MS patients are less likely to have molecular features of Alzheimer’s disease

People with multiple sclerosis (MS) are much less likely than those without it 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 through which to search for treatments for Alzheimer’s, said Matthew Brier, MD PhD, assistant professor of neurology and radiology and first author of the study.

Our findings suggest that some component of MS biology, or the genetics of MS patients, is protective against Alzheimer’s disease. If we could identify which aspect is protective and apply it in a controlled way, this could inform 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 influencing research, was published in Annals of Neurology.

A collaboration between WashU Medicine’s experts in Alzheimer’s and multiple sclerosis, the research was prompted by a suspicion that Brier’s advisor and collaborator, Anne Cross, MD, had been developing a decades-long treatment for patients with multiple sclerosis, a disease caused by from the immune system attacking the central nervous system. Although her patients lived long enough to be at risk of Alzheimer’s 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 typical Alzheimer’s disease,” said Cross, Manny and Rosalyn Rosenthal, and Drs. John Trotter MS Center in Neuroimmunology. “If they had cognitive problems, I would send them to the memory and aging specialists here at WashU Medicine for an Alzheimer’s evaluation, and those doctors would always come back and say, ‘No, it’s not Alzheimer’s.’

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

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

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

“We found that 50% fewer MS patients had amyloid pathology compared to their matched peers, based on this blood test,” Brier said. This finding supported Cross’s observation that Alzheimer’s disease appeared to be less likely to develop in people with MS. It is not clear how the accumulation of amyloid is linked to the cognitive decline that is typical of Alzheimer’s disease, but the accumulation of plaques is generally understood to be the first event in the biological cascade that leads to cognitive decline.

The researchers also found that the more typical a patient’s MS history was, in terms of age of onset, severity and overall progression of the disease, the less likely they were to have amyloid plaque buildup in that patient’s brain compared to those with atypical manifestations of MS. This suggests that there is something about the nature of MS itself that is protective against Alzheimer’s, which Brier and Cross plan to investigate.

Patients with multiple sclerosis generally have multiple flares of the disease during their lifetime. During these flare-ups, the immune system attacks the central nervous system, including 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 was developing, MS patients had some degree of inflammation in their brains that was triggered by their immune responses,” Brier said. Referring to the work of co-author David M. Holtzman, MD, Barbara Burton, and the Reuben M. Morriss III Distinguished Professor of Neurology, Brier noted that activated microglia, which is part of the brain’s immune response in MS, has been shown to that clears amyloid from the brain in animal models.

Brier and Cross began the next steps in this research, both to investigate the possible human genetics involved, and to test the development of amyloid plaque in animal models that represent MS.

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