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

The median cellular circadian period in older adults with cognitive complaints was 24.2 hours, measured via ex vivo bioluminescence in dermal fibroblasts.

• Sample consisted of 135 older adults with cognitive complaints.
• Intrinsic circadian period was measured using ex vivo bioluminescence in dermal fibroblasts.
• The median cellular circadian period was 24.2 h.
• Delta-period (deviation from 24 h) increased with age.

A longer intrinsic cellular circadian period was selectively associated with higher plasma biomarker levels indicative of Alzheimer's disease-related pathology.

• Longer circadian period was associated with higher pTau-217, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) levels.
• These associations are consistent with AD-related tau pathology, neurodegeneration, and glial activation.
• Longer period was also associated with medial temporal atrophy on structural MRI.
• Associations were examined within the amyloid-tau-neurodegeneration ATN(IV) framework using multivariable models.

Greater deviation of cellular circadian period from 24 hours (Δ-period) was associated with broader aging-related neurodegenerative processes rather than AD-specific pathology.

• Greater Δ-period was associated with older age.
• Greater Δ-period was associated with poorer cognitive performance across multiple domains.
• Greater Δ-period was associated with more widespread brain atrophy, in contrast to the medial temporal-specific atrophy associated with longer period.
• These findings are described as consistent with broader aging-related neurodegenerative processes.

Both longer cellular circadian period and greater Δ-period independently predicted faster clinical decline.

• Longer circadian period predicted faster clinical decline with HR = 4.41 (95% CI: 1.52 to 12.83).
• Greater Δ-period predicted faster clinical decline with HR = 2.65 (95% CI: 1.03 to 6.86).
• Both associations were independent of each other, as determined by Cox regression analyses.
• Clinical progression was assessed within the ATN(IV) framework.

Cellular circadian period and Δ-period capture distinct biological processes and together represent complementary cellular biomarkers in cognitively impaired older adults.

• Longer period was selectively linked to AD-related tau pathology (pTau-217), neurodegeneration (NfL), and glial activation (GFAP).
• Greater Δ-period was linked to broader aging-related neurodegeneration and cognitive decline across multiple domains.
• The two measures were described as 'complementary' in capturing distinct underlying processes.
• The study used amyloid PET, structural MRI, plasma biomarkers, and cognitive function assessments to characterize the associations.