Associations of MAP2K3 Gene Variants With Superior Memory in SuperAgers

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).

The Brain Metabolic Signature in Superagers Using In Vivo 1H-MRS: A Pilot Study

“…In previous studies using the same inclusion criteria, the sample size of superagers varied from 12 2 to 56. 83 The examined metabolite concentrations were limited to those sampled in the posterior cingulate cortex; however, metabolite concentrations differ among distinct portions of the brain and between gray and white matter, 84 possibly having an unpredictable impact on normal aging and the superagers' metabolic signatures. Also, no inferences regarding the impact of aging on several metabolite levels could be drawn.…”

Tissue-specific enhancer functional networks for associating distal regulatory regions to disease

“…Perturbation of this homeostasis is a hypothesis for ASD etiology (Sohal and Rubenstein, 2019). MAP2K3 was shown to be genetically associated with memory (Huentelman et al, 2018) and displayed differential expression in autistic brains (Garbett et al, 2008;Parikshak et al, 2016).…”

Stability of memory SuperAgers over 3 years

“…Given the aging population, the cognitive health of older adults is becoming a public health concern. Most of the studies of cognitive aging focus on pathological aging, but increasing attention is being devoted to defining and researching the cognitive resilience phenomenon, which is also referred to as “superaging” or “successful memory aging” (Cabeza et al, ; Huentelman et al, ; Nyberg & Pudas, ). In the Northwestern University SuperAging Study, individuals aged over 80 years who had episodic memory performance at or above the norm for 50‐ to 65‐year‐olds were referred to as SuperAgers (SAs) (Harrison, Weintraub, Mesulam, & Rogalski, ).…”