Next Generation Sequencing Analysis in Early Onset Dementia Patients

Abstract

Background: Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. Objective: To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E ( APOE ) and prion protein ( PRNP ) genes were also assessed. Methods: We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping. Results: We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN , VCP , MAPT , FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants ( APOE and PRNP ), and one did not show any risk mutation/variant. Overall, 69% ( n = 9) of our early onset Alzheimer’s disease (EAOD) patients, compared with 34% ( n = 13) of sporadic late onset Alzheimer’s disease (LOAD) patients and 27% ( n = 73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations. Conclusion: This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD.

Mutation Analysis of the Genes Linked to Early Onset Alzheimer’s Disease and Frontotemporal Lobar Degeneration

“…The carrier of the TREM2 p.Arg62His variant had also APOE genotype E3/E4. TREM2 p.Arg62His has been reported as a possible risk factor for LOAD (OR 0.8-2.3) [34] and it has also been found in a few EOAD cases [12]. The interaction of the APOE4 allele and TREM2 has been suggested to accelerate the development of neurodegeneration [35].…”

“…Recent genome-wide association studies (GWAS) and next generation sequencing studies (NGS) have so far identified over 20 other AD risk genes and genetic loci [11]. The genetic risk factors identified for LOAD have been suggested to modulate the risk for EOAD as well [12,13]. Previous NGS studies have shown that EOD patients are more often associated with multiple rare variants or risk alleles than LOAD patients or healthy controls [12].…”

“…The genetic risk factors identified for LOAD have been suggested to modulate the risk for EOAD as well [12,13]. Previous NGS studies have shown that EOD patients are more often associated with multiple rare variants or risk alleles than LOAD patients or healthy controls [12].…”

Association Between Cytomegalovirus Disease and Dementia: A Population-Based Cohort Study

“…Moreover, the APOE ε4 allele was associated with new-onset AD or a decline in cognition in the earlier clinical stages [38][39][40][41]. However, this study had some strengths.…”

Activate or Inhibit? Implications of Autophagy Modulation as a Therapeutic Strategy for Alzheimer’s Disease

“…There have been no reports of an association of OPTN or UBQLN2 variants with AD. However, a recent study identified a variant of unknown significance in VCP in an EOAD patient [82]. Transcript analysis from the cerebellum and temporal cortex of AD patients highlighted that an OPTN single nucleotide polymorphism previously associated with Paget's disease of bone was linked with increased OPTN expression [83].…”