SuperAging is not the inverse of common-variant Alzheimer’s risk: evidence across genetic ancestries
As longevity increases and the population over age 65 expands, advancing age remains the most reliable predictor of cognitive decline, highlighting the need to identify biological mechanisms that support exceptional cognitive aging. We tested whether lower inherited risk of Alzheimer’s disease (AD) dementia predicts SuperAger status (adults ≥ 80 years with episodic memory at least as good as middle-age adults) using prospectively enrolled SuperAgers and Cognitively Average Controls (Controls) from the multisite SuperAging Research Initiative. We studied 231 participants (SuperAgers n = 142; Controls n = 89). We confirmed that the genetic ancestry structure across groups was comparable. We evaluated whether APOE status (ε2, ε3, ε4) and three AD polygenic risk scores (PRS) derived from large contemporary Genome-Wide Association Studies (GWAS) (PRS Lambert , PRS Wightman , PRS Bellenguez ) predicted SuperAging status using logistic regression models adjusted for age, sex, and education, considering ancestry interactions. APOE allele and genotype distributions did not differ between groups, and neither APOE nor any of the three PRS predicted SuperAger status. Results were unchanged when accounting for global non-European or African ancestry or principal components. In this well-characterized cohort, neither APOE nor contemporary PRS explained SuperAger status. These findings suggest that the exceptional late-life memory phenotype that is characteristic of SuperAging is not explained by common-variant AD genetic risk captured by APOE or contemporary AD PRS, motivating a deeper investigation of potential rare genetic variations and experiential factors contributing to exceptional cognitive aging.
Authors
- Anna Bonfitto (ORCID: https://orcid.org/0009-0001-5796-5167)
- Amanda Cook Maher (ORCID: https://orcid.org/0000-0001-6229-4743)
- Ana W. Capuano (ORCID: https://orcid.org/0000-0002-3505-344X)
- Francis Taguinod
- Serena Song
- Rhiana Schafer (ORCID: https://orcid.org/0000-0003-0328-2499)
- Ignazio Stefano Piras (ORCID: https://orcid.org/0000-0003-4024-3368)
- RH Swartz
- Matt Huentelman
- GA Lincoln
- AC Roberts
- Angela Roberts
- Ozioma Okonkwo
- A Cardaio
- M Bruce
- H Paulson
- L Kaddoura
- S Jesso
- K Doyle-Thomas
- D Qui
- M McCarthy
- R Devine
- J El-Khoury
- I Culum
- AR Trammell
- B Stark
- M Parker
- J Chung
- K Beyer
- M Mesulam
- E Finger
- J Reader
- S Saleh
- Y Tuncel
- JB Orange
- A Lim
- L Wathen
- V Balog
- S Wang
- S Moore
- E Rose
- B Haller
- K Van Ooteghem
- M Kharitonova
- Adam Martersteck
- Felicia Goldstein
- Y Sturt
- C Dunne
- S Lose
- G Harris
- Emily Rogalski
- E Narayan
- R Bartha
- H Ahmed
- K Seibert
- C Geula
- DO Ofori
- J Li
- P Timpo
- A Bhaumik
- H Peirce
- H Whitmore
- K Warner
- A Pandos
- V Uday
- C Silveira
- N Aulakh
- A Ellison
- C Zolliecoffer
- K Coleman
- I Ayala
- A Capuano
- B McIlroy
- E Addison
- S McDermott
- K Hearns
- J Engelmeyer
- J Bross
- V Thai
Institutions
- Western University (CA)
- Alzheimer's Association (US)
- Translational Genomics Research Institute (US)
- University of Wisconsin–Madison (US)
- University of Michigan (US)
- Alzheimer’s Disease Neuroimaging Initiative (US)
- Arizona Alzheimer’s Consortium
Publication Details
- Journal
- Alzheimer s Research & Therapy
- Published
- 2026-07-23
- DOI
- https://doi.org/10.1186/s13195-026-02124-2
- Primary Topic
- Genetic Associations and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Brain Research Foundation
- McKnight Foundation
- Evelyn F. McKnight Brain Research Foundation
- National Institutes of Health