Genetic variants in longevity gene KLOTHO are associated with increased brain volumes in aging. J. S. Yokoyama1, V. E. Sturm1, L. W. Bonham1, E. Klein2, K. Arfanakis3, L. Yu3, G. Coppola2, J. H. Kramer1, D. A. Bennett3, L. Mucke1,4, B. L. Miller1, D. B. Dubal1 1) Dept of Neurology, University of California San Francisco, San Francisco, CA; 2) Dept of Neurology and Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA; 3) Rush Alzheimers Disease Center, Rush University Medical Center, Chicago, IL; 4) Gladstone Institute of Neurological Disease, San Francisco, CA.

   Identification of genetic variants associated with human brain structures in aging may elucidate new biologic mechanisms underlying resilience to age-dependent cognitive decline and disease - and identify brain regions critical to healthy aging. Two variants in the gene KLOTHO (KL), rs9536314 (F352V) and rs9527025 (C370S) segregate together and form a haplotype (KL-VS) associated with longevity and protection from cardiovascular disease in heterozygous carriers. Since brain size decreases with age, we sought to determine whether carrying one copy of the protective KL-VS allele is associated with larger brain volumes in healthy aging individuals. Using voxel-based morphometry, we blindly and broadly analyzed brain regions by magnetic resonance imaging (MRI) in a cohort of 217 healthy older adults (meanSE 70.20.5 years). Using linear regression models adjusted for total intracranial volume, age, sex, education, and APOE 4 status, we found the KL-VS haplotype to be associated with increased volumes of frontal cortical brain regions. After adjusting for multiple testing, one of the strongest associations was a greater grey matter volume of the right dorsolateral prefrontal cortex (DLPFC, MaxT=4.55, PFWE=0.03), a finding that replicated in an independent cohort of 224 healthy older adults (age: 81.20.5 years, beta=0.490.24, P=0.04). Because the right DLPFC is a critical component of neural networks engaged in executive cognitive abilities, we analyzed working memory and processing speed in individuals of both cohorts. By meta-analysis, greater executive function was associated with carrying one copy of the KL-VS haplotype (beta=0.390.11, P=0.0003), and the volume of the right DLPFC correlated with increased executive function in both cohorts (r=0.11, P=0.03). These results identify genetic variation in KLOTHO as a potential determinant of DLPFC volume, confirm the involvement of the right DLPFC in executive function, and implicate klotho in mechanisms of healthy cognitive aging.

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