Aims

In a cohort of Flanders Belgian Alzheimer’s disease (AD) patients, we identified 11 unrelated index patients carrying the presenilin 1 (PSEN1) missense mutation, p.Cys263Phe, plus three affected relatives of family DR1633 (n=14). We aimed to delineate a clinicopathological phenotype, and next compared this to genotype–phenotype data of AD patients carrying other causal gene mutations i.e. PSEN1 (n=25), PSEN2 (n=1), and APP (n=5).

Methods

Reviewing medical records of mutation carriers to obtain clinicopathological data for defining genotype-phenotype data.

Results

Mean onset age of the PSEN1 p.Cys263Phe carriers was 62.3±4.5 years (range 53-69), with a disease duration of 9.0±4.0 years (range 4-13). We observed a positive familial history in 90% of carriers and in family DR1633 co-segregation of AD was found with an autosomal dominant inheritance pattern. Amnestic presentation was present in all carriers, however, three patients also showed important frontal symptoms. Neuroimaging (n=10) displayed diffuse (sub)cortical atrophy, with evident hippocampal atrophy in three carriers. We observed severe signs of small vessel disease in four patients. Cerebrospinal fluid AD biomarkers were characteristic of AD in all. Neuropathology in two patients demonstrated severe levels of AD hallmarks plus cerebral amyloid angiopathy (CAA).

Carriers of PSEN1 p.Cys263Phe mutation had a later age at onset (62.3 years) than other PSEN1 carriers (50.8 years) or other causal gene mutation carriers (51.1 years).

Conclusions

PSEN1 p.Cys263Phe carriers presented with early-onset AD. Severe levels of AD neuropathology were seen with high levels of CAA. Disease onset of PSEN1 p.Cys263Phe carriers was later than other causal gene mutation carriers.