Abstract
OBJECTIVES: We investigated tau and neurodegeneration patterns and clinical phenotypes in carriers of a specific pathogenic variant in the PSEN1 gene and 1 nonaffected relative. METHODS: We included 3 symptomatic carriers of the c.436 A>C, p.Met146Leu, NM_000021.4, rs63750306 variant in the PSEN1 gene, pathogenic for autosomal dominant Alzheimer disease (AD), 1 asymptomatic carrier of the same variant, and 1 noncarrier, all belonging to the same "N" family. All subjects underwent clinical evaluations, (18)F-flortaucipir-PET, and MRI. (18)F-fludeoxyglucose-PET was available for 3 cases. RESULTS: All symptomatic carriers showed advanced AD tau patterns. Symptomatic female carriers presented an earlier age at onset and more pronounced tau pathology in temporoparietal and frontal regions than male carriers, at comparable disease severity and duration. The presymptomatic male carrier showed a negative tau scan 4 years before symptom onset. MRI showed no severe cortical and hippocampal atrophy in all individuals. Brain metabolism showed neurodegeneration patterns typical of AD in symptomatic carriers. DISCUSSION: In PSEN1 Met146Leu variant carriers, high cortical tau load, without significant atrophy, was present during early memory deficits. In the asymptomatic phase, all biomarkers were negative. More pronounced tau pathology in female than male individuals highlights the need to investigate sex differences in autosomal dominant AD.