Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Familial cases suggest genetic components; however, monogenetic causes are few, and the vast majority of incidences have unknown cause. Sequencing efforts have focused on germline mutations, but improved technology has opened up for studies on somatic mutations in affected brain tissue samples. Here we use ultra-deep sequencing on brain and blood from early-onset AD (EOAD) and late-onset AD (LOAD) patients and non-AD individuals (n = 16). In total, 2.86 Mb of genomic regions, previously associated with AD, were targeted included 28 genes and upstream and downstream regulatory regions. Tailored downstream bioinformatics filtering identified 11 somatic single nucleotide variants in the temporal cortex in AD patients and none in the controls. One variant was validated to be present at 0.4% allele frequency in temporal cortex of a LOAD patient. This variant was predicted to affect transcription factor binding sites upstream of the CD55 gene, contributing to AD pathogenesis by affecting the complement system. Our results suggest that future studies targeting larger portions of the genome for somatic mutation analysis are important to obtain an increased understanding for the molecular basis of both EOAD and LOAD.
Highlights
Alzheimer’s disease (AD, OMIM 104300) is a neurodegenerative disorder mainly affecting elderly people and is the main cause for late-onset dementia
Deep sequencing and somatic mutation calling To assess the presence of tissue-specific mutations in the brain, we obtained blood and frozen temporal cortex samples from early-onset AD (n=4) and late-onset AD (n=4) patients, as well as aged- and gender matched non-AD individuals (n=8) (Supplementary Material, Table S1)
We analyzed 0.1% of the human genome that cover regions that previously have been associated with AD and genes that have shown to be mutated in AD
Summary
Alzheimer’s disease (AD, OMIM 104300) is a neurodegenerative disorder mainly affecting elderly people and is the main cause for late-onset dementia. Cognitive functions are affected, causing memory impairment and personality changes. The disease is classified into early-onset AD (onset before age 65 years) and late-onset AD. While the APOE ɛ4 allele is the major genetic attributable risk factor for AD, mutations in the genes APP (Amyloid precursor protein), PSEN1 (Presenilin 1) and PSEN2 (Presenilin 2) are known causes for autosomal dominant early onset AD. Genome wide association studies (GWAS) have reported several variants linked to AD [1], and mosaic loss of chromosome Y in the blood has been associated with the disease [2]. Most AD cases are sporadic with unknown causes
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