Circadian rhythm disruption is recognized as a feature of aging and neurodegenerative disease, yet whether intrinsic cellular circadian properties relate to underlying processes in humans remains unknown. We measured intrinsic circadian period and its deviation from 24 h (Δ-period) using ex vivo bioluminescence in dermal fibroblasts from 135 older adults with cognitive complaints. Associations with plasma biomarkers (pTau-217, neurofilament light chain NfL, and glial fibrillary acidic protein GFAP), amyloid positron emission tomography (PET), structural MRI, cognitive function, and clinical progression were examined within the amyloid–tau–neurodegeneration ATN (IV) framework, using multivariable models and Cox regression analyses. The median cellular circadian period was 24.2 h, while Δ-period increased with age. A longer intrinsic circadian period was selectively associated with higher pTau-217, NfL, and GFAP levels and medial temporal atrophy, consistent with Alzheimer’s disease (AD)-related tau pathology, neurodegeneration, and glial activation. In contrast, greater Δ-period was associated with older age, poorer cognitive performance across multiple domains, and more widespread brain atrophy, consistent with broader aging-related neurodegenerative processes. Both longer period (HR = 4.41, 95% CI: 1.52 to 12.83) and greater Δ-period (HR = 2.65, 95% CI: 1.03 to 6.86) independently predicted faster clinical decline. Thus, cellular circadian period and Δ-period capture distinct biological processes—AD-related tau pathology vs. broader aging-related neurodegeneration—and together represent complementary cellular biomarkers with potential prognostic value in older adults with cognitive concerns.
Roh et al. (Mon,) studied this question.