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

Abstract

Background: A complex set of interactions between biological, genetic, and environmental factors likely underlies the development 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 [ F (1,677) = 4.057, p = 0.044, R 2 = 0.002]. Further analyses showed this effect was driven by the left hippocampus [ F(1,677) = 5.256, p = 0.022, R 2 = 0.003] and right entorhinal cortex [ F (1,677) = 6.078, p = 0.014, 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.

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

“…Whereas our moderation analysis results are consistent with those previously found for PHS ( Prieto et al, 2020 ), our meditational analyses reported novel findings. Mediation models in cognitive neurogenetic research provide a useful framework for directional hypotheses, which are generally appropriate for cognitive neurogenetics because effects generally transmit from genes to brain and cognition, rather than vice versa.…”

“…The predictive capabilities of PHS may have contributed to our finding of genetics moderating the relationship between the right fimbria/hippocampus VR and episodic memory. Similar findings were observed in a prior study in old adults ( Prieto et al, 2020 ) that the PHS moderated episodic memory through the left hippocampus in the MCI group.…”

“…We observed no main effect of PHS status but prominent interaction between PHS and disease status (NC, MCI, and AD) in the right fimbria. This finding, although counter-intuitive, is supported by the previous work suggesting that brain injury in AD results from interactions between disease status and PHS ( Prieto et al, 2020 ). We confirmed that the effect of genetic risks for AD on the hippocampus was driven by disease status (e.g., the clinical symptoms).…”

“…Finally, in AD, APOE, which asserted different effects on episodic memory, was associated with different compensatory recruitment processes in the hippocampus. A recent study revealed that PHS moderated the relationship between the medial temporal lobe (MTL) volume and episodic memory in older AD adults ( Prieto et al, 2020 ). However, it is unknown whether PHS has similar effects on the association of hippocampal subfield volumes with episodic memory across the AD continuum.…”