Rare Coding Mutations Associated with Alzheimer’s Disease

Alzheimer disease (AD) is the most common type of dementia and affects an estimated 5.7 million individuals in the USA, with the number projected to rise to 14 million by 2050.

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.


A team of scientists collaborating with Boston University School of Medicine (Boston, MA, USA) performed whole-exome sequencing (WES) on DNA samples obtained from participants of non-Hispanic European ancestry (EA) and a group of Caribbean Hispanic individuals that was deemed too small for inclusion in this study. A total of 5,617 participants with AD met National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association criteria for possible, probable, or definite AD after clinical and/or neuropathological examination and 4,594 controls were cognitively normal.

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. To extend and enhance the discovery of novel associations, the team evaluated WES data obtained from 19 AD-affected first- or second-cousin pairs identified in the Utah Population Database belonging to a pedigree with a statistical excess of AD risk. Only variants that overlapped the target regions captured by kits by Illumina and Nimblegen used by the three sequencing centers were included.

The scientists reported that among 5,617 participants with AD, 57.0% were women; mean age, 76.4 ± 9.3 years and 4,594 controls, 59.0% were women; mean 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 one participant with AD and one 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 (2,314 versus 3,354 cumulative variants, respectively).

The authors concluded that 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. The study was published on March 29, 2019, in the journal JAMA Network Open.

Related Links:
Boston University School of Medicine