| Title: |
Genetic variants linked to cognitive longevity in SuperAgers |
| Authors: |
Durant, Alaina; Walters, Skylar; Mahoney, Emily R.; Mukherjee, Shubhabrata; Lee, Michael L.; Choi, Seo‐Eun; Scollard, Phoebe; Klinedinst, Brandon; Trittschuh, Emily H.; Mez, Jesse; Farrer, Lindsay A.; Gifford, Katherine; Cruchaga, Carlos; Hassenstab, Jason J.; Naj, Adam C.; Wang, Li‐San; Johnson, Sterling C.; Engelman, Corinne D.; Kukull, Walter W.; Keene, C. Dirk; Saykin, Andrew J.; Cuccaro, Michael L.; Kunkle, Brian W.; Pericak‐Vance, Margaret; Martin, Eden R.; Bennett, David A. A.; Barnes, Lisa L.; Schneider, Julie A.; Bush, William S.; Haines, Jonathan L.; Mayeux, Richard; Vardarajan, Badri N.; Albert, Marilyn S. S.; Thompson, Paul M.; Jefferson, Angela L.; Crane, Paul K.; Dumitrescu, Logan; Archer, Derek B.; Hohman, Timothy J.; Gaynor, Leslie S.; The Alzheimer's Disease Neuroimaging Initiative (ADNI); Alzheimer's Disease Genetics Consortium (ADGC); The Alzheimer's Disease Sequencing Project (ADSP) |
| Contributors: |
Radiology and Imaging Sciences, School of Medicine |
| Source: |
PMC |
| Publisher Information: |
Wiley |
| Publication Year: |
2025 |
| Collection: |
Indiana University - Purdue University Indianapolis: IUPUI Scholar Works |
| Subject Terms: |
SuperAgers; Genome wide association study (GWAS); APOE |
| Description: |
Background “SuperAgers” are oldest‐old (ages 80+) adults with memory performance resembling adults in their 50s to mid‐60s. This study investigates the genetic drivers of SuperAging using a genome wide association study (GWAS). Method Harmonized, longitudinal memory, executive function, and language scores for participants with European ancestry were obtained from the ADSP Phenotype Harmonization Consortium. In addition to exceptional memory, SuperAgers (N = 1,171) must have language and executive function domain scores within normal limits and remain cognitively normal across visits if longitudinal datapoints were available. We compared SuperAgers to Alzheimer's disease (AD) cases (N = 5,372) and controls (N = 4,012) in age‐defined subgroups (middle‐aged=ages 50‐64, old=ages 65‐79, oldest‐old=age 80+). We performed a logistic regression based GWAS comparing SuperAgers and their counterparts, adjusting for age, sex, education, and the first five principal components for population substructure. Result Comparing SuperAgers with middle‐aged cases (ages 50‐64, Figure 1), multiple variants in the confirmed AD loci APOE and BIN1 regions were associated with genome‐wide significance (GWS; indexes p = 1.12×10‐41 and p = 5.48×10‐9, respectively). Additionally, we observed GWS association on chromosome 4 loci (rs79973832, index p = 2.95×10‐8, Figure 2), which centers on a ring finger protein gene, RNF150. This family of genes are involved in the ubiquitin‐proteasome system and regulate antiviral immune responses. While several members of the RNF gene family have been liked to AD and cognitive performance, there is currently no established association between RNF150 and AD. Analyses comparing SuperAgers to old and oldest‐old cases (ages 65‐79 and 80+, respectively) found GWS only in the APOE region (indexes p = 1.90×" role="presentation" style="‐webkit‐user‐drag: none; ‐webkit‐tap‐highlight‐color: transparent; margin: 0px; padding: 0px; user‐select: text; display: inline‐table; font‐style: normal; font‐weight: normal; ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Alzheimer's & Dementia; Durant A, Walters S, Mahoney ER, et al. Genetic variants linked to cognitive longevity in SuperAgers. Alzheimers Dement. 2025;21(Suppl 1):e107245. Published 2025 Dec 24. doi:10.1002/alz70855_107245; https://hdl.handle.net/1805/53293 |
| Availability: |
https://hdl.handle.net/1805/53293 |
| Rights: |
Attribution 4.0 International ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.1BAEF08A |
| Database: |
BASE |