The Memory and Aging Project is a longitudinal, epidemiologic clinical-pathologic cohort study of common chronic conditions of aging with an emphasis on decline in cognitive and motor function and ...risk of Alzheimer's disease (AD). In this manuscript, we first summarize the study design and methods. Then, we present data on: (1) the relation of motor function to cognition, disability, and death; (2) the relation of risk factors to cognitive and motor outcomes, disability and death; (3) the relation of neuropathologic indices to cognitive outcomes; (4) the relation of risk factors to neuropathologic indices; and (5) additional study findings. The findings are discussed and contextualized.
Cross-sectional studies suggest that sleep fragmentation is associated with cognitive performance in older adults. We tested the hypothesis that sleep fragmentation is associated with incident ...Alzheimer's disease (AD) and the rate of cognitive decline in older adults.
Prospective cohort study.
Community-based.
737 community dwelling older adults without dementia.
Sleep fragmentation was quantified from up to 10 consecutive days of actigraphy. Subjects underwent annual evaluation for AD with 19 neuropsychological tests. Over a follow-up period of up to 6 years (mean 3.3 years), 97 individuals developed AD. In a Cox proportional hazards model controlling for age, sex, and education, a higher level of sleep fragmentation was associated with an increased risk of AD (HR = 1.22, 95%CI 1.03-1.44, P = 0.02 per 1SD increase in sleep fragmentation). An individual with high sleep fragmentation (90
percentile) had a 1.5-fold risk of developing AD as compared with someone with low sleep fragmentation (10
percentile). The association of sleep fragmentation with incident AD did not vary along demographic lines and was unchanged after controlling for potential confounders including total daily rest time, chronic medical conditions, and the use of common medications which can affect sleep. In a linear mixed effect analysis, a 0.01 unit increase in sleep fragmentation was associated with a 22% increase in the annual rate of cognitive decline relative to the average rate of decline in the cohort (Estimate = -0.016, SE = 0.007, P = 0.03).
Sleep fragmentation in older adults is associated with incident AD and the rate of cognitive decline.
Lim ASP; Kowgier M; Yu L; Buchman AS; Bennett DA. Sleep fragmentation and the risk of incident alzheimer's disease and cognitive decline in older persons.
2013;36(7):1027-1032.
The impact of cardiovascular risk burden on cognitive trajectories and brain structure changes remains unclear.
This study aimed to examine whether cardiovascular risk burden assessed by the ...Framingham General Cardiovascular Risk Score (FGCRS) is associated with cognitive decline and structural brain differences.
Within the Rush Memory and Aging Project, 1,588 dementia-free participants (mean age: 79.5 years) were followed for up to 21 years. FGCRS was assessed at baseline and categorized into tertiles (lowest, middle, and highest). Episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with a battery of 19 tests, from which composite scores were derived. A subsample (n = 378) of participants underwent magnetic resonance imaging. Structural total and regional brain volumes were estimated. Data were analyzed using linear mixed-effects models and linear regression models.
In all participants, FGCRS ranged from 4 to 28 (mean score: 15.6 ± 3.7). Compared with the lowest tertile of FGCRS, the highest tertile was associated with faster decline in global cognition (β = −0.019; 95% confidence interval CI: −0.035 to −0.003), episodic memory (β = −0.023; 95% CI: −0.041 to −0.004), working memory (β = −0.021; 95% CI: −0.035 to −0.007), and perceptual speed (β = −0.027; 95% CI: −0.042 to −0.011) over the follow-up. In magnetic resonance imaging data analyses, higher FGCRS was related to smaller volumes of the hippocampus (β = −0.021; 95% CI: −0.042 to −0.000), gray matter (β = −1.569; 95% CI: −2.757 to −0.382), and total brain (β = −1.588; 95% CI: −2.832 to −0.344), and greater volume of white matter hyperintensities (β = 0.035; 95% CI: 0.001 to 0.069).
Higher cardiovascular risk burden may predict decline in episodic memory, working memory, and perceptual speed and is associated with neurodegeneration and vascular lesions in the brain.
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First, we tested the hypothesis that the rate of change of physical frailty and cognitive function in older adults are correlated. Next, we examined if their rates of change are associated with the ...same brain pathologies.
About 2,167 older adults participating in the Religious Orders Study and the Rush Memory and Aging Project had annual clinical evaluations. Bivariate random coefficient models were used to estimate simultaneously the rates of change in both frailty and cognition, and the correlation of change was characterized by a joint distribution of the random effects. Then, we examined whether postmortem indices from deceased were associated with the rate of change of frailty and cognition.
