We aimed to delineate a clinicopathological phenotype of patients carrying the presenilin 1 (PSEN1) missense mutation p.Cys263Phe, and to compare genotype–phenotype data of Alzheimer’s disease (AD) patients carrying other causal gene mutations i.e. PSEN1 (n=25), Presenilin 2 (n=1), and Amyloid Precursor Proteine (n=5).

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

Mean age at onset of all 14 PSEN1 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. Three carriers first presented with mild cognitive impairment, with conversion to AD dementia after an average disease duration of 5.0 ± 2.0 years. Amnestic presentation was present in all carriers, however three patients also showed important frontal symptoms. Neuroimaging displayed diffuse (sub)cortical atrophy, with evident hippocampal atrophy in three carriers (33%). Severe signs of small vessel disease were seen in four patients (44%). Cerebral fluid AD biomarkers of six carriers were characteristic for AD. 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) (P = 0.037) or other causal gene mutation carriers (51.1 years) (P = 0.010).

PSEN1 p.Cys263Phe carriers present with early-onset AD and an autosomal dominant co-segregation pattern. Severe levels of AD neuropathological changes were seen with extensive levels of CAA. In comparison to other causal gene mutation carriers, onset age was higher.