Alzheimer’s disease (AD) is the most common type of primary neurodegenerative dementia (60-80% of cases). Approximately 25% of patients with AD have two or more affected relatives. Among familial forms, only 5% have an early onset (<65 years of age). In these cases, the inheritance is autosomal dominant and is caused by pathogenic variants in the PSEN1 (30-70%), PSEN2 (<5%), and APP (10-15%) genes (Loy et al., 2014). The ℇ4 allele of the APOE gene represents a risk factor for AD (OR=2-3 in heterozygosity, OR=14,9 in homozygosity; Farrer et al., 1997), although the presence of the ℇ4 allele in APOE is not necessary or sufficient to produce the disease. Thus, although APOE genotyping may have some clinical use for supporting AD diagnosis, particularly in late-onset forms (>65 years), its use is not indicated in asymptomatic individuals.
Between 5% and 15% of presenile dementias (<65 years) are of the frontotemporal type, with a prevalence of 10-15 per 100,000 in the 45-65 years group. Between 25% and 50% of patients with frontotemporal dementia present previous familial cases of dementia or psychiatric disease, and between 10% and 30% are consistent with an autosomal dominant inheritance pattern (Rohrer et al., 2009). Pathogenic variants in C9orf72, GRN, and MAPT are involved in 80% of these autosomal dominant forms. In the case of C9orf72, a single genetic alteration associated with amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia has been detected, consisting of a (GGGGCC) hexanucleotide expansion not detectable by NGS.
