New research supports the hypothesis that Alzheimer’s disease is caused by a decline in levels of a protein called amyloid-beta. UC researchers led by Alberto Espay, MD, and Andrea Sturchio, MD, in collaboration with the Karolinska Institute in Sweden, published the research on Oct. 4 in the Journal of Alzheimer’s Disease.
The research is focused on a protein called amyloid-beta. The protein normally carries out its functions in the brain in a form that is soluble, meaning dissolvable in water, but it sometimes hardens into clumps, known as amyloid plaques. The conventional wisdom in the field of Alzheimer’s research for more than 100 years stated that Alzheimer’s was caused by the buildup of amyloid plaques in the brain. But Espay and his colleagues hypothesized that plaques are simply a consequence of the levels of soluble amyloid-beta in the brain decreasing. These levels decrease because the normal protein, under situations of biological, metabolic or infectious stress, transform into the abnormal amyloid plaques.
“The paradox is that so many of us accrue plaques in our brains as we age, and yet so few of us with plaques go on to develop dementia,” said Espay, professor of neurology in the UC College of Medicine, director and endowed chair of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the UC Gardner Neuroscience Institute and a UC Health physician. “Yet the plaques remain the center of our attention as it relates to biomarker development and therapeutic strategies.” Sturchio noted that many research studies and clinical trials over the years have aimed at reducing amyloid plaques in the brain, and some have lessened plaques, but until the September 27 announcement of a positive trial by Biogen and Eisai (lecanemab), none slowed the progression of Alzheimer’s disease. More importantly, in support of their hypothesis, in some clinical trials that reduced the levels of soluble amyloid-beta, patients showed worsening in clinical outcomes.
“I think this is probably the best proof that reducing the level of the soluble form of the protein can be toxic,” said Sturchio, first author of the report and adjunct research instructor at UC’s College of Medicine. “When done, patients have gotten worse.” Previous research from the team found that regardless of the buildup of plaques in the brain, people with high levels of soluble amyloid-beta were cognitively normal, while those with low levels of the protein were more likely to have cognitive impairment.
In the current study, the team analyzed the levels of amyloid-beta in a subset of patients with mutations that predict an overexpression of amyloid plaques in the brain, which is thought to make them more likely to develop Alzheimer’s disease. “One of the strongest supports to the hypothesis of amyloid toxicity was based on these mutations,” Sturchio said. “We studied that population because it offers the most important data.”
Even in this group of patients thought to have the highest risk of Alzheimer’s disease, the researchers found similar results as the study of the general population. “What we found was that individuals already accumulating plaques in their brains who are able to generate high levels of soluble amyloid-beta have a lower risk of evolving into dementia over a three-year span,” Espay said.
The research found that with a baseline level of soluble amyloid-beta in the brain above 270 picograms per milliliter, people can remain cognitively normal regardless of the amount of amyloid plaques in their brains. “It’s only too logical, if you are detached from the biases that we’ve created for too long, that a neurodegenerative process is caused by something we lose, amyloid-beta, rather than something we gain, amyloid plaques,” Espay said. “Degeneration is a process of loss, and what we lose turns out to be much more important.”