PROJECT SUMMARY Alzheimer?s disease (AD) is a major public health problem affecting over 5 million people in the US. Patients with AD have beta-amyloid (A?) and tau pathology and typically present with memory loss. However, approximately 25% of AD subjects do not present with early memory loss and instead present with other cognitive complaints, and are referred to as atypical AD. The most common atypical AD syndromes include logopenic aphasia (LPA), a syndrome affecting language syndrome, and posterior cortical atrophy (PCA), a syndrome affecting visuospatial/perceptual skills. In the 1st cycle of this R01 we used positron emission tomography (PET) to assess A? and tau deposition across atypical and typical variants of AD, and we found a large degree of heterogeneity both cross-sectionally and longitudinally that was associated with syndrome and age. The goal of the 2nd cycle of the R01 is to investigate the degree to which other biological mechanisms are related to the heterogeneity we observed in tau and A?. In aim 1, we will assess how both functional connectivity, measured using resting state fMRI, and iron deposition, measured using quantitative susceptibility mapping, are related to cross-sectional and longitudinal heterogeneity in tau and A? in AD. In aim 2, we will assess how genetic risk factors are related to heterogeneity in tau and A?. We will assess the relationship between apolipoprotein (APOE) ?4 and tau and A?, and we will also perform a whole genome sequencing analysis to identify genetic variants associated with heterogeneity in tau and A? in AD. In aim 3, we will model the system of genetic and multi-modal imaging mechanisms in order to determine inter- relationships and independent contributions of each of our disease mechanisms to the heterogeneity of tau and A?. We plan to recruit a cohort of 100 subjects (33 LPA, 33 PCA, 34 typical AD) into the 2nd cycle of the R01. Each subject will undergo two serial assessments 12 months apart that will include neurological and neuropsychological testing, 3T MRI that includes resting state fMRI and quantitative susceptibility mapping, A? PET using Pittsburgh Compound B and tau-PET using [18F]flortaucipir. All subjects will also undergo a blood draw for genetic analysis. These 100 subjects will be used to address aims 1 and 3. For aim 2, we will utilize the 100 subjects from the 2nd cycle plus the 70 subjects recruited into the 1st cycle that underwent A? and tau PET and provided a blood sample (total=170 subjects), and we will replicate our whole genome sequencing analyses in the AD Neuroimaging Initiative (ADNI) cohort. Our R01 will have a major impact on public health since atypical AD effects ~1,000,000 Americans. Our research will increase understanding of biological mechanisms underlying phenotypical and age differences in AD and mechanisms that may determine routes of protein spread through the brain. This knowledge will be useful to aid in the future development of mechanistically based treatments and interventions for AD.
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