An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults

Background: The UNC5C rs3846455(G) allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele's effect on hippocampal neurodegeneration needs to be examined. Objective: To further validate the association between rs3846455(G) and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455(G) predicts accelerated hippocampal volume loss in older adults. Methods: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n = 174). Linear mixed effect models were used to examine the effect of rs3846455(G) on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-beta (A beta) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455(G) and greater PACC decline through a mediation analysis. Results: rs3846455(G) was associated with greater PACC decline (beta = -0.087/year, 95% CI -0.169 to -0.005, p = 0.039) after controlling for baseline A beta. Further, rs3846455(G) predicted accelerated hippocampal atrophy after controlling for baseline A beta (beta = -57.3 mm(3)/year, 95% CI -102.8 to -11.9, p = 0.014). The association between rs3846455(G) and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = -0.014, 95% CI -0.032 to -6.0 x 10(-4), p = 0.039). Conclusion: UNC5C rs3846455(G) predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults.