Parkinson’s-Linked Protein May Drive Faster Alzheimer’s Progression in Women

Alzheimer’s is defined by beta-amyloid plaques which build up between brain cells and tau tangles that slowly destroy them from the inside. But many people with the disease also accumulate other toxic proteins within the brain. 

Alpha-synuclein, a protein that misfolds across Parkinson’s and dementia with Lewy bodies, is also commonly found clumping up in the brains of around half of Alzheimer’s cases. 

Until recently, scientists could only measure alpha-synuclein during an autopsy. Using new cerebrospinal fluid tests, researchers from the Mayo Clinic could detect these misfolded proteins in living study participants. 

Their latest research, published in JAMA Network Open adds sex to the story. The presence of misfolded alpha-synuclein was linked with 20-fold faster accumulation of tau tangles in women but not in men. 

“This finding may explain why some women experience more aggressive dementia progression,” said lead author Elijah Mak of the Mayo Clinic. “Although we’d like to emphasize that more research is needed with larger sample sizes.”

Alpha-synuclein and Alzheimer’s risk

The researchers used data from 415 older adults, who were on average in their 70s, who took part in the Alzheimer’s Disease Neuroimaging Initiative. Just over half of the participants in the study were women and about half were cognitively impaired at the start of the study. Each participant received two tau-PET brain scans, an average of 1.2 years apart, to measure the levels of tau tangles. They also provided a sample of cerebrospinal fluid which would detect if they had alpha-synuclein buildup in their brain.

In total, 69 tested positive for alpha-synuclein. In women, but not men, testing positive for alpha-synuclein was linked to faster tau accumulation over time and a higher risk of developing cognitive decline.

Geidy Serrano, director of the Brain and Body Donation Program Neuropathology Laboratory at Banner Sun Health Research Institute, who wasn’t involved in the study, told Being Patient that the results align with what she’s observed in her work.

“There’s a higher chance that females who have a higher level of tau in their brain will have more alpha-synuclein in their cerebrospinal fluid,” Serrano said.

But testing positive for alpha-synuclein doesn’t necessarily mean someone will develop Alzheimer’s. “To really tackle this question, we ideally need to follow alpha-synuclein positive people over time to see if they’re more likely to develop Alzheimer’s pathology compared to those who test negative,” Mak said. 

Why is alpha-synuclein involved?

There’s a growing body of research showing that many people have mixed forms of dementia, defined by multiple different protein plaques including alpha-synuclein. 

Women already form tau tangles faster than men. Why is alpha-synuclein further accelerating the process?

“All these proteins, when they’re abnormal, can influence each other,” Serrano said. 

Tau tangles might make alpha-synuclein more prone to misfold and vice-versa. While both of these misfolded proteins might be found in similar regions of the brain in Alzheimer’s, they’re seldom co-localized within the same neuron, fuelling questions about these mechanisms. 

Sex likely plays a role as well. “One hypothesis is that estrogen depletion after menopause may impair protective mechanisms that normally help to clear pathologies,” Dr. Kejal Kantarci, professor at the Mayo Clinic, who helped design and oversee the study, told Being Patient. “Against this backdrop of reduced neuroprotection, alpha-synuclein pathology may act as a second hit that exploits these existing vulnerabilities.”

Other research conducted by the Mayo Clinic showed that early menopause induced by surgery increased the levels of Alzheimer’s biomarkers, providing some proof that hormones play a role. However, Kantarci said that more research is needed.

Understanding the mechanisms behind these sex differences, Serrano said, will help researchers design and test new treatments for the disease.