Risk factors for Alzheimer's disease and cognitive function before middle age in a U.S. representative population-based study

Allison E Aiello; Jennifer Momkus; Rebecca C Stebbins; Yuan S Zhang; Chantel L Martin; Y Claire Yang; Lauren Gaydosh; Taylor Hargrove; Adina Zeki Al Hazzouri; Kathleen Mullan Harris

doi:10.1016/j.lana.2025.101087

Risk factors for Alzheimer's disease and cognitive function before middle age in a U.S. representative population-based study

Lancet Reg Health Am. 2025 Apr 5:45:101087. doi: 10.1016/j.lana.2025.101087. eCollection 2025 May.

Authors

Allison E Aiello^{1

2}, Jennifer Momkus^{3

4}, Rebecca C Stebbins¹, Yuan S Zhang^{1

5}, Chantel L Martin^{3

4}, Y Claire Yang^{3

6}, Lauren Gaydosh^{3

6}, Taylor Hargrove^{3

6}, Adina Zeki Al Hazzouri^{1

2}, Kathleen Mullan Harris^{3

6}

Affiliations

¹ Robert N. Butler Columbia Aging Center, Columbia University, New York, NY, USA.
² Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
³ Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁵ Department of Sociomedical Sciences, Mailman School of Public Health, Columbia University, New York, NY, USA.
⁶ Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Abstract

Background: Alzheimer's disease is a major health concern in the U.S., but most research has focused on older populations. We examined whether established risk factors and blood biomarkers are associated with cognition before midlife.

Methods: 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 cross-sectionally analyzed weighted survey and biomarker data from Waves IV and V. We measured the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score comprised of age, education, sex, systolic blood pressure, body mass index, cholesteroal, and physical activity and apolipoprotein E ε4 allele (APOE ε4) status. We also measured 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). Outcomes included immediate word recall, delayed word recall, and backward digit span.

Findings: Analytic sample sizes ranged from 4507 to 11,449 participants in Wave IV and from 529 to 1121 participants in Wave V. The survey-weighted median (IQR) age was 28 (26-29) years in Wave IV and 38 (36-29) years in Wave V. About half of the survey-weighted Wave IV participants were female (48.4-52.1% across analytic samples), 71.4-72.5% were White, 12.5-14.9% were Black, and 9.3-10.2% were Hispanic. In Wave V, 43.6-46.8% were female, 68.7-69.3% were White, 17.1%-20.0% were Black, and 7.3%-9.6% were Hispanic. 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 standard deviation lower backward digit span score (95% CI: -0.04, -0.02). Total Tau was associated with immediate word recall in Wave V (β = -0.13, 95% CI: -0.23, -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.

Interpretation: Key risk factors for Alzheimer's Disease are linked to cognitive function as early as ages 24-44, highlighting the need for early prevention in the US.

Funding: NIHP01HD31921, U01AG071448, U01AG071450, R01AG057800, P30AG066615, T32HD091058, P2CHD050924.

Keywords: APOE; ATN biomarkers; Alzheimer’s disease; CAIDE risk score; Cognitive function; Dementia risk factors; Dementia risk score; Early midlife; Immune biomarkers; Inflammatory biomarkers; Life course; Neurofilament light chain; Population-based; Tau; US-Representative; Young adulthood.

Grants and funding

T32 HD091058/HD/NICHD NIH HHS/United States