ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2025
Evaluating pathogenicity of variants of unknown significance in APP, PSEN1, and PSEN2.
Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- NovelWorld journal of radiology · 2026Article
- Genetic analysis of neurodegenerative diseases.The Journal of clinical investigation · 2026Review
- Review of Artificial Intelligence for Clinical Use in Alzheimer's Disease and Related Dementias.Seminars in neurology · 2026Review
- Benchmarking AlphaMissense pathogenicity predictions againstBiochemistry and biophysics reports · 2025Article
- Correlations ofAlzheimer's & dementia (New York, N. Y.)Article
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Authors and funding
13 authors.
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Abstract
Autosomal dominant Alzheimer's disease (ADAD) is driven by rare variants in APP, PSEN1, and PSEN2. Although more than 200 pathogenic variants in these genes are known to cause ADAD, other variants are benign, may act as risk factors, or may even reduce Alzheimer's disease risk (e.g. protective). Classifying novel variants in APP, PSEN1, or PSEN2 as pathogenic, risk, benign, or protective is a critical step in evaluating disease risk profiles which further impacts eligibility for clinical trials focused on the ADAD population. Here, we classify 53 novel variants in APP, PSEN1, and PSEN2 based on bioinformatic data and cell-based assays. We identified 6 benign variants, 2 risk variants, and 32 likely pathogenic variants. Thirteen variants were associated with reduced Aβ levels in cell-based assays, consistent with a potential protective effect. Together, this study highlights the complexities associated with classification of rare variants in ADAD genes.
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