Mutation analysis of sporadic early-onset Alzheimer's disease using the NeuroX array

Abstract

We have screened sporadic early-onset Alzheimer’s disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson’s disease; p.T240M (n = 1) and p.Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p.A469T), which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration.

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

“…LOAD has a heritability estimated to be around 70%, lower than estimates of heritability for EOAD, which vary between 80% and 100% (Barber et al, 2017; Wingo et al, 2012). An estimated 10% of EOAD cases have a familial aspect and are subsequently classified as early-onset familial AD (EOFAD).…”

“…At least 1 APOE ε4 allele was present in 57.6% of cases, with 22.3% of which being homozygotes (n = 58); 22.7% of controls harbored at least 1 ε4 allele, 9 control samples were ε4 homozygotes. These samples are described in greater detail in the article by Barber et al (2017). Full details of the samples used in this study are outlined in Table 1.…”

“…AD can be categorized based on the age of onset, where presentation of symptoms in individuals before the age of 65 years are classified as early-onset Alzheimer’s disease (EOAD), whereas late-onset Alzheimer’s disease (LOAD) classifies individuals with onset over 65 years (Barber et al, 2017; Wingo et al, 2012). LOAD has a heritability estimated to be around 70%, lower than estimates of heritability for EOAD, which vary between 80% and 100% (Barber et al, 2017; Wingo et al, 2012).…”

“…The remaining early-onset cases, classed as sporadic (sEOAD), are thought to be predominantly polygenic. The accumulation of variants which independently increase the risk of LOAD may lead to sEOAD at an earlier stage of life (Barber et al, 2017; Wingo et al, 2012). …”

“…The array is designed to collect genotype information at markers across the entire genome. The HumanExome BeadChip foundation is made up of 242,901 markers, identifying variants in a series of metabolic, cancerous, diabetic, and psychiatric disorders (Barber et al, 2017; Nalls et al, 2015). The custom content includes 24,706 markers from candidate loci associated with neurological diseases such as AD, frontotemporal dementia, Parkinson’s disease, multiple system atrophy, amyotrophic lateral sclerosis, myasthenia gravis, Charcot-Marie-Tooth, and progressive supranuclear palsy (Nalls et al, 2015).…”