Project Abstract: Alzheimer’s disease (AD) and related dementias (ADRD) represent an enormous burden for patients, families, and health care systems, underscoring the urgent need for efficacious, widely-accessible, and cost- effective disease-modifying therapies. The over-production of longer, aggregation-prone Ab fragments (esp. Ab42 and 43) relative to shorter, non-aggregating fragments (esp. Ab37 and 38) appears to be a critical initiating pathological event in both late-onset, sporadic AD (LOAD) and Autosomal Dominant AD (ADAD). The balance between production of aggregating and non-aggregating forms of Ab is a direct result of the efficiency and kinetics with which the γ-secretase complex sequentially cleaves b-amyloid precursor protein (APP). Subtle alterations in γ-secretase function can have profound neurodegenerative and cognitive consequences, while modulation of γ-secretase has therapeutic potential in both LOAD and ADAD. Over 200 pathogenic variants in Presenilin-1 (PS1), the key catalytic subunit in the γ-secretase complex, have been identified and are the most common cause of ADAD. Despite near complete penetrance, there is substantial heterogeneity in age of symptom onset (a range of >30 years) and rates of cognitive and biomarker change between PS1 variants. In this proposal, we hypothesize that differences in γ-secretase function between ADAD-causing PS1 mutations measured in cell-based, biochemical, and primary neuronal model systems will help explain heterogeneity in age of symptom onset, cognitive, and biomarker changes seen in PS1 pathogenic variant carriers in vivo. We test this hypothesis through systematic characterization of γ-secretase function across PS1 pathogenic variants and comparing the resulting immunoassay and mass spectroscopy measures of g-secretase function to cognitive and biomarker data from carriers of corresponding PS1 variants participating in the Dominantly Inherited Alzheimer’s Network Observational Study (DIAN-Obs), a large international study in which over 80 unique PS1 pathogenic variants are represented. Determining which variant-specific differences in γ-secretase function translate into differences in age of symptom onset and cognitive and biomarker trajectories in PS1 carriers represents a unique opportunity to elucidate AD pathobiology, inform therapeutic and biomarker development, and impact ADAD clinical trials.