Hand grip strength (HGS) is a predictor of cognitive decline in aging. To understand the direct and indirect mechanisms underlying this association, we performed integrative analyses of genetic, cognitive, and autopsy data. A polygenic risk score for HGS (PRSHGS) was calculated in two independent studies of aging (total n = 25,227). Cross-sectional and longitudinal modeling, including mediation with physical activity, assessed the effects of PRSHGS on cognitive performance and postmortem neuropathology. In both cohorts, higher PRSHGS predicted better global cognitive performance (p = 7.77 × 10-4 and p = 0.025) and improved the predictive performance of an Alzheimer's disease PRS (likelihood ratio test p = 2.5 × 10-5 and p = 0.007). PRSHGS was not associated with levels of any postmortem neuropathology. PRSHGS effects on cognition were only partially and inconsistently mediated by physical activity. Genetic predisposition for greater HGS predicts better cognitive performance in late life, independent from Alzheimer's disease-related neuropathology.

Relationships between Alzheimer's disease (AD) pathologies in cognitively unimpaired adults and in vivo neurometabolic properties measured directly from the hippocampus, a vulnerable region early along the AD continuum, are not well-understood in the earliest stages of AD. In a 3T 1H-MRS study, we assessed age and AD-related changes in estimates of absolute concentrations of neurometabolites in the right hippocampus. Participants included older adults (age range: 60-85, n = 19) primarily cognitively unimpaired (CU, n = 16), as well as some with cognitive impairment (n = 3). All participants previously received a lumbar puncture for AD disease staging from cerebrospinal fluid (CSF) AD biomarkers (Aβ42, p-tau181 and t-tau), where all were amyloid positive (A+) and most had subthreshold tau pathology (T-). Hippocampal 1H-MRS metabolites included total N-acetylaspartate (tNAA), myo-inositol (mIns), total creatine (tCr) and total choline (tCho). Regression analyses were performed for assessing relationships among CSF biomarkers, age, and 1H-MRS metabolites measured as tissue-corrected estimates of absolute concentrations (millimoles/kilogram) and as ratios (/tCr and tNAA/mIns). We identified age-related decreases to mIns/tCr, where estimated absolute concentrations revealed that tCr increased while mIns remained stable. Concentrations for tNAA and mIns were positively associated with CSF p-tau181 and t-tau. Levels of tCr and tCho were not associated with any CSF biomarkers. Overall, our results demonstrate that sub-threshold tau pathologies in cognitively unimpaired A+ individuals are associated with hippocampal metabolite changes related to neural metabolism and glial reactivity early in disease progression.