Lab-based γ-secretase activity measures linked to Alzheimer's disease progression, researchers stress validation still needed.

Evidence before this study

We searched PubMed from Sept 1, 1990, to April 25, 2024, for relevant articles in English relating to autosomal dominant Alzheimer's disease pathogenic variants that affect γ-secretase processing of amyloid-β precursor protein (APP). Search terms were “dominantly inherited Alzheimer's disease”, “autosomal dominant Alzheimer's disease”, “familial Alzheimer's disease”, “gamma-secretase”, “amyloid-beta precursor protein”, “presenilins”, “γ-secretase”, “amyloid”, “PSEN1”, “APP”, “Aβ42”, and “Aβ40”. Previous studies have suggested that an increase in production of longer, aggregation-prone amyloid β fragments (eg, Aβ42 and Aβ43) relative to shorter, non-aggregating fragments (eg, Aβ37 and Aβ38) is a crucial initiating pathogenic event in people with both late-onset Alzheimer's disease and autosomal dominant Alzheimer's disease. Previous work also suggests that some pathogenic PSEN1 variants might not substantially alter Aβ42 production, indicating that a thorough investigation is needed to understand how these pathogenic variants can lead to autosomal dominant Alzheimer's disease and the mechanisms that can cause earlier versus later disease onset and progression. Findings from our group and others suggest that probing the ratios of short-to-long amyloid β peptide production across pathogenic variants might help to explain the heterogeneity among people with autosomal dominant Alzheimer's disease.

Added value of this study

Our findings indicate that variant-level differences in γ-secretase activity are associated with measures of progression of autosomal dominant Alzheimer's disease. As the HEK293T cell-based measures of γ-secretase activity used in our analysis are derived outside the context of family polygenic factors, age, and estimated years to symptom onset, they offer a potentially unique source of information in terms of disease progression compared with these other factors, and could therefore complement these measures in clinical trials of people with autosomal dominant Alzheimer's disease. Cell-based measures of γ-secretase activity could be particularly useful to assess pathogenicity, potential estimated age at symptom onset, and predicted trajectories of Alzheimer's disease for newly discovered PSEN1 pathogenic variants or for variants without sufficient clinical history.

Implications of all the available evidence

Our cell-based methods could improve understanding of observed heterogeneity in the progression of Alzheimer's disease in clinical and research settings and could be a way to assess variants of autosomal dominant Alzheimer's disease of unknown significance. Our findings and those of others suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by varying effects of PSEN1 variants on γ-secretase activity. If our findings are substantiated by prospective longitudinal studies, assessment of γ-secretase activity across PSEN1 variants or within individuals at risk for Alzheimer's disease might eventually be useful for prognosis and identifying new therapeutic approaches.

Source: The Lancet Neurology