Dementia constitutes an important social, health, and economic problem. Twenty five percent of people over age 55 have a family history of dementia. In 2016, it affected 46.8 million people worldwide. With an exponential growth, this number is estimated to reach 131.5 million by 2050 (World Alzheimer Report 2016).
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 (age <65 years). In these cases, transmission is autosomal dominant and is caused by pathogenic variants in genes PSEN1 (30%-70%), PSEN2 (<5%), and APP (10%-15%) (Loy et al., 2014). Allele 4 of the APOE gene represents a risk factor for AD (OR=2-3 in heterozygosis, OR=14.9 in homozygosis; Farrer et al., 1997),
although the presence of the allele 4 of APOE is not necessary or sufficient to develop disease. Therefore, although genotyping of APOE can be clinically useful to support diagnosis in the context of other data suggesting AD, particularly in late-onset forms (age >65), its use is not indicated in asymptomatic individuals.
Between 5% and 15% of pre-senile dementia cases (<65 years) are frontotemporal type, with a prevalence of 10-15/100 000 in the age group between 45 and 65 years. 25%-50% of patients with frontotemporal dementia have a family history of dementia or psychiatric disease, and 10%-30% are compatible with an autosomal dominant inheritance pattern (Rohrer et al., 2009). Pathogenic variants in C9orf72, GRN, and MAPT are involved in 80% of families with autosomal dominant forms. A single genetic alteration in the C9orf72 gene has been identified, consisting in a GGGGCC hexanucleotide expansion, not detectable by next-generation-sequencing.