Alzheimer’s disease genetic risk and cognitive reserve in relationship to long-term cognitive trajectories among cognitively normal individuals
Year: 2023
Type: article
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: ) 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.
Source: Alzheimer s Research & Therapy
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, John C. Morris, Jason Hassenstab, Carlos Cruchaga, Susan M. Resnick, Melissa H. Kitner-Triolo, Yang An, Marilyn Albert
Institutions: Johns Hopkins University, University of Wisconsin–Madison, Vanderbilt University Medical Center, University of Miami, The University of Melbourne, Florey Institute of Neuroscience and Mental Health, Edith Cowan University, Curtin University, Washington University in St. Louis, National Institute on Aging
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,690
Awards: G1007389970, G1602390028, G1648032802, G2880069213, G2957681590, USING QUANTITATIVE TRAITS TO IDENTIFY NOVEL GENES FOR ALZHEIMERS DISEASE AND OTHER COMPLEX TRAITS, G4427631003, Biomarkers of Cognitive Decline Among Normal Individuals: The Biocard Cohort, G5105220586, G6024075114, IDENTIFYING RARE VARIANTS THAT INCREASE RISK FOR ALZHEIMER'S DISEASE, Dominantly Inherited Alzheimer Network, Preclinical AD Consortium, G9000050228, G9000060740, G9000096510, Socioeconomic and Cardiovascular Sources of Cross-National Variation in Cognitive Health Among Older Adults, Alzheimer's Disease Research Center, Alzheimer's Disease Neuroimaging Initiative (ADNI4), Johns Hopkins Alzheimer's Disease Research Center, Integrating Information about Aging Surveys: Novel Integration of Contextual Data to Study Late-Life Cognition and Alzheimer’s Disease and Related Dementia and Dementia Care
OpenAlex ID: W4361224312