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

• 成果类型: Article
• 署名作者: Roh, Hyun Woong; Seo, Sang Won; Choi, Seong Hye; Kim, Eun - Joo; Cho, Soo Hyun; Kim, Byeong C.; Choi, Jin Wook; An, Young - Sil; Kim, Na - Rae; Park, Bumhee; Lee, Sun Min; Moon, So Young; Lee, Dongha; Hong, Chang Hyung; Son, Sang Joon; Kim, Eun Young
• 署名单位: Ajou University; Ajou University; Ajou University; Sungkyunkwan University (SKKU); Samsung Medical Center; Inha University; Pusan National University; Pusan National University Hospital; Chonnam National University; Chonnam National University Hospital; Ajou University; Ajou University; Ajou University; Ajou University; Korea Brain Research Institute (KBRI); Ajou University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2527236123
• 发表日期: 2026-03-10
• 页码: e2527236123
• 关键词: Alzheimer's disease; biomarkers; cellular circadian period; neurodegeneration; dermal fibroblast; sleep; rhythms; disease; dementia; Mutation; time; AGE; temperature; expression; STABILITY

摘要

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 (o-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 o-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 o-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 o-period (HR = 2.65, 95% CI: 1.03 to 6.86) independently predicted faster clinical decline. Thus, cellular circadian period and o-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.