Document Type
Journal Article
Publication Title
Alzheimer's Research and Therapy
Volume
15
Issue
1
PubMed ID
36978190
Publisher
Springer
School
Centre for Precision Health
RAS ID
55077
Funders
National Institutes of Health (NIH), United States [grant number RF1-AG059869], U19-AG033655, P01-AG026276, RF1-AG027161, P30-AG066507, R01-AG030153, R01-AG070953, P30-AG066444, P01-AG003991, P01-AG026276, U19-AG032438, U19-AG024904, R01-AG044546, P01-AG003991, RF1-AG053303, RF1-AG058501, U01-AG058922
Australian Commonwealth Scientific Industrial Research Organization (CSIRO)
Abstract
Background:
Both Alzheimer’s disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition.
Methods:
Analyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function.
Results:
In mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRSAPOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRSw/oAPOE) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition.
Conclusions:
These results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics.
DOI
10.1186/s13195-023-01206-9
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Comments
Pettigrew, C., Nazarovs, J., Soldan, A., Singh, V., Wang, J., Hohman, T., ... & Albert, M. (2023). Alzheimer’s disease genetic risk and cognitive reserve in relationship to long-term cognitive trajectories among cognitively normal individuals. Alzheimer's Research & Therapy, 15, Article 66.
https://doi.org/10.1186/s13195-023-01206-9