Enrichment of Rare Exonic Variants in Cognitive Superagers from Centenarian Families

Rare coding variants are enriched in 136 cognitive superagers versus 114 average-cognition controls, with 114 significant rare coding variants detected by allele frequency analysis.

• Why it matters: Cognitive decline and dementia are common at advanced ages, but the genetic basis of rare individuals who maintain high cognition is unclear.
• What they did: Whole-exome sequencing was compared across cognitive superagers, average-cognition controls, and the gnomAD reference; exome-wide single-variant and burden tests were followed by a rare variant allele frequency analysis.
• The result: Ten significant missense variants in neurovascular, immune regulation, and neuronal structural genes (including LOX, HLA-B, ITGAX, and CEP131 x2) were highlighted, supporting extreme-phenotype discovery for rare coding mechanisms linked to resilience.

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