Title | FASTKD2 is associated with memory and hippocampal structure in older adults. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Ramanan, VK, Nho, K, Shen, L, Risacher, SL, McDonald, BC, Farlow, MR, Foroud, T, Gao, S, Soininen, H, Kloszewska, I, Mecocci, P, Tsolaki, M, Vellas, B, Lovestone, S, Aisen, PS, Petersen, RC, Jack, CR, Shaw, LM, Trojanowski, JQ, Weiner, MW, Green, RC, Toga, AW, de Jager, PL, Yu, L, Bennett, DA, Saykin, AJ |
Journal | Mol Psychiatry |
Volume | 20 |
Issue | 10 |
Pagination | 1197-204 |
Date Published | 2015 Oct |
ISSN Number | 1476-5578 |
Keywords | Age Factors, Aged, Aged, 80 and over, Alzheimer disease, Female, Genetic Association Studies, Genome-Wide Association Study, Hippocampus, Humans, Longitudinal Studies, Male, Memory, Memory Disorders, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases, Structure-Activity Relationship |
Abstract | Memory impairment is the cardinal early feature of Alzheimer's disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics approach to perform the largest study to date of human memory (n=14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia. |
DOI | 10.1038/mp.2014.142 |
User Guide Notes | |
Endnote Keywords | Genetic analysis/Alzheimer disease/Memory impairment/predictors/FASTKD2 |
Endnote ID | 999999 |
Alternate Journal | Mol Psychiatry |
Citation Key | 8326 |
PubMed ID | 25385369 |
PubMed Central ID | PMC4427556 |
Grant List | K01 AG030514 / AG / NIA NIH HHS / United States RC4 AG039029 / AG / NIA NIH HHS / United States RC4AG039029 / AG / NIA NIH HHS / United States P41 EB015922 / EB / NIBIB NIH HHS / United States P30AG010129 / AG / NIA NIH HHS / United States P30 AG010124 / AG / NIA NIH HHS / United States R01 AG019771 / AG / NIA NIH HHS / United States S10 RR027710 / RR / NCRR NIH HHS / United States UL1 RR025761 / RR / NCRR NIH HHS / United States RF1 AG015819 / AG / NIA NIH HHS / United States RR020128 / RR / NCRR NIH HHS / United States R01AG19771 / AG / NIA NIH HHS / United States R00 LM011384 / LM / NLM NIH HHS / United States U01 AG009740 / AG / NIA NIH HHS / United States P30 AG010133 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States P30AG10133 / AG / NIA NIH HHS / United States K99 LM011384 / LM / NLM NIH HHS / United States U01 AG024904 / AG / NIA NIH HHS / United States R01 AG017917 / AG / NIA NIH HHS / United States R01LM011360 / LM / NLM NIH HHS / United States U24AG21886 / AG / NIA NIH HHS / United States UL1 TR001108 / TR / NCATS NIH HHS / United States K01AG030514 / AG / NIA NIH HHS / United States R01 LM011360 / LM / NLM NIH HHS / United States C06 RR020128 / RR / NCRR NIH HHS / United States P30 AG010161 / AG / NIA NIH HHS / United States RR027710-01 / RR / NCRR NIH HHS / United States U01AG009740 / AG / NIA NIH HHS / United States K01 AG049050 / AG / NIA NIH HHS / United States RC2 AG036495 / AG / NIA NIH HHS / United States P30 AG010129 / AG / NIA NIH HHS / United States U54 RR025761 / RR / NCRR NIH HHS / United States R00LM011384 / LM / NLM NIH HHS / United States RC2AG036495 / AG / NIA NIH HHS / United States |