Dementia-related genetic variants in an Italian population of early-onset Alzheimer’s disease

Abstract

Early-onset Alzheimer’s disease (EOAD) is the most common form of early-onset dementia. Although three major genes have been identified as causative, the genetic contribution to the disease remains unsolved in many patients. Recent studies have identified pathogenic variants in genes representing a risk factor for developing Alzheimer’s disease (AD) and in causative genes for other degenerative dementias as responsible for EOAD. To study them further, we investigated a panel of candidate genes in 102 Italian EOAD patients, 45.10% of whom had a positive family history and 21.74% with a strong family history of dementia. We found that 10.78% of patients carried pathogenic or likely pathogenic variants, including a novel variant, in PSEN1, PSEN2, or APP, and 7.84% showed homozygosity for the ε4 APOE allele. Additionally, 7.84% of patients had a moderate risk allele in PSEN1, PSEN2, or TREM2 genes. Besides, we observed that 12.75% of our patients carried only a variant in genes associated with other neurodegenerative diseases. The combination of these variants contributes to explain 46% of cases with a definite familiarity and 32% of sporadic forms. Our results confirm the importance of extensive genetic screening in EOAD for clinical purposes, to select patients for future treatments and to contribute to the definition of overlapping pathogenic mechanisms between AD and other forms of dementia.

The innate immune response in tauopathies

“…Recent GWAS findings, along with exome sequencing, have exposed several variants of TREM2 to be strongly associated with AD diagnosis and increased rates of cognitive decline [142][143][144][145]. Of the known TREM2 variants, the histidine to arginine switch at position 47 (R47H) variant is the one most highly associated with increased AD risk [144,[146][147][148].…”

Recent research advances in young-onset dementia

“…The APOEε4 allele is a risk factor for developing AD in older people but the impact of this allele on younger people remains inconsistent [47]. Next generational sequencing such as specific panels [48,49], whole exome sequencing [50] and whole genome sequencing [51] are being utilized internationally and may increase diagnostic yield in YOD. Sophisticated genetic analysis and machine learning has also identified shared genetic overlap [52 ▪ ], structural neuroimaging and clinical data [53 ▪▪ ] between FTD and schizophrenia, which furthers understanding between overlapping pathophysiology and clinical symptoms.…”