Cannabis use, cognition, and dementia risk: an observational and Mendelian randomization study
Poster No:
147
Submission Type:
Abstract Submission
Authors:
Saba Ishrat1, Klaus Ebmeier1, Anya Topiwala1
Institutions:
1University of Oxford, Oxford, United Kingdom
First Author:
Co-Author(s):
Introduction:
Cannabis use for medical and recreational purposes has increased significantly over the past decade. [1,2] While adverse effects on neurocognitive performance have been reported in adolescents and young adults [3], its impact on cognition and dementia risk in older adults remains unclear.
In this study, we examined the associations between lifetime cannabis use and cognitive functioning in cohorts from the UK Biobank. To enhance the robustness of our findings, we supplemented our observational analyses with Mendelian randomization to assess causal relationships utilizing summary-level genome-wide association studies (GWAS). Furthermore, we used this approach to investigate the causal association between cannabis use and dementia risk.
In this study, we examined the associations between lifetime cannabis use and cognitive functioning in cohorts from the UK Biobank. To enhance the robustness of our findings, we supplemented our observational analyses with Mendelian randomization to assess causal relationships utilizing summary-level genome-wide association studies (GWAS). Furthermore, we used this approach to investigate the causal association between cannabis use and dementia risk.
Methods:
All analysis were performed in R (version 4.0.0). We analysed data from approximately 15,000 to 18,000 lifetime cannabis users and 48,000 to 56,000 controls in UK Biobank, to assess observational associations between cannabis use and cognitive performance. Cognitive performance was examined though five different tests: Numeric Memory, Fluid intelligence, Trail making, Symbol digit substitution and Pairs matching test. [4] Multiple linear regression and linear mixed-effects models were conducted in R to examine cross-sectional and longitudinal changes, respectively, while adjusting for potential covariates.
Additionally, bidirectional two-sample Mendelian randomization analyses were used to explore potential causal relationships. We used single nucleotide polymorphisms (SNPs) associated with cannabis use as an exposure variable from two large GWAS: a) cannabis dependence and abuse [5] and b) lifetime cannabis use. [6]. Genetic associations with the cognitive test outcomes were identified from summary statistics of UK Biobank including: fluid intelligence score, pairs matching and prospective memory. Dementia outcomes included: a) all-cause dementia [7] and b) all-cause and vascular dementia [8].
Additionally, bidirectional two-sample Mendelian randomization analyses were used to explore potential causal relationships. We used single nucleotide polymorphisms (SNPs) associated with cannabis use as an exposure variable from two large GWAS: a) cannabis dependence and abuse [5] and b) lifetime cannabis use. [6]. Genetic associations with the cognitive test outcomes were identified from summary statistics of UK Biobank including: fluid intelligence score, pairs matching and prospective memory. Dementia outcomes included: a) all-cause dementia [7] and b) all-cause and vascular dementia [8].
Results:
Lifetime cannabis users (mean age = 58.14 years, standard deviation (SD) = 7.28) were significantly younger than the control group (mean age = 62.24 years, SD = 7.50). There was a slightly higher proportion of males in the user group, a higher proportion of the user group had college degrees.
Lifetime cannabis use was associated with better performance on numeric memory (β = 0.110, p < 0.001), and fluid intelligence test (β = 0.239, p < 0.001) compared to controls (Figure 1). However, cannabis users experienced greater cognitive decline over time compared with controls in fluid intelligence (β = -0.012, p < 0.001) (Figure 2) and Trail Making (A) test (β = 0.135, p < 0.001).
Genetically-predicted cannabis dependence or abuse, as well as lifetime cannabis use, was not associated with any of the cognitive phenotypes. Additionally, there were no observed associations between genetically-predicted cannabis use and the risk of all-cause dementia or vascular dementia.
Lifetime cannabis use was associated with better performance on numeric memory (β = 0.110, p < 0.001), and fluid intelligence test (β = 0.239, p < 0.001) compared to controls (Figure 1). However, cannabis users experienced greater cognitive decline over time compared with controls in fluid intelligence (β = -0.012, p < 0.001) (Figure 2) and Trail Making (A) test (β = 0.135, p < 0.001).
Genetically-predicted cannabis dependence or abuse, as well as lifetime cannabis use, was not associated with any of the cognitive phenotypes. Additionally, there were no observed associations between genetically-predicted cannabis use and the risk of all-cause dementia or vascular dementia.
·Associations between cannabis use and cognitive functioning (Cross sectional analysis)
·Associations between cannabis use and Fluid Intelligence test over time (Longitudinal analysis)
Conclusions:
Lifetime cannabis users had better cross-sectional performance but experienced faster decline over time in observational analyses. Genetically-predicted cannabis use did not associate with cognitive or dementia phenotypes, suggesting higher cross-sectional cognitive performance of cannabis users may be due to residual confounding. Further research is needed to understand the mechanisms underlying these associations which do not appear to be causal.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Genetics:
Genetic Association Studies 2
Learning and Memory:
Working Memory
Lifespan Development:
Aging
Modeling and Analysis Methods:
Other Methods
Keywords:
Addictions
ADULTS
Aging
Cognition
Data analysis
Memory
Psychiatric Disorders
1|2Indicates the priority used for review
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2. Han, B. H., & Palamar, J. J. (2018). Marijuana use by middle-aged and older adults in the United States, 2015-2016. Drug and Alcohol Dependence, 191, 374. https://doi.org/10.1016/j.drugalcdep.2018.07.006
3. Kroon, E., Kuhns, L., & Cousijn, J. (2021). The short-term and long-term effects of cannabis on cognition: recent advances in the field. Current Opinion in Psychology, 38, 49-55. https://doi.org/10.1016/j.copsyc.2020.07.005
4. Fawns-Ritchie, C., & Deary, I. J. (2020). Reliability and validity of the UK Biobank cognitive tests. PLoS ONE, 15(4), e0231627. https://doi.org/10.1371/journal.pone.0231627
5. Levey, D. F., Galimberti, M., Deak, J. D., Wendt, F. R., Bhattacharya, A., Koller, D., Harrington, K. M., Quaden, R., Johnson, E. C., Gupta, P., Biradar, M., Lam, M., Cooke, M., Rajagopal, V. M., Empke, S. L., Zhou, H., Nunez, Y. Z., Kranzler, H. R., Edenberg, H. J., . . . Gelernter, J. (2023). Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications. Nature Genetics, 55(12), 2094-2103. https://doi.org/10.1038/s41588-023-01563-z
6. Pasman, J. A., Verweij, K. J., Gerring, Z., Stringer, S., Treur, J. L., Abdellaoui, A., Nivard, M. G., Baselmans, B. M., Ong, J., Ip, H. F., D., M., Bartels, M., Day, F. R., Fontanillas, P., Elson, S. L., de Wit, H., Davis, L. K., MacKillop, J., Derringer, J. L., . . . Vink, J. M. (2018). GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal effect of schizophrenia liability. Nature Neuroscience, 21(9), 1161-1170. https://doi.org/10.1038/s41593-018-0206-1
7. Topiwala, A. et al. (2024) Alcohol use and risk of dementia in diverse populations, medRxiv. Available at: https://www.medrxiv.org/content/10.1101/2024.05.20.24307606v1 (Accessed: 17 December 2024).
8. Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium (2024). A genome-wide association meta-analysis of all-cause and vascular dementia. Alzheimer's & dementia : the journal of the Alzheimer's Association, 20(9), 5973–5995. https://doi.org/10.1002/alz.14115