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JAMA Netw Open. 2019 Mar 1;2(3):e191350. doi: 10.1001/jamanetworkopen.2019.1350.

Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry.

Author information

Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.
Bioinformatics Graduate Program, Boston University, Boston, Massachusetts.
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts.
Department of Neurology, Columbia University, New York, New York.
Department of Biology, Brigham Young University, Provo, Utah.
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts.
Department of Physiology & Biophysics, Boston University School of Medicine, Boston, Massachusetts.
George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah.
Huntsman Cancer Institute, Salt Lake City, Utah.
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City.
Department of Mathematics and Statistics, Utah State University, Logan.
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Department of Population & Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio.
John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts.
Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts.



Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations.


To identify genetic variants associated with AD risk using a nonstatistical approach.

Design, Setting, and Participants:

Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018.

Main Outcomes and Measures:

Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer's Disease Neuroimaging Initiative.


Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006).

Conclusions and Relevance:

Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets.

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