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

Abstract

Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of lateonset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

Screening exons 16 and 17 of the amyloid precursor protein gene in sporadic early-onset Alzheimer's disease

“…Nicolas et al (Nicolas et al ., 2015) screened 264 EOAD samples and found three samples (1%) heterozygous for one of three PSEN1 variants that are possibly or probably pathogenic; they also found one sample (0.4%) heterozygous for a causative PSEN2 mutation. None of the patients in this study harboured APP mutations.…”

TYROBP genetic variants in early-onset Alzheimer's disease

“…We studied 111 EOAD patients without mutations in the known AD genes and 292 healthy individuals from the Knight ADRC at Washington University by Sanger sequencing and we assessed exome sequencing data available on 484 French EOAD patients and 498 French controls without mutation in the known AD genes. Interestingly, we identified and confirmed by Sanger sequencing two rare coding variants in three unrelated French patients (Nicolas, et al, 2015), whereas no rare coding variants were detected in controls (n=595 EOAD patients and n=790 healthy subjects, Table 3, Supplementary Table 3). When combining these results, we observed a significant association between rare coding variants and EOAD: 6 rare coding TYROBP variants were identified in 9 unrelated patients out of 1110 white non-Hispanic EOAD patients as compared to an absence of such variants in 1826 healthy subjects (p-value=0.0001; CMC test).…”

Controlled population-based comparative study of USA and international adult [55-74] neurological deaths 1989-2014

“…Moreover, compared with the earlier analyses between 1989 and 2010 where there were notable rises in males in six countries and in four countries for females, by 2014 there had been rises of equivalent to >10% in twelve countries for men and in eleven countries for females. A Gompertzian perspective also ignores rises in early onset dementia (EOD) reported in many countries 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 19, 20, 22, 25. For example, one found 29% of their cohort were aged under 65 years, which 30 years before would have been considered extraordinary 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 19, 20, 22, 25.…”

“…This is not to discount studies that identified genetic and familial patterns20, 21, 22 but others recognize lifestyle and possible interactive environmental contributions 2, 4, 6, 7, 8, 25. Including such factors as occupation, heavy metals, petro‐chemicals, organophosphate/pesticides26, 27, 28, 29, 30 and possible influence of electromagnetic field (EMF)18, 25, 31 and military service 32.…”

“…Moreover, the Gompertzian position appears to have ignored the marked changes between the sexes and in different countries 1, 5, 6, 7, 8, 9, 10, 11. Crucially, the Gompertzian hypothesis does not account for the substantial rise in early onset dementia reported in many Western countries 12, 13, 18, 19, 20, 21, 22…”