Brain volume loss predominantly occurred in temporal lobe regions.
Men at high risk of cardiovascular disease had brain volume changes a decade earlier than women, U.K. Biobank data showed.
Cardiovascular risk and obesity had the strongest relationship with lower gray matter volume in men between the ages of 55 and 64, according to Paul Edison, MD, PhD, of Imperial College London, and co-authors.
In contrast, the relationship was strongest in women 10 years later, when they were 65 to 74 years old, the researchers reported in the Journal of Neurology, Neurosurgery, and Psychiatry.
Relationships were seen in both APOE4 carriers and non-carriers, Edison and colleagues said. Loss of brain volume was seen predominantly in temporal lobe regions.
"Men were more likely to be affected by the influence of cardiovascular risk on memory problems a decade earlier than women," Edison told MedPage Today. "This was noticeable on MRI scans of the brain, where the risk of heart problems and obesity in males ages 55-64 years old were associated with reduced brain volumes, particularly in regions involved in learning and memory."
Obesity, along with variables tied to cardiovascular disease, are established modifiable risk factors for dementia, the researchers pointed out. What wasn't known was that cardiovascular disease may influence brain volumes a decade earlier in men, Edison said.
"Men also are more likely than women to suffer from heart problems particularly at younger ages," he pointed out. Sex-dependent hormonal differences, variances in fat distribution and inflammation between men and women, and differences in diet, smoking, and alcohol consumption all may be contributing factors, he noted.
"Estrogen in women has protective effects, which reduces LDL levels while increasing HDL levels," he said. "Following menopause, the risk of having heart problems begins to increase in women. The protective effect of estrogen pre-menopause may explain why women face problems a decade later than men."
Edison and colleagues followed 34,425 U.K. Biobank participants with a mean age of about 64. The researchers used Framingham risk scores -- which incorporated age, cholesterol levels, systolic blood pressure, hypertension treatment, smoking, and diabetes status -- to measure general cardiovascular risk.
All participants had abdominal and brain MRIs. Abdominal subcutaneous adipose tissue and visceral adipose tissue volumes were used as markers of obesity. Brain imaging was T1-weighted structural MRI and brain volumetric changes were assessed with voxel-based morphometry. To evaluate the effect of sex, the researchers performed voxelwise models of the interaction of sex and cardiovascular risk on brain volume in different age cohorts.
Cardiovascular risk and obesity showed a bell-shaped relationship with neurodegeneration as participant ages increased. "The detrimental impact of cardiovascular risk was widespread throughout cortical regions, highlighting how cardiovascular risk can impair a range of cognitive functions," the researchers wrote.
The findings underscore "the importance of aggressively targeting cardiovascular risk factors before the age of 55 years to prevent neurodegeneration and Alzheimer's disease, in addition to the benefit of preventing other cardiovascular events, such as myocardial infarction and stroke," they noted.
"Targeting cardiovascular risk and obesity a decade earlier in males than females may be imperative for potential candidates to achieve a therapeutic benefit in preventing neurodegeneration and cognitive decline," they observed.
One possible solution may be repurposing obesity and diabetes drugs to treat Alzheimer's disease, Edison and co-authors suggested. Two phase III trials -- EVOKE and EVOKE Plus -- currently are testing the effects of semaglutide (Ozempic, Wegovy) in early Alzheimer's disease. Anti-hypertensives, metformin, and intranasal insulin also have shown promise, they added.
U.K. Biobank data did not include Alzheimer's biomarkers of amyloid and tau, the researchers noted. Brain atrophy is part of the normal aging process, and differentiating the effects of cardiovascular risk factors on specific neurodegenerative diseases is difficult, the researchers added.
"However, accelerated atrophy to temporal lobe regions is strongly linked with the stage and intensity of Alzheimer's disease," they wrote.