Study reveals how sex-specific risks of obesity and heart health shape brain aging, offering new insights into preventing Alzheimer’s disease.
Study: Cardiovascular risk and obesity impact loss of grey matter volume earlier in males than females. Image Credit: Jorm Sangsorn / Shutterstock
In a recent study published in the Journal of Neurology, Neurosurgery & Psychiatry, researchers investigated how cardiovascular risk and obesity impact brain volume and whether the apolipoprotein (APOE) genotype affects this relationship in females and males of various ages.
Their findings indicate specific age ranges as the most vulnerable to the impact of obesity and cardiovascular risk on brain volume, with implications for neurodegeneration prevention and the development of Alzheimer’s disease.
Background
Alzheimer’s disease affects approximately 50 million people worldwide, but avenues 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, dysfunction in synapses, resistance to insulin, and oxidative stress.
Researchers have linked cardiovascular risk factors, including smoking, hypertension, obesity, and type 2 diabetes, to a higher probability of developing dementia. Of 12 risk factors identified by the Lancet Commission that are modifiable, obesity may contribute to Alzheimer’s through inflammation and hormonal changes. Adipose tissue can release pro-inflammatory molecules, such as cytokines and leptin, that cross the blood-brain barrier, potentially triggering neurodegenerative pathways.
Sex hormones like estrogen and testosterone have neuroprotective effects, but women experience a rapid loss of ovarian hormones at 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 the ages of 45 and 82, with an average age of 63.6. Participants underwent abdominal and structural brain magnetic resonance imaging (MRI) scans.
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 subcutaneous and visceral adipose tissue volumes, indicating obesity. Visceral adipose tissue is linked to higher cardiovascular risk, insulin resistance, and metabolic syndrome.
The APOE genotype, a marker of 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 for unbiased evaluation across cortical regions, was used to analyze changes in brain volume at minute scales. Grey and white matter images were processed and analyzed using specialized software. The analysis also accounted for individual differences in head size using total intracranial volume.
Linear models were used to assess the influence of cardiovascular risk, obesity, and APOE genotype on brain volume. They were run separately for multiple age groups and genders and adjusted for total intracranial volume.
Findings
Using data from 34,425 participants with abdominal and brain MRI scans, researchers found that higher cardiovascular risk was linked to lower grey matter volume across the brain. Specifically, the postcentral gyrus, frontal lobe, thalamus, and temporal lobe showed the most significant loss in brain volume.
Both APOE ε4 carriers and non-carriers were affected by cardiovascular risk, showing similar brain volume reductions.
The strongest effects were seen between the ages of 55 and 74, with 67% of grey matter showing reduced volume in males during these years. The temporal lobe was most affected in males between 45 and 54 and over 75. Among males, researchers found minor associations between cardiovascular risk and brain volume loss (1-2% grey matter).
In women, the strongest effects were seen between 65 and 74 (43% loss in the volume of grey matter) and 55 and 64 (27% loss). Smaller effects were seen in women younger than 54 and over 75, indicating a bell-shaped relationship.
Both subcutaneous and visceral adipose tissue volumes were linked to reduced brain volume, with the precentral and postcentral gyrus, frontal areas, thalamus, and temporal pole particularly affected. Associations remained consistent in both APOE ε4 carriers and non-carriers.
The strongest links between abdominal fat (subcutaneous and visceral) and volume of lower grey matter were found in males aged 55–64 and 65–74. In younger males (45–54), the associations were present but less pronounced. In females, weaker associations were observed.
Cardiovascular risk had a stronger and earlier impact on the volume of grey matter in males, especially in the 55–64 age group. Interestingly, visceral adipose tissue in older females (65–74) showed a stronger link with grey matter loss, suggesting an interaction between sex and cardiovascular risk.
Conclusions
This study suggests that cardiovascular risk and obesity are strongly linked to neurodegeneration, with the timing and impact varying by sex and age. Males, particularly between 55–64 years, show the earliest and most significant brain volume loss due to obesity and cardiovascular risk.
These findings underline the importance of early intervention strategies tailored to sex-specific risk profiles. Targeting cardiovascular risk factors (like obesity and hypertension) early on may help prevent Alzheimer’s disease and other forms of neurodegeneration. Drugs used for obesity and type 2 diabetes, like glucagon-like-peptide-1 receptor agonists, could be repurposed for Alzheimer’s treatment.
