# Association of the in Utero Exposome with Life-Course Cognition and Prodromal Alzheimer's Disease in Midlife.

> **NIH NIH RF1** · PUBLIC HEALTH INSTITUTE · 2022 · $2,130,150

## Abstract

We propose to discover opportunities for Alzheimer’s Disease (AD) prevention at multiple points in the life-
course: before birth, adolescence, and in midlife. We hypothesize that in utero exposure to environmental
toxicants leads to cognitive dysfunction in midlife that is accompanied by changes in the serum metabolome
and blood biomarkers associated with cognitive dysfunction and prodromal AD. We propose that metabolomics
will reveal novel, actionable midlife biomarkers for AD prevention for persons at increased risk for AD.
Our previous studies show that decline in cognition is linked to decline in plasma glutathione (GSH), which is
best represented in stored plasma by associated changes in pyrimidine and mitochondrial energy metabolism;
and that mild cognitive impairment is linked to GSH-related methionine and cysteine metabolism, pathways
linked to UDP-sugars (pyrimidine and galactose metabolism) and tyrosine metabolism. Each of these
pathways is actionable, providing a secure foundation to test these pathways as mechanisms for biological
responses to environmental exposure which could mediate neurocognitive outcomes. This prospective
study leverages a 50+ year follow-up of a subset of the Child Health and Development Studies (CHDS) birth
cohort that was designed to investigate developmental origins of health disparities; N ~400 offspring were
examined in midlife with prior follow-up in childhood and adolescence. This study has available maternal,
prenatal, and offspring midlife biospecimens as well as life-course social factors, anthropometry, and
health status, and is 40% black. We will use high resolution GC-MS and LC-MS to measure exposures and
the metabolome in both targeted and untargeted analysis. This is an efficient use of existing data and
biospecimens; no new human data collection is required. Our transdisciplinary team (Epidemiology, Cohn;
Metabolomics & Exposomics, Jones; Neurotoxicology, Richardson) has collaborated previously ensuring
feasibility. Aim 1 will identify associations of prenatal exposures (pesticides, PAHs, and novel exposures) with
midlife 50-year AD-related outcomes and altered metabolic response. Aim 2 will identify potentially actionable
biomarkers by identifying associations between altered midlife metabolome and AD-related outcomes. Aim 3
will determine if adolescent cognition: a) is associated with the prenatal exposome, b) predicts midlife AD-
related outcomes, c) mediates associations of the prenatal exposome with midlife AD-related outcomes. This
unique study can discover mechanisms that link the early life environment to AD and identify midlife
interventions that may mitigate early life insults.

## Key facts

- **NIH application ID:** 10597462
- **Project number:** 1RF1NS130713-01
- **Recipient organization:** PUBLIC HEALTH INSTITUTE
- **Principal Investigator:** BARBARA A COHN
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,130,150
- **Award type:** 1
- **Project period:** 2022-09-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10597462

## Citation

> US National Institutes of Health, RePORTER application 10597462, Association of the in Utero Exposome with Life-Course Cognition and Prodromal Alzheimer's Disease in Midlife. (1RF1NS130713-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10597462. Licensed CC0.

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