Genetic analysis shows smoking and high BMI increase dementia risk, but education and exercise protect against dementia risk

A new study from the University of Copenhagen links smoking and a genetic predisposition to high BMI to increased risk of dementia, highlighting the protective power of education and physical activity.

study: Modifiable risk factors for dementia: causal inference from individual-level data.. Image credit: Bagel Studio / Shutterstock

*Important notice: The Lancet / SSRN preprint has published preliminary scientific reports that have not been peer-reviewed and should therefore not be considered definitive, guide clinical practice or health-related behavior, or be treated as established information. Not.

Dementia is a chronic, severely debilitating disease with no established cure, highlighting the importance of its prevention and early detection. In a recent research paper* published in Lancet magazine preprint Researchers at the University of Copenhagen used extensive individual-level genomic data from more than 400,000 European participants to establish a causal link between modifiable risk factors and the disease.

A polygenic risk score (PRS) was calculated for each participant to estimate the genetic predisposition to these risk factors. Mendelian randomization (linear and nonlinear) significantly increases genetically predicted smoking, high body mass index (BMI), hypertension, type 2 diabetes (T2D), high low-density lipoprotein (LDL) cholesterol concentrations, and high triglycerides. It has been revealed that there will be an increase in Risk of dementia from all causes.

In contrast, broader education was found to demonstrate protective effects against vascular and all-cause dementia and Alzheimer's disease. No nonlinear associations were detected. This means that the genetic risks associated with these factors are consistent across different exposure levels.

These findings validate reports from the World Health Organization (WHO) and the Lancet Dementia Prevention, Intervention and Care Committee, which suggest changes in modifiable risk factors associated with dementia, and inform prioritization of dementia interventions. Inform future research on high gene targets.

background

Dementia is a serious and potentially fatal age-related neurological condition characterized by a substantial and 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.

In response to the alarming increase in global dementia prevalence, the World Health Organization (WHO) and the Lancet Dementia Prevention, Intervention and Care Commission have focused on the role of modifiable risk factors in the development of dementia. They have published guidelines on how to avoid smoking cessation (e.g. smoking cessation) and highlight how smoking cessation, e.g. ) Helps prevent dementia in old age.

The latest Lancet Commission report (2024) found that 45% of dementia could be prevented by eliminating modifiable risk associations such as smoking and high body mass index (BMI), resulting in safer and safer We estimate that a healthy tomorrow will become a reality.

Despite decades of research, the causal relationship between modifiable risk factors and dementia outcomes remains vague and often confusing. Studies have attempted to elucidate the mechanisms underlying these associations, but due to the current lack of discrete age datasets and analyses, even when using the same dataset they yield contrasting results. Some research is being done.

Therefore, the aforementioned reports are mainly based on observational evidence, with limited clinical validation. Importantly, this study uses Mendelian randomization to provide stronger evidence for a causal relationship between these risk factors and dementia outcomes.

About research

This study utilizes Mendelian randomization (MR) analysis and an extensive genomic dataset from the UK Biobank to assess individual-specific genetic odds ratios (ORs) for dementia. MR is a research method that uses genetic variation to study the causal relationship between an exposure (here, a genetic predisposition to a modifiable risk factor associated with dementia) and an outcome (here, the development of dementia). is.

Study data were obtained from the UK Biobank and comprised 408,788 British participants of European descent. Data collection included archived genome-wide association studies (GWAS), baseline anthropometric measurements (obtained during participant initial screening), and self-reported behavioral data (such as smoking status and weekly physical activity). Included. Existing medical records were retrieved from UK Biobank records and annotated using International Classification of Diseases (ICD) codes.

The primary outcome of interest is the development of dementia (all causes) or its two most common subtypes, Alzheimer's disease and vascular dementia. A polygenic risk score (PRS), which estimates the number of genetic variants carried by a person that may increase the risk of these diseases, was generated for each participant and used for MR analysis.

Both linear and nonlinear MR were used to establish the shape of the genetic association between identified continuous risk factors and subsequent dementia development. Logistic and linear regression were further utilized to account for covariates (age, gender) across both categorical and continuous risk factor datasets. However, no evidence of nonlinear effects was detected in the association between risk factors and dementia.

Research results

The study cohort (n = 408,788) comprised 53.7% women with a median age of 59 years. Baseline observations revealed an increased risk of dementia in men compared to women. At baseline testing, 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 prediction revealed that of the 14 factors listed in the Lancet Commission report, genetic predisposition to high BMI most frequently causes dementia (OR = 1.04). Similarly, frequent smoking (OR = 1.18), high systolic blood pressure (OR = 1.14) and high diastolic blood pressure (OR = 1.10), high LDL cholesterol (OR = 1.12), high triglycerides (OR = 1.19), and T2D (OR = 1.04)) significantly increased risk of future dementia.

In contrast, genetic predisposition to higher physical activity levels (OR = 0.58) and longer educational hours (OR = 0.72) were found to confer protective effects against Alzheimer's disease and all-cause dementia, respectively. The study also found that some of these findings, such as the association between cardiovascular disease and dementia, may be due to survival bias, as people with severe cardiovascular disease often die before receiving a diagnosis of dementia. It was also emphasized that this could be affected by

conclusion

This study identified populations with genetic predispositions to smoking, high BMI, hypertension, T2D, and high triglycerides as high-risk individuals who require immediate behavioral intervention to reduce future dementia risk. .

In contrast to previous reports, we found that broader education confers protection against all-cause dementia. Increased physical activity levels were similarly observed to prevent symptoms. Importantly, no nonlinear associations were found in these genetic relationships. This means that the risks from these factors remain consistent across different exposure levels.

The study authors noted that patients with severe cardiovascular disease (CVD) often die before the spontaneous onset of dementia and cannot be included in dementia testing studies, which is why they are cited in the Lancet committee report. They suggest that some of the factors, such as cardiovascular disease, cannot be tested at this time. cohort.

Despite this limitation, the current study provides insight into the genetic basis of dementia and its main risk factors, focuses on preventive measures, and informs clinicians about steps to curb this debilitating disease. and educate policy makers.

*Important notice: The Lancet / SSRN preprint has published preliminary scientific reports that have not been peer-reviewed and should therefore not be considered definitive, guide clinical practice or health-related behavior, or be treated as established information. Not.