Discovery and validation of autosomal dominant Alzheimer's disease mutations

Alzheimer's Research & Therapy
Simon HsuCeleste M Karch

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379_382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes.

References

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Citations

Feb 13, 2019·International Journal of Molecular Sciences·Maria CondelloStefania Meschini
Jul 27, 2018·Alzheimer's Research & Therapy·Celeste M KarchAlison M Goate
Sep 29, 2019·International Journal of Molecular Sciences·Vo Van GiauSangYun Kim
Feb 23, 2020·Neurobiology of Disease·Simon HsuCeleste M Karch
Sep 4, 2020·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Longfei JiaJianping Jia

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Methods Mentioned

BETA
exome sequencing
transfections
enzyme-linked immunosorbent assay
transfection
ELISA

Software Mentioned

Sequencher
PolyPhen SIFT
PolyPhen
ExAC browser

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