Analysis of the LRRK2 G2019S mutation in Alzheimer Disease.

Comment. Possessing an APOE ε4 allele is the most important genetic risk factor yet identified for sporadic AD and also significantly lowers onset age. It is therefore striking that despite their young age at onset, only 2 of our 10 biparietal patients were ε4-positive. While we believe that a lack of association between biparietal AD (or posterior cortical atrophy AD) and APOE ε4 genotype has not previously been reported, this observation is supported by supplementary online data from 1 study where only 1 of 6 patients with posterior cortical atrophy (mean age at onset, 58.5 years) with pathologically confirmed AD possessed an ε4 allele. We suggest that in biparietal AD, at least in part mediated by lack of APOE ε4, the pathological process is directed away from medial temporal structures and toward the parietal lobes. In support of this, decreased hippocampal pathologic abnormality has been reported in posterior cortical atrophy compared with typical AD and increased hippocampal atrophy in AD has been shown to be related to APOE ε4 dose. Other, as yet undetermined factors are likely to be responsible for early initiation of the pathological cascade in this distinctive phenotypic variant. This finding, if replicated in larger studies, may have implications for our understanding of the pathogenesis of AD and factors influencing the regional predilection of this and other neurodegenerative diseases. It may be important to consider biparietal and other AD variants separately in studies seeking genetic associations in AD.