ABSTRACT Background The balance between production, clearance, and toxicity of Aβ peptides is central to Alzheimer’s disease (AD) pathobiology. Though highly variable in terms of age at symptom onset (AAO), hundreds of variants in PSEN1 cause autosomal dominant forms of AD (ADAD) with nearly complete penetrance. PSEN1 forms the catalytic core of the γ-secretase complex and thereby directly mediates the production of longer, aggregation-prone Aβ peptides relative to shorter, non-aggregating peptides. We hypothesized that the broad AAO and biomarker heterogeneity seen across ADAD would be predictable based on mutation-specific differences in the production of Aβ species. Methods Aβ-37, 38, 40, 42, and 43 production was quantified from 161 unique PSEN1 variants expressed in HEK293 cells. Prediction of AAO was carried out in 106 variants with available AAO and then replicated in 55 variants represented across 190 PSEN1 mutation carriers who have detailed cognitive and biomarker data from the Dominantly Inherited Alzheimer’s Network (DIAN). Results Variations in Aβ production across the 161 mutations examined in cell-based models were highly predictive of AAO. In those with corresponding in vivo data from the DIAN study, our cell-based γ-secretase composite was strongly associated with biomarker and cognitive trajectories. Conclusions These findings elucidate the critical link between γ-secretase function, Aβ production, and AD progression and offer mechanistic support for the amyloid hypothesis. The approach used here represents a powerful tool to account for heterogeneity in disease progression in ADAD clinical trials and to assess the pathogenicity of variants of unknown significance or with limited family history.

Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer’s disease