LOS ANGELES — A longtime warning sign for Alzheimer’s disease onset may have little to do with cognitive decline after all. Researchers from USC say the buildup of a protein called amyloid beta (Aβ), long considered a “hallmark” of the disease by many experts, could actually be a sign of normal brain aging — not the beginnings of mental decline.
Although this buildup has been connected to Alzheimer’s-related neurodegeneration in the past, Professor Caleb Finch says it’s still unclear how Aβ relates to healthy brain aging. To examine this, study authors analyzed tissue samples from healthy brains and those of patients with Alzheimer’s.
Older and cognitively healthy brains had similar amounts of dissolvable, non-fibrillar amyloid protein in comparison to brain samples from people with dementia. Conversely, Alzheimer’s patients had higher amounts of insoluble Aβ fibrils. This form of the protein is what clumps together into the telltale “plaques” that are common among Alzheimer’s patients’ brains.
These results challenge the traditional thinking that simply having more amyloid protein is an underlying cause of Alzheimer’s disease. Instead, Finch and study first author Max Thorwald say the cause appears to be much more complex. An increase in soluble Aβ may be a part of the normal aging process, while more fibrillary amyloid is the real culprit behind the disease.
“These findings further support the use of aggregated, or fibrillary, amyloid as a biomarker for Alzheimer’s treatments,” Thorwald says in a university release. “The site in which amyloid processing occurs has less precursor and enzyme available for processing, which may suggest the removal of amyloid as a key issue during Alzheimer’s.”
When do people start producing more amyloid beta?
Researchers say amyloid levels start to increase during early adulthood. However, this also varies depending on brain region — making its involvement in Alzheimer’s even more difficult to diagnosis.
The team recommends that studies examining drugs which break down amyloid protein should utilize positron emission tomography (PET) imaging to find out where amyloid levels are changing over time.
“The brain’s frontal cortex has more amyloid production compared to the cerebellum during the aging process in human brains, which coincides with their Alzheimer’s-correlated pathologies in late life,” Thorwald explains. “Future projects should examine amyloid over the life course in both cognitively normal and Alzheimer’s patients with both modulation of amyloid processing or removal of amyloid through monoclonal antibodies currently used in clinical trials for Alzheimer’s treatment.”
The team specifically noted the monoclonal antibody treatment lemanecab, recently approved as an Alzheimer’s treatment by the U.S. Food and Drug Administration. The drug has shown the ability to lower levels of Aβ plaques in patients with mild cognitive impairment or early-stage dementia.
“Lecanemab clearly works to diminish fibrillar amyloid,” Finch says. “However, we are concerned with major side effects, including brain swelling and bleeding, that were 100% more than in controls, with unknown delayed or latent impact.”
The team adds that few cases of Alzheimer’s — the most common form of dementia — only have amyloid plaques as the lone symptom. In most cases, patients experience “complicated tissue abnormalities, from buildup of additional types of protein to small bleeds in the brain.”
“The aging brain is a jungle,” Finch and Thorwald conclude.
The findings are published in the journal Alzheimer’s and Dementia.