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Cited by 99Alzheimer's disease research and treatmentsGenomics and Rare DiseasesDementia and Cognitive Impairment Research

APP, PSEN1, and PSEN2 Variants in Alzheimer’s Disease: Systematic Re-evaluation According to ACMG Guidelines

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Xiao, Xuewen, Liu, Hui, Liu, Xixi, Zhang, Weiwei, Zhang, Sizhe, Jiao, Bin·2021·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2021.695808PMC PMC8249733
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Abstract

The strategies of classifying APP, PSEN1, and PSEN2 variants varied substantially in the previous studies. We aimed to re-evaluate these variants systematically according to the American college of medical genetics and genomics and the association for molecular pathology (ACMG-AMP) guidelines. In our study, APP, PSEN1, and PSEN2 variants were collected by searching Alzforum and PubMed database with keywords “PSEN1,” “PSEN2,” and “APP.” These variants were re-evaluated based on the ACMG-AMP guidelines. We compared the number of pathogenic/likely pathogenic variants of APP, PSEN1, and PSEN2. In total, 66 APP variants, 323 PSEN1 variants, and 63 PSEN2 variants were re-evaluated in our study. 94.91% of previously reported pathogenic variants were re-classified as pathogenic/likely pathogenic variants, while 5.09% of them were variants of uncertain significance (VUS). PSEN1 carried the most prevalent pathogenic/likely pathogenic variants, followed by APP and PSEN2. Significant statistically difference was identified among these three genes when comparing the number of pathogenic/likely pathogenic variants (P < 2.2 × 10–16). Most of the previously reported pathogenic variants were re-classified as pathogenic/likely pathogenic variants while the others were re-evaluated as VUS, highlighting the importance of interpreting APP, PSEN1, and PSEN2 variants with caution according to ACMG-AMP guidelines.

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  • PSEN1 mutations disrupt γ-secretase assembly and function, skewing APP cleavage toward longer, aggregation-prone Aβ42 fragments.

    “These mutations disrupt γ-secretase assembly and function, skewing APP cleavage toward longer, aggregation-prone Aβ42 fragments [148, 149].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [149]

    The Introduction (page not provided) says PSEN1 is a γ-secretase subunit and associates presenilins with an increased Aβ42-to-Aβ40 ratio. The Discussion (page not provided) links PSEN1 to γ-secretase activity and APP processing. Neither passage says PSEN1 mutations disrupt γ-secretase assembly or describes Aβ42 as longer and aggregation-prone. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Xiao, X., Liu, H., Liu, X., Zhang, W., Zhang, S., & Jiao, B.
Affiliations
Central South University (CN)
Corresponding author
Jiao, Bin
ORCID
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2021-06-18
Volume
13
Pages
695808-695808
ISSN
1663-4365 (ISSN-L)
DOI
10.3389/fnagi.2021.695808
PMC
PMC8249733
OpenAlex
W3173990459
Cited by
99
References
6
Citations by year
2026: 19 · 2025: 26 · 2024: 25 · 2023: 16 · 2022: 12 · 2021: 1
FWCI
8.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (2020YFC2008500, 82071216)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, APP gene, presenilin 1, presenilin 2, genetic variants, ACMG/AMP guidelines, variant reclassification, pathogenic variants, variants of uncertain significance

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