New research from the University of Copenhagen links genetic predisposition to smoking and a high BMI to an increased risk of dementia, while highlighting the protective power of education and physical activity.
Study: Modifiable risk factors for dementia: causal estimates on individual-level data. Image credits: Bagel Studio / Shutterstock
*Important notice: Preprints with The Lancet/SSRN publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.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 prevention and early detection. In a recent research article* published on the Preprints with The Lancet server, researchers from 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 genetic predisposition to these risk factors. Mendelian randomization (linear and non-linear) revealed that genetically predicted smoking, high body mass index (BMI), hypertension, type 2 diabetes (T2D), high low-density lipoprotein (LDL) levels, and high triglycerides increased significantly. risk of dementia from all causes.
In contrast, more extensive education demonstrated a protective effect against vascular dementia 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 reports from the World Health Organization (WHO) and the Lancet Commission for Dementia Prevention, Intervention, and Care suggesting changes in dementia-associated modifiable risk factors, and provide the basis for future research on high-priority genetic targets for interventions in the field of dementia.
Background
Dementia is a serious and potentially fatal age-related neurological disorder characterized by a substantial gradual decline in cognitive functions such as memory, thinking and judgment. It is one of the most common causes of non-communicable disability and death and unfortunately there is still no cure.
Alarming increases in the global prevalence of dementia 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, highlighting how Quitting smoking (for example) can help prevent dementia in old age.
The latest report from the Lancet Commission (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 future.
Despite decades of research, causal links between modifiable risk factors and the consequences of dementia remain vague and often confusing. Studies have attempted to elucidate the mechanisms underlying these associations, but the current lack of data sets and analyzes for separate ages leads to different studies, even using identical data sets, yielding contrasting results.
The above reports are therefore mainly based on observational evidence with limited clinical validation. Importantly, the current study uses Mendelian Randomization to provide stronger evidence for causal relationships between these risk factors and dementia outcomes.
About the study
The current study uses Mendelian Randomization (MR) analyzes and a comprehensive 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 exposure (here: genetic predisposition to dementia-related, modifiable risk factors) on an outcome (here: manifestation of dementia).
The study data was obtained from the British BioBank and consisted of 408,788 British participants of European descent. Data collection included archived genome-wide association studies (GWAS), baseline anthropometric measures (obtained at the initial screening of participants), and self-reported behavioral data (e.g., smoking status and weekly physical activity). Pre-existing medical records were obtained from the UK BioBank files and annotated using International Classification of Diseases (ICD) codes.
The main outcomes of interest are the manifestation of dementia (from any cause) or its two most common subtypes – Alzheimer’s disease and vascular dementia. Polygenic risk scores (PRSs), which estimate the number of genetic variants a person carries that may increase the risk of these conditions, were generated for each participant and used in the MR analysis.
To determine the shape of the genetic association between identified continuous risk factors and the subsequent manifestation of dementia, both linear and nonlinear MRs were used. Logistic and linear regressions were further used to account for covariates (age, gender) in both categorical and continuous risk factor datasets. However, no evidence of non-linear effects was found in the association between the risk factors and dementia.
Study findings
The study cohort (n = 408,788) consisted of 53.7% women with a median age of 59 years. Baseline observations showed that men are at higher risk of dementia than their female counterparts. At baseline examinations, 13.2% of participants reported ischemic heart disease, followed by dementia (1.7%), Alzheimer’s disease (0.9%), and vascular dementia (0.4%).
GWAS MR predictions showed that of the 14 factors identified in the Lancet Commission report, genetic predisposition to high BMI most often resulted in dementia (OR = 1.04). 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) significantly increased future dementia risk.
In contrast, genetic predispositions for higher physical activity levels (OR = 0.58) and longer school hours (OR = 0.72) were found to have 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 disease and dementia, may be influenced by survival bias, as individuals with severe cardiovascular disease often die before being diagnosed with dementia.
Conclusions
The current study identifies populations with genetic predisposition to smoking, high BMI, high blood pressure, T2D, and high triglycerides as high-risk individuals requiring immediate behavioral interventions to reduce future risk of dementia.
Contrary to previous reports, more extensive education was found to protect against dementia from all causes. Increased physical activity levels were also observed to keep the condition at bay. Importantly, no non-linear associations were found in these genetic relationships, meaning the risk from these factors remained consistent across different exposure levels.
The study authors suggest that some of the factors mentioned in the Lancet Commission report, such as cardiovascular disease, cannot currently be verified because people with severe cardiovascular disease often die before the natural onset of dementia, causing their inclusion in dementia testing research is prevented. cohorts.
Despite this limitation, the current work provides insights into the genetic underpinnings of dementia and its major 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 have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or treated as established information.