Basic Science and Pathogenesis

"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).

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.

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; line-height: normal; font-size: 16px; font-size-adjust: none; text-indent: 0px; text-align: center; text-transform: none; letter-spacing: normal; word-spacing: normal; overflow-wrap: normal; white-space: pre !important; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; position: relative;" tabindex="0">×10^-80 and p = 2.53×10^-13, respectively). No controls had GWS associations, with the strongest associations inconsistent among age group comparisons.

Our extreme-phenotype GWAS comparing SuperAgers to middle-aged cases identified both the established APOE and BIN1 genes and the novel loci rs79973832 for AD. Both Old Cases and Oldest-old Cases reached GWS only in the APOE region. With additional harmonization efforts, larger sample sizes will allow for better comprehension of the genetic architecture of SuperAging. Future work will extend to rare variant analyses of SuperAging using Whole Genome Sequencing (WGS).