Clinical phenotype of the A431E mutation in PSEN1 arising as a founder effect from the Mexican State of Jalisco

Background

Autosomal dominant Alzheimer’s disease (ADAD) is a rare subtype of AD in which the disease is caused by mutations in the PSEN1, APP, or PSEN2 genes which are essentially fully penetrant. Mutations in PSEN1 are most common and several populations have been described within which the same causative variant appears to have arisen from a common founder. The study of such populations allows for an increased sensitivity for identification of genetic and non‐genetic variables affecting phenotype and for studying the effects of interventions.

Methods

We summarize 20 years of work characterizing the population with ADAD due to the A431E mutation in PSEN1.

Results

Nine families with 60 members with ADAD due to the A431E PSEN1 mutation were originally reported by investigators in Mexico City in 2006 (Yescas et al). They noted a mean age of onset of 40 years and 1 of 13 probands had spastic paraparesis (SP). All probands hailed from the Los Altos region of Jalisco State and all affected persons shared the same CA and GT dinucleotide microsatellite alleles surrounding the PSEN1 gene, suggesting a common origin of the haplotype. U.S. Investigators then reported an additional 15 families with the A431E variant. Mean age of onset was 39.5 years and 9/20 probands (45%) had SP. In 2020 Dumois‐Petersen et al, reported their experience of 46 index patients in Guadalajara from families in which 560 persons were identified to be at 50% risk of inheriting the mutation. Mean age of onset of 42.5 years with at least a moderate degree of leg spasticity being present in 77% in the first 2 years of symptoms. Memory loss was ubiquitous with language deficits ultimately being present in 82%, depression in 53%, delusions in 30%, Parkinsonism in 28%, cerebellar dysfunction in 23%, and seizures in 15%.

Conclusions

Combined efforts in the U.S. and Mexico have allowed the identification of more than 100 superficially distinct families with the A431E PSEN1 mutation and an estimated number of 1,260 identifiable at‐risk persons, providing an attractive target for both mutation‐specific genetic interventions and for anti‐AD therapy in general.

P30AG066530, U01AG051218, R01AG062007, R01AG069013