Cellular circadian period and its deviation associate with Alzheimer’s pathology and brain aging in cognitively impaired older adults

Mar 2, 2026Proceedings of the National Academy of Sciences of the United States of America

Body Clock Timing and Its Changes Linked to Alzheimer's Signs and Brain Aging in Older Adults with Thinking Problems

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Abstract

The median cellular circadian period was 24.2 h among 135 older adults with cognitive complaints.

A longer intrinsic circadian period is associated with higher levels of biomarkers linked to Alzheimer's disease, such as pTau-217, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP).
Increased deviation from a 24-hour circadian period (Δ-period) is related to older age and poorer cognitive performance in various domains.
Greater Δ-period correlates with more widespread brain atrophy, indicating broader aging-related neurodegenerative processes.
Both longer intrinsic circadian period and greater Δ-period independently predict faster clinical decline in older adults with cognitive issues.

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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.

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Cellular circadian period and its deviation associate with Alzheimer’s pathology and brain aging in cognitively impaired older adults

Abstract

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