Genetic Architecture of Memory and Executive Functioning in Alzheimer's Disease

Abstract Ten to fifteen percent of newly-diagnosed late-onset Alzheimer’s disease (AD) patients who otherwise meet criteria for AD are noted to have impressive deficits in executive functioning. The overarching goal of this project is to further our understanding of the spectrum of executive and memory functioning among people with newly-diagnosed late-onset AD. There are several reasons this is important, including furthering our understanding of AD, identifying possible drug targets to improve the lives of people with AD, and possibly identifying people with different diseases currently labeled “AD”. We propose to leverage data collected by a variety of studies collaborating with the AD Genetics Consortium (ADGC). This highly collaborative project has published results of the largest ever case-control genome wide association study (GWAS) of AD. Our overarching hypothesis is that there is important heterogeneity in the genetic architecture associated with the heterogeneity observed in memory and executive functioning. We will test this hypothesis using the expanding resources of the ADGC along with additional phenotypic data obtained from the parent studies. We will obtain all of the neuropsychological data collected by the parent studies for these participants. We will develop psychometrically sophisticated estimates of memory and executive functioning for each person. We will consider the difference between these two scores, which defines a spectrum from individuals with memory much worse than executive functioning at one end and people with executive functioning much worse than memory at the other. We will then perform a variety of genetic and epidemiological analyses: Specific Aim 1: Discovery genetics with genome-wide single nucleotide polymorphsim (SNP) data. We will perform GWAS of SNPs, genome-wide gene analyses (our primary level of analysis), and pathway analyses. Specific Aim 2: Epidemiology, cognitive trajectories, and Mendelian randomization. Four of our collaborating studies are prospective cohort studies. We will evaluate factors associated with our cognitive spectrum phenotype. We will consider longitudinal cognitive data extending backwards from the time of AD diagnosis to determine whether trajectories are similar for people who develop executive –prominent AD and those who develop more typical AD. We will use published GWAS studies of a variety of traits (AD, vascular disease, vascular risk factors such as diabetes, hypertension, dyslipidemia, etc.) and SNP data to determine whether gene scores for these traits are associated with our cognitive spectrum phenotype. Specific Aim 3: Fine mapping and rare variant analyses with exome aray, whole exome sequence, and whole genome sequence data. Thousands of ADGC participants were genotyped with exome arrays capturing rare variants. Five thousand people with AD will have whole exome sequence data obtained from the AD Sequencing Project (ADSP). Three hundred people with AD from family studies and from the 2nd funding cycle of the AD Neuroimaging Initiative (ADNI2) will have whole genome sequence data available. These phenomenal resources will enable us to follow-up interesting findings from Aim 1 to further identify potentially causal rare variants. We will also evaluate rare variants in genetic regions already identified through GWAS to be associated with AD, vascular disease, and vascular disease risk factors. These analyses will improve our understanding of – and hopefully our armamentarium for – AD