Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer’s Disease Before 51 Years

Abstract

Background: 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). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. Objective: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. Methods: We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. Results: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p < 0.0001) and associated neurologic symptoms more frequently (p < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. Conclusion:The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages.

Accumulation of Cerebrospinal Fluid Glycerophospholipids and Sphingolipids in Cognitively Healthy Participants With Alzheimer’s Biomarkers Precedes Lipolysis in the Dementia Stage

“…Specific mutations lead inevitably to familial Alzheimer's disease (FAD; Lacour et al, 2019;Wong et al, 2020), and gene polymorphisms are associated with late-onset Alzheimer's disease (AD; Morelli et al, 1996;Casadei et al, 1999;Dursun et al, 2008;Du et al, 2016;Zuin et al, 2020), the most common form of AD. Some risk factors such as age, education, apolipoprotein ε4 (ApoE-4), hypertension, diabetes, hyperlipidemia, obesity, smoking, and head trauma have been identified, but none is necessary or sufficient to cause AD (Devanand et al, 2013;Guimas Almeida et al, 2018;Takahashi et al, 2018).…”

Genetic testing in dementia‐A medical genetics perspective

“…There may still be genes that are yet to be discovered or the genetic test used may be insufficient to pick up all types of mutations. Previous publications using NGS techniques show approximately 12%–13% mutation detection rate in dementia patients with a young age of onset with or without a family history, especially in the PSEN1 gene 5,8 . Analysis of WGS data from a clinical cohort of patients with dementia onset ≤65 years (authors' unpublished data), also showed a 14% chance of finding a causative mutation in those with dementia onset under the age of 65 and a further 20% chance of finding a genetic risk factor for their dementia, with most patients having no cause identified.…”

“…Even in the absence of a reported family history, a very young age of onset (i.e., younger than 51 years) has been shown to result in approximately 12.3% chance of finding a pathogenic mutation, especially in the PSEN1 gene 8–18 . Whilst not all EOD has a genetic basis and not all people with dementia onset over the age of 65 years are ‘non‐genetic’, the chances of finding a clinically meaningful genetic diagnosis remains higher in EOD (especially when combined with a family history), as well as those with a strong Mendelian type of family history regardless of age of onset.…”

“…Mutations in this gene can be associated with onset of AD as early as the late 20s, with most people with pathogenic mutations developing AD before the age of 60 years 45,46 . Although most cases are familial, de novo PSEN1 pathogenic variants have also been found in people with sporadic EOAD, where further testing showed that neither parent had the variant, and therefore, it likely occurred for the first time in the affected individual at conception 8–18,47 …”

Novel PSEN1 and PSEN2 Mutations Identified in Sporadic Early-onset Alzheimer Disease and Posterior Cortical Atrophy

“… 5 However, an increasing number of pathogenic variants in the 3 genes— APP , 6 PSEN1 7 and PSEN2 8 —causative for familial AD have also been identified in sEOAD. 9 Moreover, rare variants in other genes associated with neurodegenerative diseases, such as PARK2 , FUS , and MAPT , have also been associated with sEOAD. 10 Genetic studies on PCA are relatively few and there are only 4 pathogenic mutations ( PSEN1 G223R, PSEN2 M239I, MAPT V363I, and GRN R110X) that have been reported.…”