Research shows how sex-specific risks of obesity and heart health influence brain aging, offering new insights into preventing Alzheimer’s disease.
Study: Cardiovascular risk and obesity are more likely to influence gray matter volume loss in men than in women. Image credits: Jorm Sangsorn / Shutterstock
From a recent study published in the Journal of neurology, neurosurgery and psychiatryresearchers examined how cardiovascular risk and obesity affect brain volume and whether the apolipoprotein (APOE) genotype influences this relationship in women and men of different ages.
Their findings indicate that specific age groups are most vulnerable to the impact of obesity and cardiovascular risk on brain volume, with implications for the prevention of neurodegeneration and the development of Alzheimer’s disease.
Background
Alzheimer’s disease affects approximately 50 million people worldwide, but options for treatment, such as anti-amyloid therapies, remain limited. The development of the disease involves the accumulation of toxic tau and amyloid proteins, followed by neuroinflammation, synapse dysfunction, insulin resistance and oxidative stress.
Researchers have linked cardiovascular risk factors, including smoking, high blood pressure, obesity and type 2 diabetes, to a greater chance of developing dementia. Of the twelve modifiable risk factors identified by the Lancet Commission, obesity may contribute to Alzheimer’s disease through inflammation and hormonal changes. Adipose tissue can release pro-inflammatory molecules, such as cytokines and leptin, which cross the blood-brain barrier and potentially trigger neurodegenerative pathways.
Sex hormones such as estrogen and testosterone have neuroprotective effects, but women experience a rapid loss of ovarian hormones during menopause, while men gradually lose androgens. Understanding how these sex differences influence the link between cardiovascular risk and brain health is critical to the development of effective therapies.
About the study
Researchers studied 34,425 people who participated in the UK Biobank study, a large-scale prospective research program. The participants were between 45 and 82 years old, with an average age of 63.6 years. Participants underwent abdominal and structural MRI scans of the brain.
Cardiovascular risk was calculated based on factors such as diabetes, smoking, blood pressure, cholesterol and age. A well-established scoring system, the Framingham risk score, was used to quantify cardiovascular risk. Abdominal MRI is used to measure the volumes of subcutaneous and visceral adipose tissue, indicative of obesity. Visceral adipose tissue is associated with higher cardiovascular risk, insulin resistance and metabolic syndrome.
The APOE genotype, a marker for Alzheimer’s disease risk, was analyzed to assess its role in cardiovascular risk and brain health. To evaluate brain volume, structural brain scans were performed using high-resolution MRI.
Voxel-based morphometry (VBM), which detects volume changes and allows unbiased evaluation across cortical regions, was used to analyze brain volume changes on minute scales. Gray and white matter images were processed and analyzed using specialized software. The analysis also took into account individual differences in head size based on total intracranial volume.
Linear models were used to assess the influence of cardiovascular risk, obesity and APOE genotype on brain volume. They were performed separately for multiple age groups and sexes and adjusted for total intracranial volume.
Findings
Using data from 34,425 participants with MRI scans of the abdomen and brain, researchers found that higher cardiovascular risk was associated with lower gray matter volume in the brain. Specifically, the postcentral gyrus, frontal lobe, thalamus and temporal lobe showed the greatest loss in brain volume.
Both carriers and noncarriers of APOE ε4 were affected by cardiovascular risk, with similar reductions in brain volume observed.
The strongest effects were observed between the ages of 55 and 74 years, with 67% of gray matter in men showing reduced volume in these years. The temporal lobe was most affected in men between 45 and 54 years of age and over 75 years of age. In men, researchers found small associations between cardiovascular risk and brain volume loss (1-2% gray matter).
In women, the strongest effects were observed between 65 and 74 years (43% loss of gray matter volume) and 55 and 64 years (27% loss). Smaller effects were observed in women younger than 54 years and older than 75 years, indicating a bell-shaped relationship.
Both subcutaneous and visceral adipose tissue volumes were associated with reduced brain volume, mainly affecting the precentral and postcentral gyrus, frontal regions, thalamus and temporal pole. The associations remained consistent in both APOE ε4 carriers and noncarriers.
The strongest association between abdominal fat (subcutaneous and visceral) and lower gray matter volume was found in men aged 55-64 and 65-74 years. In younger men (45-54), the associations were present, but less pronounced. Weaker associations were observed in women.
Cardiovascular risk had a stronger and earlier impact on gray matter volume in men, especially in the 55-64 age group. Interestingly, visceral adipose tissue in older women (65-74) showed a stronger association with gray matter loss, suggesting an interaction between sex and cardiovascular risk.
Conclusions
This study suggests that cardiovascular risk and obesity are strongly associated with neurodegeneration, with the timing and impact varying by gender and age. Men, especially between the ages of 55 and 64, show the first and greatest brain volume loss due to obesity and cardiovascular risk.
These findings underscore the importance of early intervention strategies tailored to gender-specific risk profiles. Addressing cardiovascular risk factors (such as obesity and high blood pressure) early can help prevent Alzheimer’s disease and other forms of neurodegeneration. Drugs used for obesity and type 2 diabetes, such as glucagon-like peptide-1 receptor agonists, could be repurposed for the treatment of Alzheimer’s.