Featured Article Genetic interaction of PICALM and APOE is associated with brain atrophy and cognitive impairment in Alzheimer's disease

Background: Evidence has emerged indicating that the e4 allele of APOE and PICALM interact in conferring risk of Alzheimer’s disease (AD). The biologic basis of this interaction is unclear, but it is likely to have phenotypic relevance and contribute to the structural and clinical heterogeneity of AD. Methods: The aim of this study was to investigate interaction effects of the APOE e4 allele and the alleles at the single-nucleotide polymorphism rs3851179 located in the PICALM locus. We analyzed brain volumes and cognitive phenotypes of 165 patients with early AD dementia. Results: There was a synergistic adverse effect of homozygosity for the PICALM risk allele G in rs3851179 and APOE e4 onvolume in prefrontal and performance on the Trail Making Test A, which is sensitive to processing speed and working memory function. Conclusions: The data suggest a neural mechanism forAPOE–PICALM interactions in patients with manifest ADand indicate that thePICALMgenotypemodulates both brainatrophyand cognitiveperformance in APOE e4 carriers. 2014 The Alzheimer’s Association. All rights reserved.