Abstract
Introduction: SuperAgers are adults age 80+ with episodic memory performance that is at least as good as that of average middle-aged adults. Understanding the biological determinants of SuperAging may have relevance to preventing age-related cognitive decline and dementia. This study aimed to identify associations between genetic variations and the SuperAging phenotype using Whole Exome Sequencing (WES).Methods: Sequence Kernel Association Combined (SKAT-C) test was conducted at the gene level including both rare and common variants in 56 SuperAgers and 22 cognitively-average controls from the Alzheimer’s disease Neuroimaging Initiative (ADNI).Results: The SuperAging phenotype was associated with variants in the Mitogen-Activated Protein Kinase Kinase 3 (MAP2K3) gene. Three single nucleotide polymorphisms (SNPs) contributed to the significance (rs2363221 [intron 1], rs2230435 [exon 5], rs736103 [intron 7]).Conclusions: MAP2K3 resides in a biological pathway linked to memory. It is in a signaling cascade associated with beta-amyloid mediated apoptosis and has enriched expression in microglia. This preliminary work suggests MAP2K3 may represent a novel therapeutic target for age-related memory decline and perhaps Alzheimer’s disease (AD).
Highlights
SuperAgers are adults age 80+ with episodic memory performance that is at least as good as that of average middle-aged adults
The primary goal of Alzheimer’s Disease Neuroimaging Initiative (ADNI) has been to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer’s disease (AD)
For Whole Exome Sequencing (WES) analysis, after quality controls filtering, there were 145,891 single nucleotide polymorphisms (SNPs) shared between SuperAgers and Controls
Summary
SuperAgers are adults age 80+ with episodic memory performance that is at least as good as that of average middle-aged adults. Understanding the biological determinants of SuperAging may have relevance to preventing age-related cognitive decline and dementia. This study aimed to identify associations between genetic variations and the SuperAging phenotype using Whole Exome Sequencing (WES). Average episodic memory capacity is significantly higher in populations of 50–60 year olds than in populations of 80+ year olds. We defined SuperAgers as individuals 80 or older with episodic memory at least average for cognitively average individuals in their 50 s and 60 s. SuperAgers have superior memory capacity for age and are potentially resistant to age-related decline. Age (years) Education (years) Sex Men : Women. Neuropsychological test performance Rey Auditory Verbal Learning Test (RAVLT) Delay Raw Score (out of 15) Category fluency (animals)
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