TY - JOUR T1 - FASTKD2 is associated with memory and hippocampal structure in older adults. JF - Mol Psychiatry Y1 - 2015 A1 - Vijay K Ramanan A1 - Nho, Kwangsik A1 - Shen, Li A1 - Shannon L Risacher A1 - Brenna C McDonald A1 - Martin R Farlow A1 - Tatiana Foroud A1 - Gao, Sujuan A1 - Soininen, Hilkka A1 - Kloszewska, Iwona A1 - Mecocci, Patrizia A1 - Tsolaki, Magda A1 - Vellas, Bruno A1 - Lovestone, Simon A1 - Aisen, Paul S. A1 - Ronald C Petersen A1 - Jack, Clifford R. A1 - Shaw, Leslie M. A1 - Trojanowski, John Q. A1 - Weiner, Michael W. A1 - Green, Robert C. A1 - Arthur W. Toga A1 - Philip L de Jager A1 - Lei Yu A1 - David A Bennett A1 - Andrew J Saykin KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alzheimer disease KW - Female KW - Genetic Association Studies KW - Genome-Wide Association Study KW - Hippocampus KW - Humans KW - Longitudinal Studies KW - Male KW - Memory KW - Memory Disorders KW - Polymorphism, Single Nucleotide KW - Protein-Serine-Threonine Kinases KW - Structure-Activity Relationship AB -

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.

PB - 20 VL - 20 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25385369?dopt=Abstract U2 - PMC4427556 U4 - Genetic analysis/Alzheimer disease/Memory impairment/predictors/FASTKD2 ER - TY - JOUR T1 - The apolipoprotein E genotype predicts longitudinal transitions to mild cognitive impairment but not to Alzheimer's dementia: findings from a nationally representative study. JF - Neuropsychology Y1 - 2013 A1 - Brainerd, C. J. A1 - V. F. Reyna A1 - Ronald C Petersen A1 - Glenn E Smith A1 - Kenney, A. E. A1 - C. J. Gross A1 - Taub, E. S. A1 - Brenda L Plassman A1 - Gwenith G Fisher KW - Aged KW - Aged, 80 and over KW - Alzheimer disease KW - Apolipoproteins E KW - Cognitive Dysfunction KW - disease progression KW - Female KW - Genetic Predisposition to Disease KW - Genetic Testing KW - Genotype KW - Humans KW - Logistic Models KW - Longitudinal Studies KW - Male KW - National Institutes of Health (U.S.) KW - Neuropsychological tests KW - Risk Factors KW - United States AB -

OBJECTIVE: The ε4 allele of the apolipoprotein E (APOE) genotype is the most widely accepted genetic risk factor for Alzheimer's dementia (AD), but findings on whether it is a risk factor for the AD prodrome, mild cognitive impairment (MCI), have been inconsistent. In a prospective longitudinal design, we investigated (a) whether transitions to MCI and other forms of neurocognitive impairment without dementia (CIND) are more frequent among normal ε4 carriers than among noncarriers and (b) whether subsequent transitions to AD from MCI and from other forms of CIND are more frequent among ε4 carriers than among noncarriers.

METHOD: The frequency of the ε4 allele was studied in older adults (mean age > 70), who had participated in two or more waves of neuropsychological testing and diagnosis in the Aging, Demographics, and Memory Study (ADAMS) of the United States Department of Health and Human Services, National Institutes of Health, National Institute on Aging's Health and Retirement Study, conducted by the University of Michigan. The association between ε4 and longitudinal transitions to specific types of CIND and dementia can be determined with this data set.

RESULTS: Epsilon 4 increased the rate of progression from normal functioning to MCI (58% of new diagnoses were carriers) but not to other forms of CIND. The rate of progression to AD from MCI or from other forms of CIND was not increased by ε4.

CONCLUSIONS: The results support the hypothesis that ε4 is a risk factor for transitions from normal functioning to MCI but not for subsequent transitions to AD. In the ADAMS sample, the reason ε4 is elevated in AD individuals is because it is already elevated in MCI individuals, who are the primary source of new AD diagnoses.

VL - 27 UR - http://psycnet.apa.org/journals/neu/27/1/86/ IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23356599?dopt=Abstract ER - TY - JOUR T1 - Is the apolipoprotein e genotype a biomarker for mild cognitive impairment? Findings from a nationally representative study. JF - Neuropsychology Y1 - 2011 A1 - Brainerd, Charles J A1 - V. F. Reyna A1 - Ronald C Petersen A1 - Glenn E Smith A1 - Taub, Emily S KW - Aged KW - Aged, 80 and over KW - Aging KW - Analysis of Variance KW - Apolipoprotein E4 KW - Cognitive Dysfunction KW - Dementia KW - Female KW - Gene Frequency KW - Genetic Markers KW - Genetic Testing KW - Genotype KW - Humans KW - Male KW - National Institute on Aging (U.S.) KW - Neuropsychological tests KW - Reference Values KW - Reproducibility of Results KW - Risk Factors KW - United States AB -

OBJECTIVE: Although the ε4 allele of the apolipoprotein E (APOE) genotype is a known risk factor for Alzheimer's dementia (AD), prior findings on whether it is also a risk factor for mild cognitive impairment (MCI) have been inconsistent. We tested two contrasting explanations: (a) an ε4-AD specificity hypothesis, and (b) a measurement insensitivity hypothesis.

METHOD: The frequency of the ε4 allele was investigated in older adults (mean age > 70) with various types of cognitive impairment (including MCI) and various types of dementia (including AD) with the aging, demographics, and memory study (ADAMS) of the National Institute on Aging's Health and Retirement Study (HRS). The ADAMS controls sources of Type I and Type II error that are posited in the ε4-AD specificity hypothesis and the measurement insensitivity hypothesis, and it is the only nationally representative data set on aging and cognitive impairment.

RESULTS: ε4 was a reliable predictor of MCI, with a frequency of 32% in MCI subjects versus 20% in healthy control subjects. This link was specific to MCI because ε4 was not a risk factor for other forms of cognitive impairment without dementia.

CONCLUSIONS: The results support the measurement insensitivity hypothesis rather than the ε4-AD specificity hypothesis and are consistent with recent research showing modest reductions in cognitive performance among normal functioning ε4 carriers.

PB - 25 VL - 25 IS - 6 N1 - Brainerd, Charles J Reyna, Valerie F Petersen, Ronald C Smith, Glenn E Taub, Emily S 1RC1AG036915-01/AG/NIA NIH HHS/United States U01AG009740/AG/NIA NIH HHS/United States Research Support, N.I.H., Extramural United States Neuropsychology. 2011 Nov;25(6):679-89. U1 - http://www.ncbi.nlm.nih.gov/pubmed/21728427?dopt=Abstract U3 - 21728427 U4 - Aging/Analysis of Variance/Apolipoprotein E4/genetics/genetics/Dementia/Gene Frequency/Genetic Markers/Genetic Testing/Genotype/Mild Cognitive Impairment/Neuropsychological Tests/Reference Values/Reproducibility of Results/Risk Factors/Alzheimer disease/epsilon4 allele ER -