Objective: To determine the rate of tau accumulation in healthy older adults (OA) and patients with Alzheimer disease (AD), as well as the relationship of tau accumulation to cortical atrophy. Methods: Two longitudinal flortaucipir (FTP) positron emission tomography (PET) and magnetic resonance imaging (MRI) scans were acquired from 42 OA (21 Pittsburg compound B [PiB] + , age = 77.6 AE 4.6 years, 25 female [F]/17 male [M]) and 19 PiB + patients with AD (age = 63.1 AE 10.3 years, 12 F/7 M) over 1 to 3 years of follow-up. FTP change, structural MRI measures of atrophy, and cross-modal correlations were examined on a voxelwise level. Regional annual percentage change in FTP was also calculated. Results: Voxelwise FTP change in AD showed the greatest increases in lateral and medial frontal lobes. Atrophy over the same interval was more widespread and included posteromedial cortical areas, where tau accumulation rates were lower. In OA, FTP binding increased in bilateral temporal lobe and retrosplenial cortex, accompanied by atrophy in the same regions. There were no associations between voxelwise change in FTP and sex, PiB, or APOE. Regional FTP significantly increased at follow-up in OA and patients with AD. Mixed effects models showed greater FTP increases in AD compared to OA, and no differences within OA based on PiB status. Interpretation: Our findings indicate that tau accumulates even in amyloid-negative healthy OA and this process can be measured with in vivo tau-PET. In OA, tau accumulation and atrophy share a similar topography. In AD, tau increases more rapidly and accumulation occurs in frontal regions that are not yet undergoing significant atrophy.

Intestinal epithelial cells (IECs) form a physical and immunological barrier that separates the vast gut microbiota from host tissues. MyD88-dependent Toll-like receptor signaling is a key mediator of microbial–host cross-talk. We examined the role of epithelial MyD88 expression by generating mice with an IEC-targeted deletion of the Myd88 gene (MyD88ΔIEC). Loss of epithelial MyD88 signaling resulted in increased numbers of mucus-associated bacteria; translocation of bacteria, including the opportunistic pathogen Klebsiella pneumoniae, to mesenteric lymph nodes; reduced transmucosal electrical resistance; impaired mucus-associated antimicrobial activity; and downregulated expression of polymeric immunoglobulin receptor (the epithelial IgA transporter), mucin-2 (the major protein of intestinal mucus), and the antimicrobial peptides RegIIIγ and Defa-rs1. We further observed significant differences in the composition of the gut microbiota between MyD88ΔIEC mice and wild-type littermates. These physical, immunological, and microbial defects resulted in increased susceptibility of MyD88ΔIEC mice to experimental colitis. We conclude that MyD88 signaling in IECs is crucial for maintenance of gut homeostasis.

Alzheimer's disease is associated with poor sleep, but the impact of tau and b-amyloid (Ab) pathology on sleep remains largely unknown. Here, we test the hypothesis that tau and Ab predict unique impairments in objective and self-perceived human sleep under real-life, free-living conditions. Eighty-nine male and female cognitively healthy older adults received 18 F-FTP-tau and 11 C-PIB-Ab PET imaging, 7 nights of sleep actigraphy and questionnaire measures, and neurocognitive assessment. Tau burden, but not Ab, was associated with markedly worse objective sleep. In contrast, Ab and tau were associated with worse self-reported sleep quality. Of clinical relevance, Ab burden predicted a unique perceptual mismatch between objective and subject sleep evaluation, with individuals underestimating their sleep. The magnitude of this mismatch was further predicted by worse executive function. Thus, early-stage tau and Ab deposition are linked with distinct phenotypes of real-world sleep impairment, one that includes a cognitive misperception of their own sleep health.

Both sleep duration and sleep efficiency have been associated with risk of Alzheimer’s disease, suggesting that interventions to promote optimal sleep may be a way to reduce Alzheimer’s disease risk. However, studies often focus on average sleep measures, usually from self-report questionnaires, ignoring the role of intra-individual variability in sleep across nights quantified from objective sleep measures. The current cross-sectional study sought to investigate the role of intra-individual variability in accelerometer-based objective sleep duration and sleep efficiency in relation to in vivo Alzheimer’s disease pathology (β-amyloid and tau) using positron emission tomography imaging and cognition (working memory, inhibitory control, verbal memory, visual memory, and global cognition). To examine these relationships, we evaluated 52 older adults (age=66.4+6.89, 67% female, 27% Apolipoprotein E4 carriers) with objective early mild cognitive impairment. Modifying effects of Apolipoprotein E4 status were also explored. Less intra-individual variability in sleep duration was associated with lower β-amyloid burden, higher global cognition, and better inhibitory control, with a trend for lower tau burden. Less intra-individual variability in sleep efficiency was associated with lower β-amyloid burden, higher global cognition and better inhibitory control, but not with tau burden. Longer sleep duration was associated with better visual memory and inhibitory control. Apolipoprotein E4 status significantly modified the association between intra-individual variability in sleep efficiency and β-amyloid burden, such that less sleep efficiency variability was associated with lower β-amyloid burden in Apolipoprotein E4 carriers only. There was a significant interaction between sleep duration and Apolipoprotein E4 status, suggesting that longer sleep duration is more strongly associated with lower β-amyloid burden in Apolipoprotein E4 carriers relative to non-carriers. These results provide evidence that lower intra-individual variability in both sleep duration and sleep efficiency, and longer mean sleep duration are associated with lower levels of β-amyloid pathology and better cognition. The relationships between sleep duration and intra-individual variability in sleep efficiency with β-amyloid burden differ by Apolipoprotein E4 status, indicating that longer sleep duration and more consistent sleep efficiency may be protective against β-amyloid burden in Apolipoprotein E4 carriers. Longitudinal and causal studies are needed to better understand these relationships. Future work should investigate factors contributing to intra-individual variability in sleep duration and sleep efficiency to inform intervention studies.

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