Studies of neuropathologic and immunologic traits integrate the effect of CR1 and CD33 variants on Alzheimer's-related amyloid pathology

The study of intermediate phenotypes provides insights into the causal chain linking risk factors and a syndromic diagnosis of AD. Targeted studies of specific genetic variants explore their functional consequences and repercussions along the causal chain, which we illustrate here with an investigation of the CD33 locus; CD33 is a transmembrane protein which has been implicated as a negative regulator of myeloid cells. CR1 is found on myeloid cells as well, and the CR1 locus has been shown to influence cognitive decline and neuritic plaque accumulation in the brain. One possible mechanism for CR1-mediated amyloid clearance is phagocytosis. Clinical and post-mortem data come two prospective clinical-pathologic cohort studies of aging: the Memory and Aging Project and the Religious Order Study. Each subject is non-demented at the time of entry into the study, undergoes detailed annual clinical evaluation, and a blood draw for DNA and viable lymphocytes for immunologic profiling, and neuropathologic profiles are collected prospectively from each subject. In characterizing the CD33 locus, we found that its risk allele is associated with lower CD33 expression at the RNA level (P = 0.0004) and at the cell-surface of monocytes (P = 0.0001). Further, uptake of amyloid beta 1-42 by monocytes in vitro is reduced in the context of the risk allele (P = 0.003), and there are more activated microglia in the brains of subjects bearing the CD33 risk allele (P = 0.009). These insights into the functional consequences of the CD33 locus led us to assess whether there may be evidence of statistical interaction with the CR1 locus since CR1 mediates recognition of the C1q opsonin for internalization of the target material. We see suggestive evidence (P = 0.01) for the interaction term assessing the roles of CD33 and CR1 on aging-related cognitive decline. Intermediate phenotypes are rapidly emerging as an important component to the investigation of the genetic architecture of AD: we are beginning to map the molecular consequences of these variants and to uncover evidence that functionally link susceptibility loci such as CR1 and CD33.