Genetic Risk for Alzheimer's Disease Moderates the Association Between Medial Temporal Lobe Volume and Episodic Memory Performance Among Older Adults

Background: A complex set of interactions between biological, genetic, and environmental factors likely underlies thedevelopment of Alzheimer's disease (AD). Identifying which of these factors is most associated with AD is important for early diagnosis and treatment. Objective: We sought to examine genetic risk and structural brain volume on episodic memory in a sample of older adults ranging from cognitively normal to those diagnosed with AD. Methods: 686 adults (55-91 years old) completed a 3T MRI scan, baseline cognitive assessments, and biospecimen collection through the Alzheimer's Disease Neuroimaging Initiative. Hierarchical linear regression analyses examined main and interaction effects of medial temporal lobe (MTL) volume and polygenic hazard score (PHS), indicating genetic risk for AD, on a validated episodic memory composite score. Results: Genetic risk moderated the relationship between MTL volume and memory, such that individuals with high PHS and lower hippocampal and entorhinal volume had lower memory composite scores [Delta F (1,677) = 4.057, p = 0.044, Delta R-2 = 0.002]. Further analyses showed this effect was driven by the left hippocampus [Delta F(1,677) = 5.256, p = 0.022, Delta R-2 = 0.003] and right entorhinal cortex [Delta F (1,677) = 6.078, p = 0.014, Delta R-2 = 0.003]. Conclusions: Among those with high genetic risk for AD, lower volume was associated with poorer memory. Results suggest that the interaction between AD genetic risk and MTL volume increases the likelihood for memory impairment among older adults. Results from this study suggest that genetic risk and brain volume should be considered key factors in tracking cognitive decline.