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Introduction The molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation. Methods and findings 'Residual cognition' was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487). Given that our sample size was underpowered to detect genome-wide significance, we applied a multistep approach to identify genes influencing residual cognition, based on our prior observation that independent genetic and epigenetic risk factors can converge on the same locus. In the first step (n = 979), we performed a genome-wide association study with a predefined suggestive p < 10.sup.-5, and nine independent loci met this threshold in eight distinct chromosomal regions. Three of the six genes within 100 kb of the lead SNP are expressed in the dorsolateral prefrontal cortex (DLPFC): UNC5C, ENC1, and TMEM106B. In the second step, in the subset of participants with DLPFC DNA methylation data (n = 648), we found that residual cognition was related to differential DNA methylation of UNC5C and ENC1 (false discovery rate < 0.05). In the third step, in the subset of participants with DLPFC RNA sequencing data (n = 469), brain transcription levels of UNC5C and ENC1 were evaluated for their association with residual cognition: RNA levels of both UNC5C (estimated effect = -0.40, 95% CI -0.69 to -0.10, p = 0.0089) and ENC1 (estimated effect = 0.0064, 95% CI 0.0033 to 0.0096, p = 5.7 x 10.sup.-5) were associated with residual cognition. In secondary analyses, we explored the mechanism of these associations and found that ENC1 may be related to the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622.sup.A (r.sup.2 = 0.66), a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies. Conclusions Through a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expanded our understanding of the TMEM106B haplotype that is protective against TDP-43 proteinopathy., Author(s): Charles C. White 1,2, Hyun-Sik Yang 1,2,3,4, Lei Yu 5,6, Lori B. Chibnik 2,7, Robert J. Dawe 5,8, Jingyun Yang 5,6, Hans-Ulrich Klein 1,2,4, Daniel Felsky 1,2,4, Alfredo Ramos-Miguel [...]

Background: Wearable sensors are increasingly employed to quantify diverse aspects of mobility. We developed novel tandem walking (TW) metrics, validated these measures using data from community-dwelling older adults, and evaluated their association with mobility disability and measures of gait and postural control.Methods: Six hundred ninety-three community-dwelling older adults (age: 78.69 ± 7.12 years) wore a 3D accelerometer on their lower back while performing 3 tasks: TW, usual-walking, and quiet standing. Six new measures of TW were extracted from the sensor data along with the clinician's conventional assessment of TW missteps (ie, trip other loss of balance in which recovery occurred to prevent a fall) and duration. Principal component analysis transformed the 6 new TW measures into 2 summary TW composite factors. Logistic regression models evaluated whether these TW factors were independently associated with mobility disability.Results: Both TW factors were moderately related to the TW conventional measures (r < 0.454, p < .001) and were mildly correlated with usual-walking (r < 0.195, p < .001) and standing, postural control (r < 0.119, p < .001). The TW frequency composite factor (p = .008), but not TW complexity composite factor (p = .246), was independently associated with mobility disability in a model controlling for age, sex, body mass index, race, conventional measures of TW, and other measures of gait and postural control.Conclusions: Sensor-derived TW metrics expand the characterization of gait and postural control and suggest that they reflect a relatively independent domain of mobility. Further work is needed to determine if these metrics improve risk stratification for other adverse outcomes (eg, falls and incident disability) in older adults. [ABSTRACT FROM AUTHOR]

Background: Gait speed is a robust nonspecific predictor of health outcomes. We examined if combinations of gait speed and other mobility metrics are associated with specific health outcomes. Methods: A sensor (triaxial accelerometer and gyroscope) placed on the lower back, measured mobility in the homes of 1,249 older adults (77% female; 80.0, SD = 7.72 years). Twelve gait scores were extracted from five performances, including (a) walking, (b) transition from sit to stand, (c) transition from stand to sit, (d) turning, and (e) standing posture. Using separate Cox proportional hazards models, we examined which metrics were associated with time to mortality, incident activities of daily living disability, mobility disability, mild cognitive impairment, and Alzheimer’s disease dementia. We used a single integrated analytic framework to determine which gait scores survived to predict each outcome. Results: During 3.6 years of follow-up, 10 of the 12 gait scores predicted one or more of the five health outcomes. In further analyses, different combinations of 2–3 gait scores survived backward elimination and were associated with the five outcomes. Sway was one of the three scores that predicted activities of daily living disability but was not included in the final models for other outcomes. Gait speed was included along with other metrics in the final models predicting mortality and activities of daily living disability but not for other outcomes. Conclusions: When analyzing multiple mobility metrics together, different combinations of mobility metrics are related to specific adverse health outcomes. Digital technology enhances our understanding of impaired mobility and may provide mobility biomarkers that predict distinct health outcomes. [ABSTRACT FROM AUTHOR]

Background: Physical activity is a modifiable risk factor associated with health benefits. We hypothesized that a more active lifestyle in older adults is associated with a reduced risk of incident parkinsonism and a slower rate of its progression.Methods: Total daily physical activity was recorded with an activity monitor in 889 community-dwelling older adults participating in the Rush Memory and Aging Project. Four parkinsonian signs were assessed with a modified motor portion of the Unified Parkinson's Disease Rating Scale and summarized as a categorical measure and continuous global parkinsonian score. We used Cox models to determine whether physical activity was associated with incident parkinsonism and linear mixed-effects models to examine if physical activity was associated with the rate of progressive parkinsonism.Results: During an average follow-up of 4 years, 233 of 682 (34%) participants, without parkinsonism, developed incident parkinsonism. In Cox models controlling for age, sex, and education, a higher level of physical activity was associated with a reduced risk of developing parkinsonism (hazard ratio = 0.79; 95% CI = 0.70-0.88, p < .001). This association was not attenuated when controlling for cognition, depressive symptoms, Apolipoprotein E ℇ4 allele, and chronic health conditions. In a linear mixed-effects model including all participants (N = 889) which controlled for age, sex, and education, a 1 SD total daily physical activity was associated with a 20% slower rate of progression of parkinsonism.Conclusion: Older adults with a more active lifestyle have a reduced risk for parkinsonism and a slower rate of its progression. [ABSTRACT FROM AUTHOR]

Background: Total daily physical activity is associated with a wide range of adverse health outcomes. We examined the extent to which quantitative measures of gait and balance abilities were associated with total daily physical activity, controlling for a variety of potential covariates.Methods: Participants (n = 608) were older adults participating in the Rush Memory and Aging Project, a community-based cohort study of aging. Objective measures of total daily physical activity were derived from a wearable device. Gait and balance abilities were objectively quantified using a body-fixed sensor. We also collected measures of other motor functions, cognitive and psychosocial factors, and chronic health. We employed linear regression models to identify facets of mobility significantly associated with total daily physical activity, and tested for independence of these associations when all significant covariates were considered together in a final model.Results: Three gait and balance measures were independently associated with total daily physical activity (p < .01), together accounting for approximately 16% of its variance. Other motor measures, cognitive and psychosocial factors, and chronic health accounted for 8.8%, 4.9%, and 6.4% of the variance, respectively, when considered in isolation. Considered together in a single model, all significant covariates accounted for approximately 21% of the variance in physical activity.Conclusions: Gait and balance measures from a body-fixed sensor are strongly associated with objectively measured total daily physical activity in older adults. However, given the importance of physical activity to many health outcomes, further work is needed to more completely characterize the factors that may influence physical activity. [ABSTRACT FROM AUTHOR]