An Exploration of the Relationship Between Genetic Variants Associated with Alzheimer’s Disease and Measurements of Cognitive Processes Over Time

Abstract

Late-onset Alzheimer’s Disease (LOAD) has been associated with more than twenty genetic susceptibility loci, to date. The present analysis builds on the work of the Alzheimer’s Disease Genetics Consortium (ADGC), the Alzheimer’s Disease Research Centers (ADRCs), and the National Alzheimer’s Coordinating Center (NACC) by attempting to determine whether two of those loci, MS4A6A and BIN1, are associated with rate of symptom progression. Participants who had visited the clinic at least five times and who were classified as either cases or as having mild cognitive impairment (MCI) were stratified by the presence or absence of APOE E4 alleles and by their cognitive status at their initial clinic visit. Six clinical outcomes, including 1) rate of change from visit to visit of the sum of boxes of the CDR® Dementia Staging Instrument, 2) rate of change from visit to visit of scores on the Mini-Mental State Examination (MMSE), 3) mode of onset of behavioral symptoms, 4) mode of onset of cognitive symptoms, 5) mode of onset of motor symptoms, and 6) overall course of decline were regressed on genetic variants within MS4A6A and BIN1, using genetic data stored in the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS). Four of the five variants within MS4A6A were significantly associated with rate of change of MMSE score for individuals with normal initial cognition and no APOE E4 alleles. Although a few other models did achieve significance at an alpha level of 0.05, the number of significant results is no higher than what would be expected simply from random chance. Therefore, it can be tentatively concluded that there is a relationship between MS4A6A and rate of change in MMSE scores.