Smoking Impairs Women’s Verbal Learning and Memory Performance More than Men’s: An International Web-Cohort Study of 70,000 Participants

Background Vascular contributions to cognitive impairment and dementia (VCID) include structural and functional blood vessel injuries linked to poor neurocognitive outcomes. Smoking might indirectly increase the likelihood of cognitive impairment by exacerbating the risks associated with underlying vascular disease. Sex disparities in VCID have been reported, however, few studies have assessed the sex-specific impact of smoking on cognitive function and with contradictory results. This is an important topic since smoking and cardiovascular disease negatively impact health and possibly women have the greater lifetime risk of stroke and dementia than men. In this study, we sought to investigate the effect-modification of sex on the relationship between smoking, cardiovascular disease and verbal learning and memory function. Methods Using MindCrowd, a web-based cohort of over 70,000 people aged 18 - 85, we investigated whether sex modifies the impact of smoking and cardiovascular disease on verbal memory performance on a paired-associate learning task using both multiple regression and propensity matching approaches. Artificial error introduction and permutation testing underscored the stability of our results. To demonstrate the necessity of large sample sizes to detect an interaction of sex and smoking, we performed down sampling analyses. Findings We found significant interactions in that smoking impacts verbal learning performance more in women and cardiovascular disease more in men across a wide age range. Interpretation These results suggest that smoking and cardiovascular disease impact verbal learning and memory throughout adulthood. Smoking particularly affects learning and memory in women and cardiovascular disease has a larger effect in men. Although the reasons for these sex-modification effects are not entirely understood, our findings highlight the importance of considering biological sex in VCID. Funding Mueller Family Charitable Trust; Arizona Alzheimer’s Consortium; Flinn Foundation; The McKnight Brain Research Foundation; NIH-NIA grant R01-AG049465. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding: Mueller Family Charitable Trust; Arizona Alzheimers Consortium; Flinn Foundation; The McKnight Brain Research Foundation; NIH-NIA grant R01-AG049465. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by WIRB. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data will be made available in a public repository (e.g. Dryad).