During an average follow-up of 6 years, frailty worsened by 0.09 unit/y and cognition declined by 0.08 unit/y. Most individuals showed worsening frailty and cognition (82.8%); 17% showed progressive frailty alone and <1% showed only cognitive decline. The rates of change of frailty and cognition were strongly correlated (ρ = -0.73, p < .001). Among deceased (N = 828), Alzheimer's disease pathology, macroinfarcts, and nigral neuronal loss showed independent associations with the rate of change in both frailty and cognition (all ps < .001). In these models, demographics explained about 9% of the variation in individual rate of change in frailty, and neuropathologies explained about 8%. In contrast, demographics and neuropathologies accounted for 2% and 30%, respectively, of the variance in the cognitive decline.
The rates of change in frailty and cognition are strongly correlated and this may be due in part because they share a common pathologic basis.
The Religious Orders Study and Rush Memory and Aging Project are both ongoing longitudinal clinical-pathologic cohort studies of aging and Alzheimer's disease (AD).
To summarize progress over the ...past five years and its implications for understanding neurodegenerative diseases.
Participants in both studies are older adults who enroll without dementia and agree to detailed longitudinal clinical evaluations and organ donation. The last review summarized findings through the end of 2011. Here we summarize progress and study findings over the past five years and discuss new directions for how these studies can inform on aging and AD in the future.
We summarize 1) findings on the relation of neurobiology to clinical AD; 2) neurobiologic pathways linking risk factors to clinical AD; 3) non-cognitive AD phenotypes including motor function and decision making; 4) the development of a novel drug discovery platform.
Complexity at multiple levels needs to be understood and overcome to develop effective treatments and preventions for cognitive decline and AD dementia.
Objective
We examined whether sarcopenia is associated with the occurrence of late‐life cognitive impairment.
Methods
Nondemented older adults (N = 1175) underwent annual testing with 17 cognitive ...tests summarized as a global cognitive score. A composite sarcopenia score was constructed based on muscle mass measured with bioelectrical impedance and muscle function based on grip strength. Cox proportional hazard models were employed to examine associations of sarcopenia with incident Alzheimer's dementia (AD) and incident mild cognitive impairment (MCI). Linear mixed‐effect models determined the association of sarcopenia with cognitive decline. All models controlled for age, sex, education, race, and height squared.
Results
Average follow‐up was 5.6 years. More severe sarcopenia at baseline was associated with a higher risk of incident AD (hazard ratio HR, 1.50 95% confidence interval 1.20–1.86; p < 0.001) and of MCI (1.21 1.01–1.45; 0.04) and a faster rate of cognitive decline (estimate = −0.013; p = 0.01). Analyses of the individual components of sarcopenia showed that muscle function was associated with incident AD, incident MCI, and cognitive decline with and without a term for lean muscle mass in the model. In contrast, lean muscle mass was not associated with incident cognitive impairment or cognitive decline when a term for muscle function was included in the model.
Conclusions
Poor muscle function, but not reduced lean muscle mass, drives the association of sarcopenia with late‐life cognitive impairment. Further work is needed to identify features of muscle structure, which may increase the specificity of sarcopenia for identifying older adults at risk for late‐life cognitive impairment.
IMPORTANCE The apolipoprotein E (APOE GenBank, 348; OMIM, 107741) ε4 allele is a common and well-established genetic risk factor for Alzheimer disease (AD). Sleep consolidation is also associated ...with AD risk, and previous work suggests that APOE genotype and sleep may interact to influence cognitive function. OBJECTIVE To determine whether better sleep consolidation attenuates the relationship of the APOE genotype to the risk of incident AD and the burden of AD pathology. DESIGN, SETTING, AND PARTICIPANTS A prospective longitudinal cohort study with up to 6 years of follow-up was conducted. Participants included 698 community-dwelling older adults without dementia (mean age, 81.7 years; 77% women) in the Rush Memory and Aging Project. EXPOSURES We used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation and ascertained APOE genotype. MAIN OUTCOMES AND MEASURES Participants underwent annual evaluation for AD during a follow-up period of up to 6 years. Autopsies were performed on 201 participants who died, and β-amyloid (Aβ) and neurofibrillary tangles were identified by immunohistochemistry and quantified. RESULTS During the follow-up period, 98 individuals developed AD. In a series of Cox proportional hazards regression models, better sleep consolidation attenuated the effect of the ε4 allele on the risk of incident AD (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .04 per allele per 1-SD increase in sleep consolidation). In a series of linear mixed-effect models, better sleep consolidation also attenuated the effect of the ε4 allele on the annual rate of cognitive decline. In individuals who died, better sleep consolidation attenuated the effect of the ε4 allele on neurofibrillary tangle density (interaction estimate, −0.42; SE = 0.17; P = .02), which accounted for the effect of sleep consolidation on the association between APOE genotype and cognition proximate to death. CONCLUSIONS AND RELEVANCE Better sleep consolidation attenuates the effect of APOE genotype on incident AD and development of neurofibrillary tangle pathology. Assessment of sleep consolidation may identify APOE+ individuals at high risk for incident AD, and interventions to enhance sleep consolidation should be studied as potentially useful means to reduce the risk of AD and development of neurofibrillary tangles in APOE ε4+ individuals.
