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OBJECTIVE: To determine whether common genetic variants in , a recently identified late-onset Alzheimer disease (LOAD) dementia susceptibility gene, are associated with AD susceptibility or AD-related clinical/pathologic phenotypes.

METHODS: We used data from deceased individuals of European descent who participated in the Religious Orders Study or the Rush Memory and Aging Project (n = 1,288). We examined whether there were associations between single nucleotide polymorphisms (SNPs) within ±100 kb of the gene and a diagnosis of AD dementia, global cognitive decline, a pathologic diagnosis of AD, β-amyloid load, neuritic plaque count, diffuse plaque count, paired helical filament tau density, neurofibrillary tangle count, and cerebral amyloid angiopathy (CAA) score. We also evaluated the relation of the CAA-associated variant and dorsolateral prefrontal cortex (DLPFC) RNA expression. Secondary analyses were performed to examine the interaction of the CAA-associated SNP and known genetic risk factors of CAA as well as the association of the SNP with other cerebrovascular pathologies.

RESULTS: A set of SNPs tagged by rs28660566 was associated with a higher CAA score ( = 2.3 × 10): each additional rs28660566 allele was associated with a 0.60 point higher CAA score, which is equivalent to approximately 75% of the higher CAA score associated with each allele of ε4. rs28660566 was weakly associated with lower expression in the human DLPFC ( = 0.036). Moreover, rs28660566 had a synergistic interaction with ε4 on their association with higher CAA severity ( = 0.027) and was associated with more severe arteriolosclerosis ( = 0.0065).

CONCLUSIONS: Targeted analysis of the region uncovered a set of SNPs associated with CAA.