Enrichment of Rare Exonic Variants in Cognitive Superagers from Centenarian Families

Although cognitive decline and dementia are common at advanced ages, a fraction of individuals reach extreme ages maintaining high levels of cognitive function. Here, we compared whole-exome sequencing data from 136 cognitive superagers, individuals whose memory performance matches normative expectations for persons ~30 years younger, to 114 average-cognition controls and the gnomAD population reference database. While standard single-variant and burden analyses did not identify exome-wide significant loci, a rare variant allele frequency analysis identified 114 significant rare coding variants enriched in cognitive superagers. We highlight ten significant missense variants in genes implicating neurovascular biology (LOX, CLEC4M, CBWD6), immune regulation (HLA-B, HLA-DRB1, ITGAX, MUC4, MUC1), and neuronal structural (CEP131 x2). Together, these findings support an extreme-phenotype strategy as a tractable discovery framework for rare coding variation and nominate a set of biologically plausible loci to reveal potential genetic mechanisms for resilience to age-related cognitive impairment.