Alzheimer’s disease genetic risk and cognitive reserve in relationship to long-term cognitive trajectories among cognitively normal individuals

Authors

Corinne Pettigrew
Jurijs Nazarovs
Anja Soldan
Vikas Singh
Jiangxia Wang
Timothy Hohman
Logan Dumitrescu
Julia Libby
Brian Kunkle
Alden L. Gross
Sterling Johnson
Qiongshi Lu
Corinne Engelman
Colin L. Masters
Paul Maruff
Simon M. Laws, Edith Cowan UniversityFollow
John C. Morris
Jason Hassenstab
Carlos Cruchaga
Susan M. Resnick
Melissa H. Kitner-Triolo
Yang An
Marilyn Albert

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)

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

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-PRS_APOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRS_w/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.