Genotype-phenotype of PSEN1 p.CYS263PHE carriers in Flanders-Belgian Alzheimer's disease patients.

Abstract

We identified 13 unrelated index patients carrying the presenilin 1 (PSEN1) missense mutation, p.Cys263Phe in a Flanders-Belgian cohort of Alzheimer's disease (AD) patients. Seven affected relatives in three different families also carried the PSEN1 p.Cys263Phe mutation (n=20). We aimed to delineate a clinicopathological phenotype of p.Cys263Phe carriers. We compared the p.Cys263Phe genotype-phenotype with that of AD patients carrying autosomal dominant mutations i.e. PSEN1 (n=29), PSEN2 (n=1), and APP (n=5). Reviewing of medical records of autosomal dominant mutation carriers to obtain clinical and pathological data for defining genotype-phenotype data. Mean onset age of the p.Cys263Phe carriers is 63.9±5.5 years (range 53-79), with a disease duration of 7.0±3.5 years (range 4-13). APOE genotypes have no significant effects on onset age. A positive familial history is present in 92.9% of the carriers. Segregation with disease is present in two families with autosomal dominant inheritance of AD (figure 1). In all carriers the clinical presentation is predominantly amnestic, although 35.7% (5/14) of the patients also show significant frontal symptoms. Structural neuroimaging displays diffuse (sub)cortical atrophy with evident hippocampal atrophy in 26.7% (4/15) of the carriers. In 40.0% (6/15) of the patients we observe severe signs of small vessel disease. Brain perfusion SPECT or fluorodeoxyglucose PET imaging shows bilateral temporoparietal involvement in 57.1% (4/7) of carriers. Cerebrospinal fluid AD biomarkers were analyzed in eight carriers, and all are characteristic for AD. Neuropathological examination in three carriers shows severe levels of hallmark AD lesions combined with pronounced cerebral amyloid angiopathy (CAA) and multiple intracerebral hemorrhages in one patient. Carriers of p.Cys263Phe have a later age at onset (63.9 years) compared to PSEN1 carriers (50.9 years) and other PSEN1, PSEN2 and APP mutation carriers (51.4 years) (figure 2). PSEN1 p.Cys263Phe carriers present with early-onset familial AD with autosomal dominant co-segregation. Important is that frontal symptoms are seen in 35.7% of the carrier while neuropathological examination reveals severe levels of AD neuropathology with prominent presence of CAA. The disease onset of PSEN1 p.Cys263Phe carriers is later in comparison with other autosomal dominant gene mutation carriers.