New research from the University of Copenhagen links genetic predispositions to smoking and high BMI with elevated dementia risk while highlighting the protective power of education and physical activity.

Study: Modifiable Risk Factors for Dementia: Causal Estimates on Individual-Level Data. Image Credit: Bagel Studio / Shutterstock

*Important notice: Preprints with The Lancet / SSRN publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Dementia is a chronic and severely debilitating disease with no known cure, underscoring the importance of its prevention and early detection. In a recent research paper* published on the Preprints with The Lancet server, researchers at the University of Copenhagen used extensive, individual-level genomic data from more than 400,000 European participants to establish causal relationships between modifiable risk factors and the disease.

Polygenic risk scores (PRS) were calculated for each participant to estimate the genetic predispositions to these risk factors. Mendelian randomization (linear and non-linear) revealed that genetically predicted smoking, high body mass index (BMI), high blood pressure, type 2 diabetes (T2D), high low-density lipoprotein (LDL) cholesterol concentrations, and high triglycerides significantly increased all-cause dementia risk.

In contrast, more extended education was found to demonstrate a protective effect against vascular- and all-cause dementia and Alzheimer’s disease. No non-linear associations were detected, meaning that the genetic risk associated with these factors was consistent across different exposure levels.

These findings validate the World Health Organization (WHO) and the Lancet Commission for Dementia Prevention, Intervention, and Care’s reports suggesting alteration in dementia-associated modifiable risk factors and inform future research on high-priority genetic targets for dementia interventions.

Background

Dementia is a serious and potentially lethal age-associated neurological condition characterized by a substantial gradual decline in cognitive functions such as memory, thinking, and judgment. It is one of the most prevalent causes of non-communicable disability and death and, unfortunately, remains without cure.

Alarming increases in global dementia prevalence have prompted the World Health Organization (WHO) and the Lancet Commission for Dementia Prevention, Intervention, and Care to release guidelines highlighting the role of modifiable risk factors in dementia incidence, emphasizing how the cessation of smoking (for example) can help prevent dementia during old age.

The most recent Lancet Commission report (2024) estimates that 45% of dementia can be prevented by eliminating modifiable risk associations, including smoking and high body mass index (BMI), resulting in a safer, healthier tomorrow.

Despite decades of research, causal associations between modifiable risk factors and dementia outcomes remain vague and often confounding. Studies have attempted to elucidate the mechanisms underpinning these associations, but the current lack of discrete-age datasets and analyses leads to several studies, even using identical datasets, providing contrasting outcomes.

The aforementioned reports are, therefore, based predominantly on observational evidence with limited clinical validation. Importantly, the present study uses Mendelian Randomization to provide stronger evidence for causal relationships between these risk factors and dementia outcomes.

About the Study

The present study leverages Mendelian Randomization (MR) analyses and an extensive, United Kingdom (UK) BioBank-derived genomic dataset to evaluate the individual-specific genetic odds ratios (ORs) of dementia. MR is a research method that uses genetic variation to study the causal effect of exposures (herein, genetic predispositions to dementia-related modifiable risk factors) on an outcome (herein, dementia manifestation).

Study data was obtained from the UK BioBank and consisted of 408,788 British participants of European ancestry. Data collection included archived genome-wide association study (GWAS), baseline anthropometric measurements (obtained at participants’ initial screening), and self-reported behavioral data (e.g., smoking status and weekly physical activity). Preexisting medical records were obtained from UK BioBank records and were annotated using International Classification of Diseases (ICD) codes.

The main outcomes of interest are the manifestation of dementia (all-cause) or its two most prevalent subtypes – Alzheimer’s disease and vascular dementia. Polygenic risk scores (PRSs), which estimate the number of genetic variants a person carries that may increase their risk for these conditions, were generated for each participant and used in the MR analysis.

To establish the shape of the genetic association between identified continuous risk factors and subsequent dementia manifestation, both linear and non-linear MRs were employed. Logistic and linear regressions were further utilized to account for covariates (age, sex) across both categorical and continuous risk factor datasets. However, no evidence of non-linear effects was detected in the association between the risk factors and dementia.

Study Findings

The study cohort (n = 408,788) comprised 53.7% women with a median age of 59. Baseline observations revealed a higher dementia risk in men compared with their female counterparts. At baseline examinations, 13.2% of participants reported ischemic heart disease, followed by all-cause dementia (1.7%), Alzheimer’s disease (0.9%), and vascular dementia (0.4%).

GWAS MR predictions revealed that of the 14 factors listed in the Lancet Commission report, genetic predispositions to high BMI resulted in dementia (OR = 1.04) most frequently. Similarly, frequent smoking (OR = 1.18), high systolic (OR = 1.14) and diastolic blood pressure (OR = 1.10), high LDL cholesterol (OR = 1.12), high triglycerides (OR = 1.19), and T2D (OR = 1.04) substantially increased future dementia risk.

In contrast, genetic predispositions to higher physical activity levels (OR = 0.58) and longer education times (OR = 0.72) were found to confer a protective effect against Alzheimer’s disease and all-cause dementia, respectively. The study also highlighted that some of these findings, such as the link between cardiovascular conditions and dementia, may be impacted by survival bias, as individuals with severe cardiovascular diseases often die before receiving a dementia diagnosis.

Conclusions

The present study identifies populations with genetic predispositions for smoking, high BMI, high blood pressure, T2D, and high triglycerides as high-risk individuals requiring immediate behavioral interventions to reduce future dementia risk.

Contrasting previous reports, more extended education was found to confer protection against all-cause dementia. Increased physical activity levels were similarly observed to keep the condition at bay. Importantly, no non-linear associations were found in these genetic relationships, which means that the risk from these factors remained consistent across different exposure levels.

The study authors suggest that some of the factors listed in the Lancet Commission report, such as cardiovascular conditions, cannot currently be verified since people with severe cardiovascular diseases (CVDs) often die before the natural onset of dementia, preventing their inclusion in dementia testing study cohorts.

This limitation notwithstanding, the present work provides insights into the genetic underpinnings of dementia and its main risk factors, highlighting preventive measures and educating clinicians and policymakers on steps to curb this debilitating disease.

*Important notice: Preprints with The Lancet / SSRN publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.