# Extreme Longevity, Cognitive Impairment, Alzheimer's Disease and Related Dementias

> **NIH NIH U19** · TRANSLATIONAL GENOMICS RESEARCH INST · 2024 · $1,419,394

## Abstract

PROJECT SUMMARY- PROJECT 3
Extreme longevity (EL) is influenced by combinations of gene variants that may hold the explanation of why and
how many centenarians and their offspring reach extreme old ages with good cognitive function and delay or
even escape Alzheimer’s disease and related dementias (ADRD). In the last cycle of the Longevity Consortium
(LC), we established the LC Centenarian (LCC) project. By leveraging productive synergy within the LC and with
external collaborators, our genetic analyses identified new EL associated genes including genes that correlate
with protection from ADRD. We generated proteomic and metabolomic signatures of age, extreme old age, and
survival that revealed a snapshot of the complexity of molecular aging and EL, and we demonstrated that
longevity variants have distinct and well-replicated proteomic and metabolomic signatures that may help prioritize
targets for healthy aging therapeutics. These signatures include biomarkers of cognitive impairment (CI) and
ADRD. These results provide strong evidence for the hypothesis that genes related to EL, CI, and ADRD have
intertwined effects that we aim to dissect and characterize. We propose to conduct this work by augmenting our
existing collection of genome-wide genotype data with new multi-omics data, further our analyses of EL with new
genetic data, characterize genetic and associated multi-omics signatures that correlate with EL and protect
centenarians and their offspring from CI and ADRD, and examine the effects of sex, race and genetic diversity
on these associations. The LC is an ideal environment for these investigations by providing integration with
functional validation [Projects 2 and 5], additional cohorts of human aging [Project 1], and translational
opportunities [Project 4], further facilitated by the Integrative Analysis Core (IAC). The analyses in Project 3 will
clarify the relationships between factors related to EL and factors influencing CI and risk or severity of ADRD
and specifically address Objective 3 of the RFA: “Clarify the relationships between factors related to exceptional
longevity in humans and factors influencing cognitive function in old age and risk or severity of Alzheimer’s
disease and related dementias”. We propose the following Project 3 specific aims: Aim 1 [Multi-phenotype/Multi-
omics Data Generation]: We will generate multi-omics data in LCC participants, continue the annual follow-up
phenotyping and expand the medical history data by linkage to Centers for Medicare & Medicaid Services (CMS)
data. Aim 2 [Genetics and Genomics Signatures of Extreme Longevity and Effect on ADRD/CI]: We will conduct
genetic/genomic analyses of EL to characterize the genetics and multi-omics profiles of EL and their effects on
the onset of CI and risk for ADRD. Aim 3 [Genetic and Genomic signatures of ADRD/CI protection and effect on
EL]: We will identify DNA fingerprints of ADRD and CI to clarify the effect of factors related to CI and risk or
s...

## Key facts

- **NIH application ID:** 11022978
- **Project number:** 2U19AG023122-16
- **Recipient organization:** TRANSLATIONAL GENOMICS RESEARCH INST
- **Principal Investigator:** PAOLA SEBASTIANI
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,419,394
- **Award type:** 2
- **Project period:** 2004-09-30 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11022978

## Citation

> US National Institutes of Health, RePORTER application 11022978, Extreme Longevity, Cognitive Impairment, Alzheimer's Disease and Related Dementias (2U19AG023122-16). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/11022978. Licensed CC0.

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