Genetic mutations in specific genes were identified in patients with and without familial history of early-onset Alzheimer’s Disease. Many of these mutations can now be used in genetic counseling.
Alzheimer’s disease (AD) is the most common type of dementia, but only a fraction of these patients have early-onset AD (EOAD). Genetic mutations in the amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes cause hereditary forms of EOAD. These three genes were identified over 20 years ago, but efforts to understand genetic variation in the genes and their role in the severity of EOAD is ongoing.
A paper by Hélène-Marie Lanoiselée and colleagues published in PLOS Medicine presented an update to a previous EOAD genetic screening study. Adding to previous data collected across 28 French hospitals, the current study examined 53 families where at least two first-degree relatives had EOAD at ≤65 years of age in two generations. Additionally, 129 “sporadic” cases of Alzheimer’s disease (where no familial history of EOAD existed previously) were also analyzed. These sporadic cases had an age of onset (AOO) of below age 51 (44% males, mean AOO = 45 ± 2 years). A search for genetic mutations in APP, PSEN1, and PSEN2 genes was conducted using Sanger sequencing of DNA extracted from whole blood. When combined with data from earlier studies, mutations in APP, PSEN1, and PSEN2 were identified in 170 EOAD families. In 18 sporadic cases, mutations in PSEN1 (n= 17) and APP genes (n=1) were found. In 10 sporadic cases, genetic mutations were absent in the parents, indicating a de novo mutation. Of the 90 total distinct mutations detected, 13 were previously unknown.
Investigators now have a better understanding of how approximately 77% of these 90 mutations affect disease severity, making them useful for genetic counseling. Importantly, a considerable number of PSEN1 mutations occur in the absence of familial history of EOAD. Currently, PSEN1 mutation screening is only conducted for patients with familial history of EOAD. Therefore, clinicians should include patients with sporadic EOAD in genetic screening of APP, PSEN1, and PSEN2 genes.
Written By: Cindi A. Hoover, Ph.D.
