Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians

Abstract

Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer disease (AD), we hypothesized that C9ORF72 expansions may contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a rate of 0.76% in AD cases versus zero in controls (p=3.3E-03, 1,182 cases, 1,039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0–23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological reevaluation of identified C9ORF72 expansion carriers revealed nine clinical and/or autopsy confirmed AD and two FTD finial diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.

Racial and Ethnic Disparities Among Individuals with Alzheimer’s Disease in the United States: A Literature Review

“…Recently, in a study using a relatively large sample (n = 3,100), the C9ORF72 gene was shown to be associated with AD, frontotemporal dementia, and amyotrophic lateral sclerosis among individuals of European descent, but African Americans in the sample did not have any expansions of the gene (Kohli et al, 2013). However, less than 1 percent of the sample had the genetic marker; thus, the new finding explains only a small proportion of risk differences.…”

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

“…For example, C9ORF72 GGGGCC hexanucleotide repeat expansions (which cannot be detected by sequencing), typically causing frontotemporal dementia -amyotrophic lateral sclerosis spectrum were found in patients with an AD phenotype or Parkinson's disease, but rarely in controls too, making this finding difficult to interpret. 28,29 It remains possible for these late-onset cases that AD pathology occurred independently of C9ORF72 expansions. 30 Similarly, at least one neuropathologically proven AD case was found to harbor a loss-offunction variant of GRN.…”

Emerging role of RNA•DNA hybrids inC9orf72-linked neurodegeneration

“…23,24 The C9orf72 HRE also represents the most common genetic cause of frontotemporal dementia (FTD), which is characterized by degeneration of the frontal and temporal lobes of the brain and is the second most common type of dementia in people younger than 65. 25 Furthermore, the C9orf72 HRE is linked to rare cases of other neurological conditions, including Alzheimer's disease, [26][27][28][29] Huntington's disease, 30 multiple system atrophy, 31 depressive pseudodementia, 32 bipolar disorder, [33][34][35] and schizophrenia. 36 Given these wide-ranging implications, understanding the molecular mechanisms of C9orf72 HRE-associated diseases has become a significant challenge in the study of neurodegeneration.…”