Obesity, High Blood Pressure, And Dementia: A Causal Link

The study shows that obesity can cause vascular dementia, and not just be associated with it. Part of this effect occurs because excess weight increases blood pressure, which damages the blood vessels in the brain. Controlling weight and blood pressure can be an important strategy for preventing dementia.

For a long time, obesity was seen only as a factor that increases the risk of various diseases, such as diabetes and cardiovascular problems. However, more recent research suggests something even more worrying: obesity may not only increase the risks, but also contribute directly to the development of dementia, especially vascular dementia.

Observational studies over the decades have shown inconsistent results on the relationship between obesity and dementia. An important finding, however, was that obesity in middle age, and not in old age, is associated with a higher risk of developing dementia later in life.

Furthermore, large population analyses have indicated that obese people have a higher risk of vascular dementia, a type of dementia caused by problems with blood circulation in the brain.

Obesity is often accompanied by significant metabolic changes, such as high blood pressure, elevated cholesterol, increased blood glucose, and chronic low-grade inflammation. All of these factors are known to impair blood vessels and brain function. This raises the possibility that obesity is at the beginning of a chain of events that, over time, can lead to vascular dementia.

There is evidence that treating these risk factors helps. Studies have shown that people who use medication to control blood pressure, cholesterol, or diabetes tend to have a lower risk of dementia. However, these studies cannot definitively prove whether obesity causes dementia or is merely associated with it, as many environmental and behavioral factors are intertwined in this type of analysis.

To investigate causality more robustly, researchers used a technique called Mendelian randomization. This method uses genetic variants associated with body mass index (BMI) as a kind of "natural experiment."

Because genes are randomly distributed at birth, they are not directly influenced by lifestyle, income, or environment, reducing common biases in observational studies.

In this study, researchers analyzed data from large populations in Denmark and the United Kingdom, as well as international consortia. First, they assessed the relationship between BMI and vascular dementia using individual data from different cohorts. Then, they confirmed the results with additional studies using summarized data. Finally, they investigated whether the effect of BMI on dementia was mediated by blood pressure, cholesterol, glucose, and inflammation.

The results consistently showed that a higher BMI significantly increases the risk of vascular dementia. Each standard increase in BMI was associated with a substantial increase in this risk, regardless of the statistical method used. Furthermore, the findings were similar when researchers used a larger set of genetic variants, reinforcing the robustness of the results.

A key finding was that part of this effect is explained by blood pressure. Systolic and diastolic blood pressure together mediated a significant portion of the relationship between elevated BMI and vascular dementia. This indicates that obesity contributes to the development of dementia, in part, by increasing blood pressure and consequently damaging blood vessels in the brain.

In conclusion, the study provides strong evidence that obesity is not only a risk marker but a causal factor for vascular dementia. Since both elevated BMI and hypertension are modifiable factors, the results reinforce the importance of prevention strategies focused on controlling body weight and blood pressure as concrete ways to reduce the risk of dementia in the future.

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High Body Mass Index as a Causal Risk Factor for Vascular-Related Dementia: A Mendelian Randomization Study

Liv Tybjærg Nordestgaard, Jiao Luo, Frida Emanuelsson, Genevieve Leyden, Eleanor Sanderson, George Davey Smith, Mette Christoffersen, Shoaib Afzal, Marianne Benn, Børge G Nordestgaard, Anne Tybjærg-Hansen, and Ruth Frikke-Schmidt

The Journal of Clinical Endocrinology & Metabolism, 2026, dgaf662

https://doi.org/10.1210/clinem/dgaf662

Abstract:

Obesity is associated with a high risk of vascular-related dementia with metabolic risk factors as potential mediators, but questions of causality remain unanswered. We aimed to determine whether high body mass index (BMI) is a causal risk factor for vascular-related dementia, and whether any effect is mediated by hypertension, hyperlipidemia, hyperglycemia, and low-grade inflammation. Prospective cohort studies of the general populations from the Copenhagen area and from across the United Kingdom and consortia data were included in the study. Interventions included one-sample mendelian randomization (MR), two-sample MR, and MR in mediation analyses. Both individual-level and summary-level data was used. Main outcome measures included risk of vascular-related dementia, Alzheimer's disease, and ischemic heart disease. In a meta-analysis of 2 one-sample MR studies, the odds ratio (OR) for 1-SD higher BMI in predicting vascular-related dementia was 1.63 (95% CI, 1.13-2.35). In a two-sample MR study, the OR for vascular-related dementia per 1-SD higher BMI was 1.54 (1.10-2.16) using the inverse-variance weighted, 1.87 (1.22-2.85) using the weighted median, and 1.98 (1.21-3.22) using the weighted mode methods. Results from MR analyses including extended numbers of genetic variants were directionally consistent. Finally, systolic blood pressure mediated 18% (95% CI, 10%-61%) and diastolic blood pressure mediated 25% (13%-75%) of the genetic effect of BMI on vascular-related dementia. Observationally (U-shaped) and genetically (linearly), high BMI is associated with a higher risk of vascular-related dementia, an association partly mediated through high blood pressure. This suggests that high BMI and high blood pressure are important modifiable risk factors for dementia prevention.