Polygenic hazard score modified the relationship between hippocampal subfield atrophy and episodic memory in older adults

Abstract

Understanding genetic influences on Alzheimer's disease (AD) may improve early identification. Polygenic hazard score (PHS) is associated with the age of AD onset and cognitive decline. It interacts with other risk factors, but the nature of such combined effects remains poorly understood. We examined the effect of genetic risk and hippocampal atrophy pattern on episodic memory in a sample of older adults ranging from cognitively normal to those diagnosed with AD using structural MRI. Participants included 51 memory unimpaired normal control (NC), 69 mild cognitive impairment (MCI), and 43 AD adults enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Hierarchical linear regression analyses examined the main and interaction effects of hippocampal subfield volumes and PHS, indicating genetic risk for AD, on a validated episodic memory composite score. Diagnosis-stratified models further assessed the role of PHS. Polygenic hazard score moderated the relationship between right fimbria/hippocampus volume ratio and episodic memory, such that patients with high PHS and lower volume ratio had lower episodic memory composite scores [ΔF = 6.730, p = 0.011, ΔR 2 = 0.059]. This effect was also found among individuals with MCI [ΔF = 4.519, p = 0.038, ΔR 2 = 0.050]. In contrast, no interaction effects were present for those NC or AD individuals. A follow-up mediation analysis also indicated that the right fimbria/hippocampus volume ratio might mediate the link between PHS and episodic memory performance in the MCI group, whereas no mediation effects were present for those NC or AD individuals. These findings suggest that the interaction between AD genetic risk and hippocampal subfield volume ratio increases memory impairment among older adults. Also, the results highlighted a potential pathway in which genetic risk affects memory by degrading hippocampal subfield volume ratio in cognitive decline subjects.