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

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 162 unique PSEN1 variants expressed in HEK293 cells. Prediction of AAO was carried out in 107 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 162 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. ### Competing Interest Statement Partial funding from the Alzheimers Association (SAS), NIH grants (CRJ, GSD, JMN, JCM, RJB, TLSB, JPC), NIA grants (GSD), GHR Foundation (CRJ), Alexander Family Alzheimers Disease Research Professorship of Mayo Clinic (CRJ), grants from Lilly (NGR), Biogen (NGR), AbbVie (NGR, JL), Chan-Zuckerberg Initiative (GSD), DZNE (JL), Eisai (CR), Instituto de Salud Carlos III (RSV), Anonymous Foundation (PRS). Consultations have been declared for Humana Healthcare (JPC), Roche (NCF, JL, CR, RSV, RJB), Biogen (NCF, JL, CR), Parabon Nanolabs Inc. (GSD), DynaMed (EBSCO Health) (GSD), medical testimony on legal cases pertaining to management of Wernicke Encephalopathy (GSD), MODAG (JL), GmbH (JL), Bayer Vital (JL), Axon Neuroscience (JL), Thieme Medical Publishers (JL), Prothena (CR), Wave Pharmaceuticals (RSV), Janssen (RSV), Neuraxpharm (RSV), Eisai (RJB), and Amgen (RJB). Other financial interests include owning stocks greater than $10000 are held in ANI Pharmaceuticals (GSD), being a member of the DIAN-TU Pharma Consortium which includes funding and non-financial support for the DIAN-TU-001 trial from Avid Radiopharmaceuticals, Janssen Hoffman Roche/Genentech, Eli Lilly & Co, Eisai, Biogen, AbbVie, and Bristol Meyer Squibbs (RJB, TLSB), and royalties from C2N Diagnostics with equity ownership interest (RJB). Non-financial interests include serving on an independent data monitoring board for Roche (CRJ), support from Lilly (NCF), support from Ionis (NCF), serving as director of Anti- NMDA Receptor Encephalitis Foundation (GSD), Eisai (TLSB), Siemens (TLSB), and a member of speakers bureau for Biogen (TLSB). All other authors have nothing to disclose.