# Quantifying Individual Differences in Midlife Structural Brain Integrity Associated with Later AD/ADRD Risk

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $800,463

## Abstract

PROJECT SUMMARY
The burden of Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) is growing as the
global population ages. Consistent with a newer model of geroscience, clinically detectable cognitive impairment
and AD/ADRD are hypothesized to represent the end of a lifelong aging process in which genetic predisposition,
environmental insult, and lifestyle factors interact to drive pathology. In fact, many risk factors for AD/ADRD are
measurable in childhood and midlife many decades before clinical detection. This lifespan view of aging,
together with the disappointing results of AD/ADRD prevention trials in late life, suggest that there is a promising
opportunity to design interventions that target at-risk individuals in midlife to slow the aging process before
debilitating brain decline has been cemented. Shifting AD/ADRD prevention research to midlife, however,
presents a significant challenge: identifying viable outcomes of intervention. In a typical clinical trial, incidence
of AD/ADRD is the intervention target as well as the measured outcome. While methodologically sound, this
design will be challenging to export to midlife because it will require trials to last 20 or more years to use
AD/ADRD diagnosis, which is uncommon before 65, as the outcome. One alternative strategy is to find midlife
surrogate biomarkers that index sub-clinical changes in biology and cognition that are indicative of premorbid
AD/ADRD. Such premorbid changes in midlife biology and cognition could further help identify causal disease
mechanisms. In this competing renewal application, we propose to quantify individual differences in midlife for
one such group of potential surrogate biomarkers: MRI measures of structural brain integrity, which are known
to be associated with AD/ADRD later in life. Specifically, we propose to follow up at age 52 a population-
representative cohort of 1037 infants born in one city in one year and comprehensively studied ever since: the
Dunedin Study. Through our prior award (R01AG049789), we successfully collected high-quality, reliable MRI
measures of structural brain integrity at age 45 in 93% of still-alive and participating Study members (N=875).
The proposed second wave of MRI data collection at age 52 will allow for the quantification of individual
differences in at-risk structural brain changes (e.g., greater increase in WMH, cortical thinning, and hippocampal
atrophy) between ages 45 and 52. We will then examine the extent to which these individual differences are
predicted by AD/ADRD risk indexes, trajectories of cognitive decline, and the pace of biological aging, which we
have tracked across five decades. We will also map individual differences in at-risk midlife structural brain
changes onto blood AD/ADRD biomarkers. Importantly, the Dunedin Study design allows for testing of
associations in the absence of age and/or cohort effects in a large population representative sample. The very
low attrition and ab...

## Key facts

- **NIH application ID:** 10440549
- **Project number:** 2R01AG049789-06
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** AHMAD R. HARIRI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $800,463
- **Award type:** 2
- **Project period:** 2015-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440549

## Citation

> US National Institutes of Health, RePORTER application 10440549, Quantifying Individual Differences in Midlife Structural Brain Integrity Associated with Later AD/ADRD Risk (2R01AG049789-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10440549. Licensed CC0.

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