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Introduction: Apolipoprotein E (APOE) ε4 allele status is associated with amyloid and tau-related pathological changes related to Alzheimer's disease (AD). However, it is unknown whether brain network changes are related to amyloid beta (Aβ) and/or tau-related pathology in cognitively normal APOE ε4 carriers with subthreshold Aβ accumulation., Methods: Resting state functional connectivity measures of network integrity were evaluated in cognitively normal individuals (n = 121, mean age 76.6 ± 7.8 years, 15% APOE ε4 carriers, 65% female) with minimal Aβ per cerebrospinal fluid (CSF) or amyloid positron emission tomography., Results: APOE ε4 carriers had increased lateralized connections relative to callosal connections within the default-mode, memory, and salience networks (P = .02), with significant weighting on linear regression toward CSF total tau (P = .03) and CSF phosphorylated tau at codon 181 (P = .03), but not CSF Aβ 42 ., Discussion: Cognitively normal APOE ε4 carriers with subthreshold amyloid accumulation may have network reorganization associated with tau., (© 2021 the Alzheimer's Association.) more...

Sleep monitoring may provide markers for future Alzheimer's disease; however, the relationship between sleep and cognitive function in preclinical and early symptomatic Alzheimer's disease is not well understood. Multiple studies have associated short and long sleep times with future cognitive impairment. Since sleep and the risk of Alzheimer's disease change with age, a greater understanding of how the relationship between sleep and cognition changes over time is needed. In this study, we hypothesized that longitudinal changes in cognitive function will have a non-linear relationship with total sleep time, time spent in non-REM and REM sleep, sleep efficiency and non-REM slow wave activity. To test this hypothesis, we monitored sleep-wake activity over 4-6 nights in 100 participants who underwent standardized cognitive testing longitudinally, APOE genotyping, and measurement of Alzheimer's disease biomarkers, total tau and amyloid-β42 in the CSF. To assess cognitive function, individuals completed a neuropsychological testing battery at each clinical visit that included the Free and Cued Selective Reminding test, the Logical Memory Delayed Recall assessment, the Digit Symbol Substitution test and the Mini-Mental State Examination. Performance on each of these four tests was Z-scored within the cohort and averaged to calculate a preclinical Alzheimer cognitive composite score. We estimated the effect of cross-sectional sleep parameters on longitudinal cognitive performance using generalized additive mixed effects models. Generalized additive models allow for non-parametric and non-linear model fitting and are simply generalized linear mixed effects models; however, the linear predictors are not constant values but rather a sum of spline fits. We found that longitudinal changes in cognitive function measured by the cognitive composite decreased at low and high values of total sleep time (P < 0.001), time in non-REM (P < 0.001) and REM sleep (P < 0.001), sleep efficiency (P < 0.01) and <1 Hz and 1-4.5 Hz non-REM slow wave activity (P < 0.001) even after adjusting for age, CSF total tau/amyloid-β42 ratio, APOE ε4 carrier status, years of education and sex. Cognitive function was stable over time within a middle range of total sleep time, time in non-REM and REM sleep and <1 Hz slow wave activity, suggesting that certain levels of sleep are important for maintaining cognitive function. Although longitudinal and interventional studies are needed, diagnosing and treating sleep disturbances to optimize sleep time and slow wave activity may have a stabilizing effect on cognition in preclinical or early symptomatic Alzheimer's disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.) more...

Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are recently described biomarkers for pre- and postsynaptic integrity known to be elevated in symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear. In this study, CSF SNAP-25 and Ng were compared in cognitively normal APOE ε4 carriers and noncarriers (n = 274, mean age 65 ± 9.0 years, 39% APOE ε4 carriers, 58% female). CSF SNAP-25, not CSF Ng, was specifically elevated in APOE ε4 carriers versus noncarriers (5.95 ± 1.72 pg/mL, 4.44 ± 1.40 pg/mL, p < 0.0001), even after adjusting for age, sex, years of education, and amyloid status (p < 0.0001). CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Our findings suggest APOE ε4 carriers have amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, postsynaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status., (Copyright © 2021 Elsevier Inc. All rights reserved.) more...