the effects of complex human genetics on neurotoxicity. However, the neuropathologic changes that underlie cognitive and behavioral phenotypes can only be determined at autopsy. To better correlate the biology of derived neurons with age-related and neurodegenerative changes, we generated leptomeningeal cell lines from well-characterized research subjects that have undergone comprehensive postmortem neuropathologic examinations. In a series of proof of principle experiments, we reprogrammed autopsy leptomeningeal cell lines to human-induced pluripotent stem cells (hiPSCs) and differentiated these into neurons. We show that leptomeningeal-derived hiPSC lines can be generated from fresh and frozen leptomeninges, are pluripotent, and retain the karyotype of the starting cell population. Additionally, neurons differentiated from these hiPSCs are functional and produce measurable Alzheimer disease-relevant analytes (Aβ and Tau). Finally, we used direct conversion protocols to transdifferentiate leptomeningeal cells to neurons. These resources allow the generation of in vitro models to test mechanistic hypotheses as well as diagnostic and therapeutic strategies in association with neuropathology, clinical and cognitive data, and biomarker studies, aiding in the study of late-onset Alzheimer disease and other age-related neurodegenerative diseases.

The CD33 single-nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody. We seek to evaluate the extent to which CD33 genetics in AD and AML can inform one another and advance human disease therapy. We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA. Here, we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes from AML patients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419T allele decreases prototypic full-length CD33 expression by ∼ 25% and decreases the AD odds ratio by ∼ 0.10. These results suggest that CD33 antagonists may be useful in reducing AD risk. CD33 inhibitors may include humanized CD33 antibodies such as lintuzumab which was safe but ineffective in AML clinical trials. Here, we report that lintuzumab downregulates cell-surface CD33 by 80% in phorbol-ester differentiated U937 cells, at concentrations as low as 10 ng/ml. Overall, we propose a model wherein a modest effect on RNA splicing is sufficient to mediate the CD33 association with AD risk and suggest the potential for an anti-CD33 antibody as an AD-relevant pharmacologic agent.

We examined cross-sectional associations between physical function and device-based (activPAL) sedentary patterns and physical activity. Physical function tasks included time to complete 5 chair stands and walk a 10-foot gait speed course. We estimated associations using linear regression models adjusting for age and sex; coefficients represent estimated change in mean activPAL measures associated with each second increase in gait/chair stands time. Longer gait speed times were associated with more total sitting time (b=0.19, p < 0.01), fewer steps (b=-788.0, p

Alabama Background. Dyslipidemia is common and is often treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins). Little is known about the comparative effectiveness of statins among human immunodeficiency virus (HIV)‐infected patients. This study compared the effectiveness and toxicity of statins among HIV-infected patients in clinical care. Methods. We conducted a retrospective cohort study of patients starting their initial statin medications at 2 large HIV clinics (N 5 700). The primary observation was change in lipid levels during statin therapy. Secondary observations included whether individualized National Cholesterol Education Program (NCEP) goals for low density lipoprotein cholesterol (LDL-C) and non‐high density lipoprotein cholesterol (non-HDL-C) levels were reached, and toxicity rates. We used linear regression to examine change in lipid levels, controlling for baseline lipid values and demographic and clinical characteristics. We conducted secondary analyses using propensity scores to address confounding by indication. Results. The most commonly prescribed statins were atorvastatin (N 5 303), pravastatin (N 5 280), and rosuvastatin (N 5 95). One year after starting a statin therapy, patients who received atorvastatin or rosuvastatin had significantly greater decreases in total cholesterol, LDL-C, and non-HDL-C than patients on pravastatin. The likelihood of reaching NCEP goals for LDL-C levels was higher with the use of rosuvastatin (OR 2.1; P 5 .03) and atorvastatin (odds ratio [OR], 2.1; P 5 .001) compared with that of pravastatin. The likelihood of reaching NCEP goals for non-HDL-C levels was higher for rosuvastatin (OR 2.3; P 5 .045) but not atorvastatin (OR, 1.5; P 5 .1) compared with pravastatin. Toxicity rates were similar for all 3 statins: 7.3% for atorvastatin, 6.1% for pravastatin, and 5.3% for rosuvastatin. Conclusions. Our findings suggest that atorvastatin and rosuvastatin are preferable to pravastatin for treatment of HIV-infected patients with dyslipidemia, due to greater declines in total cholesterol, LDL-C, and non-HDL-C, with similar lower toxicity rates.

Few studies have examined socioeconomic environment underlying the association between small stature and poor cognitive in older adulthood. In a cohort where immigration to the US from Japan denotes a harsh inter-war early life environment, we hypothesized that 1) immigration status partially explains the association between smaller anthropometric measures and poor cognition; 2) education mediates these associations. The Honolulu Asia Aging Study included 3743 men of Japanese descent age 71 – 93 years in 1991–1993. Height, leg length, head circumference, and arm span were measured and years of education and immigration status were reported. Respondents completed the Cognitive Abilities Screening Instrument (range 0 – 100; ≤ 82 denotes impairment). For each anthropometric measure we ran separate series of nested ordinary least squares models adjusting for age only, then additionally for immigration status. We finally included education to test for mediation. Approximately 14% of respondents were born in Japan. Those in the shortest quarter (coefficient -4.33, 95% CI -5.74, -2.94) and second shortest quarter of height (coefficient -2.46, 95% CI -3.97, -0.95) had lower cognition, compared to those in the tallest quarter, adjusting for age. Associations between leg length and cognition were similar and were more modest for head circumference. These associations remained after adjusting for immigration status and were partially mediated by education. In older Japanese American men born near the turn of the 20th century, anthropometry may represent aspects of early life development more nuanced than societal-level socioeconomic environment that relate to later life cognition through pathways including education.