“Based on human genetics data, those with a lifelong higher lean muscle mass had a 12 percent lower risk of Alzheimer’s disease and exhibited superior cognitive performance,” reports Dr. Iyas Daghlas, the lead study author from the University of California-San Francisco.
Obesity is associated with an increased risk of AD in numerous studies, which may be due to the increased inflammation, insulin resistance, and higher levels in fat tissues of amyloid beta proteins that can be harmful to brain health. Additionally, lower levels of lean muscle are associated with an increased risk of AD, but it is less clear if this precedes or succeeds a diagnosis.
To obtain genetic evidence in support of AD risk and lean muscle, Mendelian randomization techniques were used to analyze data from over a million volunteers which included 450,243 participants who were enrolled in the UK Biobank, an independent sample of 21,982 people with and 41,944 people without AD, and another independent sample of 7329 people with and 252,879 people without AD to validate the findings, along with 269,867 people who took part in genes and intelligence studies.
Bioimpedance was used to estimate lean muscle mass and fat tissue in the legs and arms of the participants, and the results were adjusted for various factors like age, sex, and genetic ancestry.
584 genetic variants were associated with lean muscle mass, none were located on the APOE gene region that is associated with vulnerability to AD. According to the researchers, these genetic variants combined explained 10% of the difference in lean muscle mass in the legs and arms of the participants.
On average, having more lean muscle was associated with a statistically robust lower risk of AD, even after accounting for various factors. Lean mass was also associated with better performance on cognitive testing/tasks. However, this association did not explain the protective effect on AD risk, nor was body fat, adjusted for lean mass, associated with the risk of AD, but it was associated with poorer cognitive performance.
“These analyses provide new evidence supporting a cause-and-effect relation between lean mass and risk of Alzheimer’s disease,” say the researchers. The findings also “refute a large effect of fat mass on the risk of Alzheimer’s disease and highlight the importance of distinguishing between lean mass and fat mass when investigating the effect of adiposity measures on health outcomes,” they add.
It was not clear whether increasing lean muscle could reverse the pathology of AD in those with preclinical disease or mild cognitive impairment. The researchers concluded that if future studies support their findings, “public health efforts to shift the population distribution of lean mass, potentially through campaigns to promote exercise and physical activity, might reduce the population burden of Alzheimer’s disease.”
“Potentially relevant secreted myokines include irisin, brain-derived neurotrophic factor 5, and cathepsin B. Identifying the key causal pathways might lead to the development of treatments that leverage and enhance the neuroprotective effects of lean mass,” Dr. Daghlas’ team adds.
But they caution: “Our findings need to be replicated with independent lines of complementary evidence before informing public health or clinical practice. Also, more work is needed to determine the cut-off values for age and degree of pathology of Alzheimer’s disease after which modifications of lean mass might no longer reduce the risk.”
