The research was led by Christopher Walsh, MD, PhD, Chief of the Division of Genetics and Genomics at Boston Children’s Hospital and an Investigator of the Howard Hughes Medical Institute. Collaborators included Alice Eunjung Lee, PhD, and August Yue Huang, PhD, also of the Division of Genetics and Genomics. All three are Professors at Harvard Medical School and Associate Members of the Broad Institute of MIT and Harvard.

The team says the findings could point to new ways to diagnose and treat Alzheimer’s disease.

“We find that to some extent, Alzheimer’s disease is a little like cancer — driven by the same mutations that drive blood cancers like lymphoma and leukemia,” said Walsh. “This is helpful because we have a lot of drugs to fight cancer and some of them might be useful therapeutically for Alzheimer’s disease.”

Cancer Driver Mutations Found in Alzheimer’s Brains

To investigate, researchers analyzed 149 cancer-driving genes in brain tissue samples from 190 people with Alzheimer’s disease and compared them with samples from 121 healthy brains.

The Alzheimer’s samples contained more single-letter DNA changes than the healthy tissue. Many of these alterations repeatedly appeared in the same five cancer driver genes, suggesting that microglia were accumulating mutations in a specific set of genes.

Microglia serve as the brain’s cleanup crew. These cells remove debris and help eliminate infected, damaged, or dying cells. Scientists had long believed that microglia remain confined to the brain and do not cross the blood brain barrier, unlike many other immune cells that circulate through the bloodstream.

Unexpected Link Between Blood Cells and the Brain

The mutations identified in microglia are commonly associated with blood cancers. That observation prompted the researchers to look for the same mutations in blood samples from people with Alzheimer’s disease.

They did not expect to find them.

Instead, the blood cells from the same Alzheimer’s patients carried the identical cancer-associated mutations.

“It was actually a really unexpected finding that suggests a totally new mechanism for Alzheimer’s disease pathogenesis,” said Huang. “The findings mean that the blood’s immune cells with cancer mutations are likely getting into the brain and contributing to disease.”

How Mutant Immune Cells May Fuel Alzheimer’s

The researchers propose that aging or injury can weaken the blood-brain barrier, allowing immune cells from the bloodstream to enter the brain. Once there, these cells may transform into microglia-like cells.

At the same time, protein clumps that build up in the brain trigger microglia to multiply and respond. Cells that possess a biological advantage are more likely to expand, including the microglia-like cells carrying cancer-related mutations.

According to the researchers, these mutated cells may create a more inflammatory and damaging environment than healthy microglia. As a result, nearby neurons can be harmed and die, contributing to the progression of Alzheimer’s disease.

Potential for New Alzheimer’s Tests and Treatments

The discovery could eventually lead to new approaches for detecting Alzheimer’s risk.

“Because it’s hard to access brain tissue in a living patient, genetic screens using blood samples could be developed to test whether a person carries these mutations, and has an increased risk of developing Alzheimer’s disease,” said Lee.

In a follow-up study posted as a preprint on bioRxiv, Huang and Lee found additional evidence supporting the connection. Their analysis showed that cancer driver mutations detected in blood samples increased Alzheimer’s disease risk independently of APOE4, a well-established genetic risk factor for the disease.

The research was conducted in collaboration with the Icahn School of Medicine at Mount Sinai. Funding was provided by the Howard Hughes Medical Institute, the National Institute on Aging, the NIH Common Fund through the Somatic Mosaicism Across Human Tissues (SMaHT) consortium, and the Suh Kyungbae Foundation (SUHF).

The benefits were even greater when strength training was combined with aerobic exercise. However, researchers found no additional advantage from doing more than 120 minutes of strength training per week. That level of exercise was linked to a 19% lower risk of death from cardiovascular disease and a 27% lower risk of death from neurological disease.

Strength Training and Long-Term Health

While the life-extending benefits of aerobic exercise are well established, the impact of muscle-strengthening activities on overall mortality and specific causes of death has been less clear. Researchers wanted to determine whether strength training alone, or combined with aerobic exercise, could influence those risks.

To investigate, they analyzed data collected over three decades from three major studies: the Health Professionals Follow-up Study (1992-2022), the Nurses’ Health Study (2002-21), and the Nurses’ Health Study II (2003-21). Together, the studies included 147,374 participants (31,540 men and 115,834 women).

Every two years, participants reported how much time they spent each week doing strength training and aerobic exercise. Aerobic activities included brisk walking, running, jogging, swimming, cycling, tennis, squash, strenuous outdoor work, and stair climbing. Strength training included exercises using weights or body weight, such as press ups, squats, and lunges.

At the start of the study, participants were an average of 54 years old. Those who reported higher levels of strength training were generally younger, weighed less, followed healthier lifestyles, and engaged in more aerobic activity than those who did no strength training.

What the Researchers Found

About three quarters (74%) of participants exceeded the recommended 150 minutes of moderate intensity aerobic exercise per week, equivalent to 7.5 MET hours over the long term. METs measure how many calories are burned during physical activity compared with resting.

Nearly half (46%) of participants reported doing some form of strength training.

Over the 30-year follow-up period, 35,798 participants died. Researchers found that higher long-term levels of weekly strength training were associated with a lower risk of death.

After accounting for other factors that could affect the results, participants who performed 90-119 minutes of strength training per week had a 13% lower risk of death from any cause. No additional reduction in risk was observed above 120 minutes per week.

That same 90-119 minute range was also associated with a 19% lower risk of death from cardiovascular disease and a 27% lower risk of death from neurological disease.

Cancer-related benefits appeared at lower amounts of strength training. Participants who performed 1-29 minutes per week had a 21% lower risk of cancer death, while those doing 30-59 minutes per week had an 18% lower risk.

The Power of Combining Cardio and Strength Training

Compared with people who did less than 7.5 MET hours of aerobic activity per week and no strength training, participants who performed strength training alone for 1-59 minutes or 60-119 minutes per week had a 7-11% lower risk of death.

Aerobic exercise on its own also showed strong benefits. Any amount above 7.5 MET hours per week was associated with a 26-43% lower risk of death.

The lowest mortality risk was seen among people who combined high levels of aerobic exercise with strength training. Those who accumulated 30-44 MET hours of aerobic activity per week and 60-119 minutes of strength training had a 45% lower risk of death.

Even greater reductions were observed among participants who performed 45+ MET hours of aerobic activity per week. In that group, the risk of death was 53% to 58% lower regardless of how much strength training they did.

Important Limitations

The researchers emphasized that this was an observational study, meaning it cannot prove that strength training directly caused the reductions in mortality risk.

They also noted several limitations. Exercise habits were self reported, which can introduce inaccuracies. The analysis did not include certain forms of strength training, such as calisthenics and Pilates. In addition, information was not available on the duration of individual workouts or the intensity of strength training sessions, factors that could have influenced the results.

Despite those limitations, the researchers concluded:

“Our findings on different dose-response relationships between long-term resistance training with all-cause and cause-specific mortality suggest that different amounts of resistance training may be needed to optimize benefits across outcomes.

“The observed pattern that adding resistance training further reduced mortality risk across all levels of aerobic activity up to 45 MET hours/week supports current recommendations encouraging both types of activity to maximize mortality benefits.”