Associations of MAP2K3 Gene Variants With Superior Memory in SuperAgers

• Main Authors: Matthew J. Huentelman, Ignazio S. Piras, Ashley L. Siniard, Matthew D. De Both, Ryan F. Richholt, Chris D. Balak, Pouya Jamshidi, Eileen H. Bigio, Sandra Weintraub, Emmaleigh T. Loyer, M.-Marsel Mesulam, Changiz Geula, Emily J. Rogalski
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2018-05-01
• Series: Frontiers in Aging Neuroscience
• Subjects: aging; Alzheimer’s disease (AD); Alzheimer’s dementia; Alzheimer’s; successful aging; genetics
• Online Access: https://www.frontiersin.org/article/10.3389/fnagi.2018.00155/full

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).