Transcriptome-wide association studies (TWAS) have been widely used to integrate transcriptomic and genetic data to study complex human diseases. Within a test dataset lacking transcriptomic data, ...traditional two-stage TWAS methods first impute gene expression by creating a weighted sum that aggregates SNPs with their corresponding cis-eQTL effects on reference transcriptome. Traditional TWAS methods then employ a linear regression model to assess the association between imputed gene expression and test phenotype, thereby assuming the effect of a cis-eQTL SNP on test phenotype is a linear function of the eQTL's estimated effect on reference transcriptome. To increase TWAS robustness to this assumption, we propose a novel Variance-Component TWAS procedure (VC-TWAS) that assumes the effects of cis-eQTL SNPs on phenotype are random (with variance proportional to corresponding reference cis-eQTL effects) rather than fixed. VC-TWAS is applicable to both continuous and dichotomous phenotypes, as well as individual-level and summary-level GWAS data. Using simulated data, we show VC-TWAS is more powerful than traditional TWAS methods based on a two-stage Burden test, especially when eQTL genetic effects on test phenotype are no longer a linear function of their eQTL genetic effects on reference transcriptome. We further applied VC-TWAS to both individual-level (N = ~3.4K) and summary-level (N = ~54K) GWAS data to study Alzheimer's dementia (AD). With the individual-level data, we detected 13 significant risk genes including 6 known GWAS risk genes such as TOMM40 that were missed by traditional TWAS methods. With the summary-level data, we detected 57 significant risk genes considering only cis-SNPs and 71 significant genes considering both cis- and trans- SNPs, which also validated our findings with the individual-level GWAS data. Our VC-TWAS method is implemented in the TIGAR tool for public use.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The relationship of cerebral vessel pathology to brain microinfarcts is not fully understood. We examined associations of cerebral vessel pathology with microinfarcts among community‐dwelling persons ...who came to autopsy. Brain specimens were derived from 1,066 deceased subjects (mean age‐at‐death = 88 years, 65% women) participating in a cohort study of aging. Microinfarcts were classified by number, age and location. Severity of vessel pathologies was graded semi‐quantitatively. Almost a third of subjects (n = 300; 28%) had at least one chronic microinfarct, including 128 cortical only, 120 subcortical only, and 47 with both. Moderate‐to‐severe atherosclerosis was present in 430 (41%) subjects, arteriolosclerosis in 382 (36%), and amyloid angiopathy in 374 (35%). The odds of one or multiple microinfarct(s) was increased for more severe atherosclerosis (OR =1.22; 95%CI: 1.03–1.45), arteriolosclerosis (OR =1.18; 95%CI: 1.02–1.37) and amyloid angiopathy (OR =1.13; 95%CI: 1.00–1.28). Separately, the odds of subcortical microinfarct(s) was increased for atherosclerosis (OR =1.49; 95%CI: 1.20–1.84) and arteriolosclerosis (OR =1.39; 95%CI: 1.16–1.67) but not amyloid angiopathy; whereas the odds of cortical microinfarct(s) was increased for amyloid angiopathy (OR =1.26; 95%CI: 1.09–1.46) only. While cerebral vessel pathologies are associated with microinfarct burden, atherosclerosis and arteriolosclerosis are associated with subcortical microinfarcts, and amyloid angiopathy with cortical microinfarcts.
Accumulating evidence suggests that Alzheimer's disease (AD) has a long preclinical phase, during which time its characteristic pathology accumulates and patient function declines, but symptoms are ...insufficient to warrant a clinical diagnosis of dementia. There have been increasing reports of noncognitive symptoms, including loss of motor function, reported to be associated with incident AD. To understand the link between motor function and preclinical AD, this article examines: our understanding of motor function and its clinical assessment in cohort studies; the relationship of motor function and loss of cognition in older persons; risk factors for cognitive and motor decline; and the relation of post-mortem indices of AD and motor function prior to death. Together, these data suggest that age-related cognitive and motor decline may share a common causation. Furthermore, individuals with a clinical diagnosis of AD may represent the 'tip of the iceberg', since AD pathology may also account for a substantial proportion of cognitive and motor dysfunction currently considered 'normal aging' in older persons without dementia. Thus, AD may have a much larger impact on the health and wellbeing of our aging population
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