Identifying therapeutic targets that confer synaptic resilience to Alzheimer's disease

Project Summary Approximately one-third of individuals without dementia at the time of death are found to harbor high levels of Alzheimer’s disease (AD) pathology at autopsy. We hypothesize that such individuals exhibit physiological resilience that confers the ability to maintain cognitive function despite the accumulation of AD-related pathologies. The identification of the specific mechanisms by which these older individuals with AD pathology avoid dementia is one of the most pivotal, unanswered questions in the field. Cognitive impairment in AD is the result of synapse loss in brain regions that are critical for memory processes. Our work and that of others has demonstrated that dendritic spine and synapse loss correlate more strongly with cognitive impairment in AD than accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. This implies that the ability to maintain cognitive function despite substantial AD neuropathology must be linked to the preservation and maintenance of synapses or spines across vulnerable brain regions. This raises important questions: 1) What are the synaptic signaling pathways that maintain cognitive abilities in resilient individuals? 2) How do Aβ and tau interact with dendritic spines to influence the brain connectivity that facilitates resilience? 3) Can we identify protein targets for therapeutic development that support cognitive functions across brain regions? Thus far, few molecules have proven effective for Alzheimer’s disease, where the goal is improving high-level, brain-spanning cognitive phenotypes. This big picture challenge of therapeutic target selection could be solved by pursuing molecules predicted to affect connectivity across brain regions, thereby improving the likelihood to affect cognitive status. Thus, the goal of this proposal is to identify key molecular mechanisms that support resilience to Alzheimer’s disease across multiple brain regions, and then carefully validate these findings by testing their relevance in computational, cellular, and animal models. In the previous funding cycle, we generated unprecedented data on functional magnetic resonance imaging and brain multi-omics from the same human subjects, which demonstrated that it is possible to combine postmortem molecular and subcellular data with antemortem neuroimaging to prioritize mechanisms underlying brain connectivity. Now, it is essential to identify the molecular and cellular mechanisms that support resiliency to Alzheimer’s disease and understand how Aβ and tau affect connectivity patterns of resilience.