Role of classical complement pathway underling glial phenotypes and multiple pathologies in Alzheimer's disease and cerebrovascular disease

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The pathologies underlying Alzheimer disease (AD) are common in the aged population and can occur more than a decade prior to clinical symptoms. In addition, aging increases the likelihood of multiple pathologies which may all contribute to cognitive impairment. Recent studies demonstrate that apolipoprotein E (APOE) and classical complement pathway genes are involved in synaptic loss and tau pathology. The objective of this project is to investigate role of APOE and complement pathway genes in determining glial, neuroinflammatory, and neuropathological alterations that ultimately lead to altered cognitive and imaging biomarker trajectories. We propose a cross-disciplinary approach in 3 specific aims. For Aim 1, we will determine how genetic and transcriptional risk profiles of complement pathway genes and their interaction with APOE genotype contribute to synaptic loss, neuroinflammation, cerebrovascular disease, and tau pathology in AD using the entire FHS cohort as well as within deceased FHS participants with brain donation (current number of autopsy cases is 241; with blood and brain tissue, n=208). For Aim 2, we will determine how glial and neuroinflammatory phenotypes associated with AD and cerebrovascular disease result in distinctive patterns of astrocytosis, microgliosis, and neuroinflammation that lead to AD and AD-related disorders using newly defined phenotypes together with traditional pathological measures developed in collaboration with the Neuropathology Core. For Aim 3, we will validate clinical implications by determining associations of the identified genetic variants and alternative transcripts and novel cellular phenotypes from Aims 1 and 2 with longitudinal changes of imaging biomarkers and cognitive function (n=3,189) as well as with quantitative vascular risk factors (e.g., blood glucose, lipid fractions, blood pressure, BMI, cigarette smoking). We anticipate that results from this project will provide opportunities for developing new genetic screening markers and biomarkers and insights about potential novel therapeutic targets for AD.