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OBJECTIVES: Longer time horizons are associated with positive health behaviors, but the associations of time horizons with disability and mortality are less understood. This study aims to test the hypothesis that longer time horizons are associated with decreased disability and mortality in older adults. METHOD: Participants were 1052 older adults (mean age = 81 ± 7 years) without dementia. Proportional hazard models adjusted for age, sex, and education were used to examine the associations of time horizons with risk of mortality and disability. RESULTS: During up to 11 years of follow up (mean = 5.7), 317 participants died. In fully adjusted models, longer time horizons were associated with reduced mortality risk (hazard rate [HR] = 0.78, 95% confidence interval [CI] = 0.68-0.89). About 36.7% of participants developed disability in instrumental activities of daily living (ADLs) and 49.3% developed disability in basic ADLs during follow up. Longer time horizons were associated with a reduced risk of disability in basic ADLs (HR = 0.89, 95% CI = 0.79-0.99) but not instrumental ADLs (HR = 0.90, 95% CI = 0.80-1.03). CONCLUSION: Longer time horizons are associated with a reduced risk of all-cause mortality and disability in basic ADLs among community-dwelling older adults, thus highlighting a potentially modifiable psychological risk factor for negative health outcomes in aging.
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Despite the significant burden, cost, and worse prognosis of Alzheimer's disease (AD) with behavioral and psychological symptoms of dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our cohort: affective, apathy, agitation, and psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem anterior cingulate cortex (ACC) tissues. Though all 4 domains are associated with a predominantly downregulated pattern of hundreds of differentially expressed genes (DEGs), most DEGs are unique to each domain, with only 22 DEGs being common to all BPSD domains, including TIMP1. Weighted gene co-expression network analysis (WGCNA) yielded multiple transcriptional modules that were shared between BPSD domains or unique to each domain, and NetDecoder was used to analyze context-dependent information flow through the biological network. For the agitation domain, we found that all DEGs and a highly associated transcriptional module were functionally enriched for ECM-related genes including TIMP1, TAGLN, and FLNA. Another unique transcriptional module also associated with the agitation domain was enriched with genes involved in post-synaptic signaling, including DRD1, PDE1B, CAMK4, and GABRA4. By comparing context-dependent changes in DEGs between cases and control networks, ESR1 and PARK2 were implicated as two high-impact genes associated with agitation that mediated significant information flow through the biological network. Overall, our work establishes unique targets for future study of the biological mechanisms of BPSD and resultant drug development.
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Doença de Alzheimer , Apatia , Transtornos Psicóticos , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Sintomas ComportamentaisRESUMO
INTRODUCTION: There is a substantial gap in knowledge regarding how perceived stress may influence the relationship between serum-measured biomarkers for Alzheimer's disease and cognitive decline. METHODS: This study consists of 1118 older adult participants from the Chicago Health and Aging Project (CHAP) (60% Black participants and 63% female participants). Linear mixed effects regression models were conducted to examine the role of perceived stress in the association between three blood biomarkers: total tau (t-tau), glial fibrillary acid protein (GFAP), and neurofilament light chain (NfL) on global cognitive decline. Stratified analysis by stress level was also conducted to evaluate the associations between each blood biomarker and baseline cognitive function and decline. All models adjusted for age, race, sex, education, time, and their interactions with time. RESULTS: The interaction of stress, NfL concentration, and time was statistically significant on global cognition ( ß = -0.064 [SE = 0.028], p = .023) and on episodic memory ( ß = -0.097 [SE = 0.036], p = .007). CONCLUSIONS: Greater stress level worsens the association between high NfL concentration and cognitive decline. Stress management interventions may be helpful to reduce the rate of cognitive decline in individuals with high concentrations of NfL.
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Biomarcadores , Disfunção Cognitiva , Proteína Glial Fibrilar Ácida , Proteínas de Neurofilamentos , Estresse Psicológico , Proteínas tau , Humanos , Feminino , Idoso , Masculino , Biomarcadores/sangue , Estresse Psicológico/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/etiologia , Idoso de 80 Anos ou mais , Proteínas de Neurofilamentos/sangue , Proteínas tau/sangue , Proteína Glial Fibrilar Ácida/sangue , Memória Episódica , Envelhecimento/sangue , Envelhecimento/fisiologia , Chicago , Doença de Alzheimer/sangueRESUMO
BACKGROUND AND OBJECTIVES: The association of statin initiation with incident Alzheimer disease (AD) dementia and cognitive decline by the APOE ε4 allele is unknown. Our objective was to examine whether the association of statin initiation with incident AD dementia and cognitive decline differs by the APOE ε4 allele. METHODS: This population-based longitudinal cohort study was conducted in 4 urban communities in Chicago, IL, United States, consisting of 4,807 participants. Statin initiation is based on the inspection of medications during home assessments. Clinical diagnosis for incident AD used the NINCDS-ADRDA criteria, and longitudinal measurements of global cognition consisted of episodic memory, perceptual speed, and the Mini-Mental State Examination tests. RESULTS: The study participants had a mean age of 72 years, consisting of 63% female individuals and 61% non-Hispanic Black individuals. During the study period, 1,470 (31%) participants reported statin initiation. In a covariate-adjusted competing risk model, statin initiation was associated with a reduced risk of incident clinical AD [hazard ratio (HR) 0.81 (95% CI 0.70-0.94)] compared with nonusers. This association was statistically significantly lower (p interaction = 0.015) among participants with the APOE ε4 allele [HR 0.60 (95% CI 0.49-0.74)] compared with those without the APOE ε4 allele [HR 0.96 (95% CI 0.82-1.12)]. The annual decline in global cognition (ß = 0.021, 95% CI 0.007-0.034) and episodic memory (ß = 0.020, 95% CI 0.007-0.033) was also substantially slower among participants with the APOE ε4 allele after statin initiation compared with nonusers. However, the association of statin initiation with cognitive decline was not significant among those without the APOE ε4 allele. DISCUSSION: Our findings suggest that statins might be associated with a lower risk of incident AD among individuals with the APOE ε4 allele. The benefits of statin therapy need further consideration in randomized clinical trials, especially among those with the APOE ε4 allele. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among those aged 65 years or older, statin initiation was associated with a reduced risk of Alzheimer disease, especially in the presence of an APOE-e4 allele.
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Doença de Alzheimer , Disfunção Cognitiva , Inibidores de Hidroximetilglutaril-CoA Redutases , Feminino , Humanos , Idoso , Masculino , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Estudos Longitudinais , Cognição , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/genética , Predisposição Genética para Doença/genéticaRESUMO
BACKGROUND: Few rare variants have been identified in genetic loci from genome wide association studies of Alzheimer's disease (AD), limiting understanding of mechanisms and risk assessment, and genetic counseling. METHODS: Using genome sequencing data from 197 families in The NIA Alzheimer's Disease Family Based Study, and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS: Eighty-six rare missense or loss of function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) of families APOE-e4 was the only variant segregating. However, in 60.3% of families neither APOE-e4 nor missense or LoF variants were found within the GWAS loci. DISCUSSION: Although APOE-ε4 and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants.