In addition, a heterozygous p.Arg71Trp mutation in PSEN2 with an uncertain pathogenic nature was identified in a patient with neuropathologically confirmed AD.
Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD).
A subset of early-onset Alzheimer's disease is inherited as an autosomal-dominant trait and is associated with mutations in the genes encoding β-amyloid precursor protein, presenilin 1, or presenilin 2.
A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP, PSEN1, or PSEN2.
We conducted a comprehensive screening of rare coding variants in an African American cohort to identify novel pathogenic mutations within the early-onset Alzheimer's disease (EOAD) genes (APP, PSEN1, and PSEN2) in this understudied population.
In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset <65 years) and 19 Caribbean Hispanic families previously screened as negative for established APP, PSEN1, and PSEN2 causal variants.
Using a control exome data set of 96 ethnically matched neurodegenerative disease controls (Parkinson's disease), we identified only 1 variant (PSEN2p.T18M) (1%), demonstrating a significantly higher mutational burden in the EOAD group (p > 0.0001).
Mutations in the PSEN1, PSEN2, and APP genes seem to be rare in this population, as these genes exhibited no pathogenic mutations in our cohort of eoAD and FTLD patients even though about 40% of the cases were familial ones.
The families from Fulda, Germany, and the American Volga German families with EOAD share the same N141IPSEN2 mutation on an identical haplotypic background.
Families with early-onset Alzheimer's disease (AD) sharing a single PSEN2 mutation exhibit a wide range of age-at-onset, suggesting that modifier loci segregate within these families.
To our knowledge, this is the first German EOAD patient without a Volga-German ancestry and a positive family history for dementia carries the mutation PSEN-2N141I.
presenilin-2 is one of the causative genes for familial Alzheimer's disease, and the apolipoprotein E epsilon4 allele is a major genetic risk factor for late-onset and sporadic early-onset Alzheimer's disease.
Beta-amyloid mediated nitration of manganese superoxide dismutase: implication for oxidative stress in a APPNLH/NLH X PS-1P264L/P264L double knock-in mouse model of Alzheimer's disease.
The beta-amyloid precursor protein (APP) gene (on chromosome 21), Presenilin 1 (PS1) gene (on chromosome 14) and Presenilin 2 (PS2) gene (on chromosome 1) are responsible for autosomal dominant early-onset Alzheimer's disease (EOAD).