Multiple sclerosis patients less likely to have molecular hallmarks of Alzheimer’s disease

People with multiple sclerosis (MS) are much less likely than people without the condition to have the molecular hallmarks of Alzheimer’s disease, according to new research from Washington University School of Medicine in St. Louis.

The discovery suggests a new avenue of research to search for treatments for Alzheimer’s disease, said Matthew Brier, MD PhD, assistant professor of neurology and radiology and the study’s first author.

Our findings imply that some part of the biology of multiple sclerosis, or the genetics of MS patients, is protective against Alzheimer’s disease. If we could identify which aspect is protective and apply this in a controlled manner, it could yield therapeutic strategies for Alzheimer’s disease.”

Matthew Brier, MD PhD, assistant professor of neurology and radiology and first author of the study

The study, an example of clinical observations directly impacting research, was published in the Annals of Neurology.

The research, a collaboration between WashU Medicine experts in Alzheimer’s disease and MS, was motivated by a suspicion that Brier’s mentor and collaborator, Anne Cross, MD, had developed over decades of treating patients with MS , an immune-mediated disease that attacks the central nervous system. Although her patients lived long enough to be at risk for Alzheimer’s disease or had a family history of the neurodegenerative disease, they did not develop the disease.

“I noticed that I couldn’t find a single MS patient of mine who had the typical Alzheimer’s disease,” says Cross, the Manny and Rosalyn Rosenthal and Dr. John Trotter MS Center Chair in Neuroimmunology. “If they had cognitive problems, I would send them to the memory and aging specialists here at WashU Medicine for an evaluation for Alzheimer’s disease, and those doctors would always come back and say, ‘No, this is not due to the disease of Alzheimer’s.'”

Cognitive impairment caused by MS can be confused with symptoms of Alzheimer’s disease; Alzheimer’s disease can be confirmed with blood and other biological tests.

To confirm Cross’s observation, the research team used a new, FDA-approved blood test developed by researchers at WashU Medicine. The blood test, known as PrecivityAD2, is very effective in predicting the presence of amyloid plaques in the brain. Such plaques are an indicator of Alzheimer’s disease and previously could only be verified with brain scans or spinal taps.

Brier, Cross and their colleagues recruited 100 patients with MS to take the blood test, 11 of whom also underwent PET scans at WashU Medicine’s Mallinckrodt Institute of Radiology. Their results were compared with the results of a control group of 300 people who did not have MS but were comparable to those with MS in terms of age, genetic risk for Alzheimer’s disease and cognitive decline.

“Based on this blood test, we found that 50% fewer MS patients had amyloid pathology compared to their comparable peers,” Brier said. This finding supported Cross’s observation that Alzheimer’s disease seemed less likely to develop in people with MS. It is not clear how amyloid accumulation is related to the cognitive impairment characteristic of Alzheimer’s disease, but it is generally believed that plaque accumulation is the first event in the biological cascade leading to cognitive decline.

The researchers also found that the more typical the patient’s MS history, in terms of age of onset, severity and overall disease progression, the less likely amyloid plaques would build up in the patient’s brain, compared with people with atypical forms of MS. This suggests that there is something in the nature of MS itself that is protective against Alzheimer’s disease, which Brier and Cross plan to investigate.

MS patients typically experience multiple flare-ups of the disease over the course of their lives. During these flare-ups, the immune system attacks the central nervous system, including in the brain. It’s possible that this immune activity also reduces amyloid plaques, the researchers said.

“Perhaps when the amyloid pathology of Alzheimer’s disease developed, the patients with MS had some degree of inflammation in their brains that was fueled by their immune responses,” Brier said. Citing the work of co-author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology, Brier noted that activated microglia, which are part of the brain’s immune response in MS, have been shown to , the amyloid from the brain in animal models.

Brier and Cross have begun the next steps of this research, both to unravel the possible human genetics involved and to test the development of amyloid plaques in animal models representing MS.

Several of Brier and Cross’ co-authors working on this study are affiliated with C2N Diagnostics, a WashU Medicine startup that provided support for the study. The PrecivityAD2 test is based on technology licensed to C2N by the university.