Prenatal Pesticide Exposure and Early Alzheimer Disease-Related Biomarker and Cognitive Changes in Midlife.

IMPORTANCE: Alzheimer disease (AD) pathogenesis begins decades before clinical symptoms, yet environmental determinants of early disease risk, particularly during fetal development, remain largely uncharacterized. Prenatal exposure to dichlorodiphenyldichloroethylene (DDE), the primary persistent metabolite of DDT, is a biologically plausible early contributor to AD risk given its long half-life in human tissue and higher levels observed in AD patients. However, prospective human evidence linking prenatal DDE to midlife AD-relevant outcomes is absent. OBJECTIVE: To determine whether prenatal DDE exposure is associated with plasma AD biomarkers and cognitive performance in midlife, and whether APOE ε4 genotype modifies these associations. DESIGN: Observational cohort analysis nested within the Child Health and Development Studies (CHDS), a population-based birth cohort. SETTING: CHDS enrolled pregnant women between 1959-1967 in the San Francisco Bay Area. PARTICIPANTS: Among 367 eligible adult offspring who participated in a follow-up study (2010-2013) at mean age 49.3 years, 179 with available prenatal DDE measurements were included. MAIN OUTCOMES AND MEASURES: Primary outcomes were prenatal DDE levels from maternal serum, plasma Aβ42/40 ratio and Digit Symbol Substitution Test (DSST) performance and APOE genotype. Secondary outcomes included plasma pTau217, GFAP, NfL and measures of verbal fluency (VF) and the Wechsler Test of Adult Reading (WTAR). RESULTS: Among 179 participants (56% female; 26% APOE ε4 carriers), mean prenatal DDE was 47.4 (25.4) ng/mL. Higher prenatal DDE was associated with lower DSST scores (β=-0.021; 95% CI, -0.041 to -0.001; P=0.039) and lower plasma Aβ42/40 ratio (β=-0.079; 95% CI, -0.133 to -0.024; P=0.005) per ng/mL DDE, adjusting for sex, race, education, and APOE ε4 status. Associations were strongest among APOE ε4 non-carriers for DSST (β=-0.033; 95% CI, -0.050 to -0.016; P=0.001) and Aβ42/40 ratio (β=-0.101; 95% CI, -0.161 to -0.040; P=0.001). No significant associations were observed for pTau217, GFAP, NfL, VF or WTAR. CONCLUSIONS AND RELEVANCE: In this prospective birth cohort study, prenatal exposure to a persistent environmental toxicant was associated with lower plasma Aβ42/40 ratio and worse cognitive performance in midlife, consistent with DDE accelerating the preclinical trajectory of AD-related biological changes decades before symptom onset. These findings support a life-course framework for AD risk and identify prenatal DDE as a potentially modifiable determinant of early AD-related pathology amenable to prevention. KEY POINTS: Question: Is prenatal exposure to dichlorodiphenyldichloroethylene (DDE), primary persistent metabolite of DDT, associated with plasma Alzheimer disease biomarkers and cognitive performance in early midlife offspring?Findings: In 179 participants from a prospective birth cohort followed for 50 years, higher prenatal DDE was associated with lower plasma Aβ42/40 and worse cognitive performance at mean age 49.3 years. Associations were substantially stronger among APOE ε4 non-carriers.Meaning: Prenatal exposure to a ubiquitous environmental toxicant is associated with amyloid-related biomarker and cognitive changes in early midlife, consistent with an accelerated preclinical Alzheimer disease trajectory and supporting fetal environmental exposures as modifiable determinants of long-term AD risk.