Study finds combined genetic risk, lower BMI, predict Alzheimer’s disease progression

Though obesity in midlife is linked to an increased risk for Alzheimer's disease, new research suggests that a high body mass index (BMI) later in life doesn't necessarily translate to greater chances of developing the brain disease, according to a new study published in the Journals of Gerontology: Series A.

For this study, the research team obtained data from the Alzheimer's Disease Neuroimaging Initiative, compiling a sample of 104 people for whom BMI and polygenic risk scores were available. Fifty-two individuals whose mild cognitive impairment (MCI) had progressed to Alzheimer's in 24 months were matched against demographically similar people whose MCI diagnosis did not change over two years. Their average age was 73.

Statistical analysis showed that individuals with mild cognitive impairment who had both a lower BMI and higher genetic risk for Alzheimer's were more likely to progress to Alzheimer's disease within 24 months compared to people with a higher BMI.

In the study, researchers compared data from two groups of people who had been diagnosed with mild cognitive impairment, half whose disease progressed to Alzheimer's in 24 months and half whose condition did not worsen.

The researchers zeroed in on two risk factors, BMI and a cluster of genetic variants associated with higher risk for Alzheimer's disease. Their analysis showed that a higher genetic risk combined with a lower BMI was associated with a higher likelihood for progression to Alzheimer's, and that the association was strongest in men.

The finding does not suggest people should consider gaining weight in their later years as a preventive effort. Instead, researchers speculate that lower BMI in these patients was likely a consequence of neurodegeneration, the progressive damage to the brain that is a hallmark of Alzheimer's. Brain regions affected by Alzheimer's are also involved in controlling eating behaviors and weight regulation.

Previous research has found a link between obesity and negative cognitive outcomes, but in older adults closer to the age at which Alzheimer's disease is diagnosed, the results have been mixed, Hayes said. And though a variant to the gene known as APOE4 is the strongest single genetic risk factor for Alzheimer's, it explains only about 10 to 15 percent of overall risk, the researchers said.

The effect of the BMI-genetic risk interaction was significant even after considering the presence of beta-amyloid and tau proteins in the patients' cerebrospinal fluid, the core biomarkers of Alzheimer's disease.

The relationship between low BMI and high genetic risk and progression to Alzheimer's was stronger in males than in females, but a larger sample size and additional biological data would be needed to expand on that finding, the researchers said. Since brain changes can begin long before cognitive symptoms surface, a better understanding of the multiple risk factors for Alzheimer's could open the door to better prevention options, they said.

To date, scientists have suggested preventive steps include maintaining a healthy weight and diet and participating in activities that reduce inflammation and promote neurofunctioning, such as exercise and mentally stimulating activities.