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Alzheimers Res Ther. 2018 Jul 18;10(1):67. doi: 10.1186/s13195-018-0392-9.

Discovery and validation of autosomal dominant Alzheimer's disease mutations.

Author information

1
Department of Psychiatry, Washington University School of Medicine, 425 S. Euclid Ave, Campus Box 8134, St. Louis, MO, 63110, USA.
2
Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
3
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
4
Clinique Interdisciplinaire de Mémoire du CHU de Québec, Département des Sciences Neurologiques, Faculté de Médecine, Université Laval, Québec City, Québec, Canada.
5
Massachusetts General Hospital/Martinos Center for Biomedical Imaging, 149 13th Street, Gerontology Research Room 2669, Charlestown, MA, 02129, USA.
6
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
7
Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
8
Department of Psychiatry, Washington University School of Medicine, 425 S. Euclid Ave, Campus Box 8134, St. Louis, MO, 63110, USA. karchc@wustl.edu.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

APP; Autosomal dominant Alzheimer’s disease; Cell-based assays; PSEN1; PSEN2; Pathogenicity algorithm

PMID:
30021643
PMCID:
PMC6052673
DOI:
10.1186/s13195-018-0392-9
[Indexed for MEDLINE]
Free PMC Article

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