# Exceptional Aging: Identifying Modifiers of Alzheimer's Disease Trajectories

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $777,951

## Abstract

PROJECT SUMMARY / ABSTRACT
 Protection against Alzheimer's disease (AD) dementia has two main components: protection against
Alzheimer's disease pathology (ADP – amyloid and tau) and protection against cognitive impairment despite
ADP (cognitive reserve). Here, we propose an “exceptional aging” hypothesis, where some subjects (>85
years of age) have no significant ADP and are cognitively normal due to protective factors against both ADP
and cognitive decline across the lifespan. This is based on the idea that a combination of environmental,
lifestyle, and genetic factors trigger the onset of AD dementia in the majority of individuals as they age but
“exceptional agers” are protected. To translate this knowledge to design successful personalized prevention
and treatment trials, it is important to identify the parsimonious set(s) of protective factors and how certain
individuals are able to outperform the average population trajectories, i.e., “exceptionally age”. Our central
hypothesis is that each individual's trajectory of amyloid, tau, and cognition will deviate from the average
population trajectories, depending on the individual's genomic variation, lifestyle enrichment, and vascular
health. The aim of this proposal is to apply the unified theoretical framework proposed here to identify
important protective factors against ADP and cognitive decline in a population-based sample and move
towards personalized medicine by discovering paths to “exceptional aging” using two independent
mathematical models (association rule mining and structural equation models).
 We will utilize the existing infrastructure of the population-based, longitudinal Mayo Clinic Study of
Aging (MCSA) (individuals aged 60-90 years) which collects imaging surrogates of amyloid (PiB PET) and tau
(tau PET), neuropsychological exams, lifestyle enrichment (midlife cognitive and physical activity), and APOE
gene status. We will also utilize the Rochester Epidemiology Project (REP) which maintains a comprehensive
medical records-linkage system (since 1965), to abstract additional information from the electronic medical
records: longitudinal lab tests (lipid panel), blood pressure, medications, BMI, and diagnosis of cardiac and
metabolic conditions (CMCs) up to 20 years before the amyloid and tau scans. Lastly, we will add a
comprehensive screen of genetic variation related to ADP, related neurodegenerative disorders, and aging
with the latest SNP-based array (NeuroX2).

## Key facts

- **NIH application ID:** 9932866
- **Project number:** 5R01AG056366-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** PRASHANTHI VEMURI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $777,951
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932866

## Citation

> US National Institutes of Health, RePORTER application 9932866, Exceptional Aging: Identifying Modifiers of Alzheimer's Disease Trajectories (5R01AG056366-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932866. Licensed CC0.

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