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Excess body weight appears to be a direct cause of vascular dementia, with the damage largely driven by high blood pressure. A new genetic analysis indicates that maintaining a healthy weight and managing hypertension could prevent a substantial number of dementia cases. These findings were detailed in a study published recently in The Journal of Clinical Endocrinology & Metabolism.
The relationship between obesity and cognitive decline has challenged researchers for decades. Previous observational studies frequently produced contradictory results regarding how body weight influences brain health. Some research indicated that obesity in midlife increased dementia risk. Other studies suggested that high body weight in late life might actually protect against the disease. This paradox often stems from the limitations of traditional observational research.
In the early stages of dementia, patients frequently lose weight due to a loss of appetite or metabolic changes. This weight loss can make it appear as though being thin carries a higher risk, when in reality the disease caused the weight loss.
To resolve these conflicting signals, a research team led by Liv Tybjærg Nordestgaard and senior author Ruth Frikke-Schmidt sought to determine if high body mass index (BMI) causes vascular dementia. Frikke-Schmidt is a professor and chief physician at Copenhagen University Hospital and the University of Copenhagen. The team aimed to move beyond simple associations to establish a cause-and-effect relationship. They also sought to identify the biological mechanisms that connect excess weight to brain damage.
The researchers utilized a sophisticated analytical method known as Mendelian randomization. This technique acts as a natural simulation of a randomized controlled trial. It relies on the random assortment of genetic variants that occurs during conception. Humans inherit genetic markers that predispose them to a slightly higher or lower BMI. These markers are fixed at birth and are generally unaffected by lifestyle choices, socioeconomic status, or environmental factors. Because these genetic variants are randomly assigned, they separate the biological effects of body mass from confounding variables like diet or exercise.
The study drew upon an immense pool of health and genetic data. The investigators analyzed records from the Copenhagen General Population Study and the Copenhagen City Heart Study. These datasets included more than 120,000 individuals from the Danish population. To validate their findings, the team also examined data from the UK Biobank. This resource provided genetic and health information for nearly 380,000 additional participants.
The observational analysis of the Danish cohorts initially reflected the confusing patterns seen in earlier research. When looking strictly at measured weight and health outcomes, the data showed a U-shaped relationship. Both underweight individuals and obese individuals appeared to have a higher risk of vascular dementia compared to those of normal weight. This finding likely reflects the issue of reverse causation, where underlying illness causes weight loss.
However, the genetic analysis told a different and much clearer story. When the researchers looked at individuals with genetic variants that predispose them to higher BMI, the relationship became linear. As genetically predicted BMI increased, the risk of vascular-related dementia rose steadily. There was no evidence of a protective effect from higher weight in the genetic data.
The magnitude of the risk was considerable. In the meta-analysis combining the Copenhagen and UK cohorts, the researchers calculated the odds ratios. For every one standard deviation increase in genetically predicted BMI, the odds of developing vascular-related dementia increased by approximately 63 percent. Further analysis using summary-level data from large international consortia supported this trend. These additional tests showed the risk increasing by anywhere from 54 percent to nearly double, depending on the specific statistical method applied.
Once the causal link was established, the team investigated the biological pathways involved. They examined whether the effect of BMI on dementia was mediated by other metabolic risk factors. The researchers looked at hypertension, high cholesterol, high blood sugar, and inflammation. These conditions are common consequences of obesity and are plausible culprits for damaging blood vessels in the brain.
The analysis identified high blood pressure as the primary mediator. The study estimated that systolic blood pressure accounted for approximately 18 percent of the genetic effect of BMI on vascular dementia. Diastolic blood pressure accounted for an even larger portion, mediating about 25 percent of the risk. This suggests that excess weight drives up blood pressure, which in turn damages the brain’s vascular system.
Vascular dementia is characterized by reduced blood flow to the brain. This restriction deprives brain cells of oxygen and nutrients. The damage often occurs through a series of small strokes or microinfarcts. Over time, these events lead to the death of brain tissue and cognitive decline. High blood pressure is a well-established risk factor for stroke. The current study connects these dots, showing that BMI-induced hypertension is a key mechanism leading to this form of dementia.
The researchers also tested other potential mediators but found weaker evidence. While high BMI was genetically linked to higher cholesterol, triglycerides, and blood sugar, these factors did not appear to be the main drivers of vascular dementia risk in this specific analysis. Inflammation, measured by C-reactive protein levels, also did not show a clear causal role in mediating the risk. The spotlight remained firmly on blood pressure.
This study included positive controls to ensure the validity of the genetic methods. The researchers checked the link between genetically predicted BMI and ischemic heart disease. The analysis confirmed a strong causal link, which aligns with established medical knowledge. This successful validation adds confidence to the novel findings regarding dementia.
“In this study, we found high body mass index (BMI) and high blood pressure are direct causes of dementia,” said Frikke-Schmidt. “The treatment and prevention of elevated BMI and high blood pressure represent an unexploited opportunity for dementia prevention.”
The implications for public health are substantial. Dementia currently affects 50 million people worldwide. That number is expected to rise as the global population ages. Currently, there are few effective treatments for established dementia. This reality makes prevention strategies essential.
“This study shows that high body weight and high blood pressure are not just warning signs, but direct causes of dementia,” Frikke-Schmidt noted. “That makes them highly actionable targets for prevention.”
The findings suggest that interventions targeting obesity could have a neuroprotective effect. Medications or lifestyle changes that lower body weight might reduce the risk of cognitive decline. “Weight-loss medication has recently been tested for halting cognitive decline in early phases of Alzheimer’s disease, but with no beneficial effect,” Frikke-Schmidt said. She added that an open question remains regarding timing. “An open question that remains to be tested is if weight-loss medication initiated before the appearance of cognitive symptoms may be protective against dementia. Our present data would suggest that early weight-loss interventions would prevent dementia, and especially vascular-related dementia.”
There are limitations to the study that warrant consideration. The research focused primarily on individuals of European descent. This demographic focus means the results may not fully apply to populations with different genetic backgrounds. Future research will need to verify these associations in more diverse groups.
Another limitation lies in the measurement of body mass index itself. BMI is a general calculation based on height and weight. It does not distinguish between fat mass and lean muscle mass. However, the researchers noted that increased fat mass is typically responsible for raising blood pressure. Consequently, it is likely that excess body fat is the specific culprit increasing dementia risk.
The study also faced the challenge of defining dementia subtypes. Diagnoses can vary between clinics and countries. Vascular dementia and Alzheimer’s disease often coexist, creating mixed pathologies that are hard to separate. Despite this complexity, the genetic signals for vascular-related dementia were distinct from those for Alzheimer’s disease in this analysis.
The researchers used blood pressure data that had been adjusted for BMI in some of the consortia datasets. This technical detail meant they could not use all available data for the mediation analysis. However, the team performed multiple sensitivity analyses to test the robustness of their conclusions. These additional tests produced consistent results, strengthening the argument for a causal relationship.
This research underscores the importance of cardiovascular health for brain function. The connection between the heart and the head appears to be mechanical and direct. Reducing the physical stress on blood vessels by managing weight and blood pressure could preserve cognitive function into old age.
The study, “High Body Mass Index as a Causal Risk Factor for Vascular-Related Dementia: A Mendelian Randomization Study,” was authored by 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.
