PICALM and CLU are two major risk genes of late-onset Alzheimer's disease (LOAD), and there is strong molecular evidence suggesting their interaction on amyloid-beta deposition, hence finding functional dependency between their risk genotypes may lead to better understanding of their roles in LOAD development and greater clinical utility. In this study, we mainly investigated interaction effects of risk loci PICALM rs3581179 and CLU rs11136000 on hippocampal degeneration in both young and elderly adults in order to understand their neural mechanism on aging process, which may help identify robust biomarkers for early diagnosis and intervention. Besides volume we also assessed hippocampal shape phenotypes derived from diffeomorphic metric mapping and nonlinear dimensionality reduction. In elderly individuals (75.6 ± 6.7 years) significant interaction effects existed on hippocampal volume (P < 0.001), whereas in young healthy adults (19.4 ± 1.1 years) such effects existed on a shape phenotype (P = 0.01) indicating significant variation at hippocampal head and tail that mirror most AD vulnerable regions. Voxel-wise analysis also pointed to the same regions but lacked statistical power. In both cohorts, PICALM protective genotype AA only exhibited protective effects on hippocampal degeneration and cognitive performance when combined with CLU protective T allele, but adverse effects with CLU risk CC. This study revealed novel PICALM and CLU interaction effects on hippocampal degeneration along aging, and validated effectiveness of diffeomorphometry in imaging genetics study. Hum Brain Mapp 37:2419–2430, 2016. © 2016 Wiley Periodicals, Inc.