Comprehensive Risk Factors for Alzheimer's Disease and Cognitive Function Before Middle Age in the U.S.

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Abstract

Importance: Alzheimer's disease (AD) is a major health concern in the U.S., but most research has focused on older populations. Few studies investigate AD risk factors and cognitive function in young to early midlife adults. Objective: To examine whether key AD risk factors are associated with cognition before midlife. Design, Setting, Participants: Data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) were analyzed. Participants were enrolled in 1994-95 (grades 7-12) and followed through 2018. We analyzed survey and biomarker data from Waves IV (median age 28) and V (median age 38). Exposures: Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score, APOE ϵ4 status, Amyloid Tau and Neurodegeneration markers (ATN), including total Tau and Neurofilament light (NfL), high sensitivity C-reactive protein (hsCRP), Interleukin (IL)-1β, IL-6, IL-8, IL-10, and Tumor necrosis factor alpha (TNF-α). Main Outcomes: Immediate word recall, delayed word recall, and digit span backwards. Results: We analyzed data separately in Wave IV (ranging from N=4,507 to N=11,449) and Wave V (ranging from N=529 to N=1,121). Approximately half were female. The CAIDE score was associated with all cognition measures in Wave IV. For example, among adults aged 24-34, each 1-point increase in CAIDE was associated with a 0.03 SD lower backward digit span score (95% CI: -0.04, -0.02). No significant associations were found between APOE ϵ4 and cognition. Total Tau was associated with immediate word recall in Wave V (β=-0.14, 95% CI: -0.24, -0.04). Wave IV hsCRP and IL-10 and Wave V IL-6, IL-1β, and IL-8 were also associated with lower cognitive scores. Conclusions: Key risk factors for AD, including cardiovascular, ATN, and immune markers, are linked to cognitive function as early as ages 24-44, highlighting the need for early prevention in the US.

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