Researchers at the UT Health Science Center at Houston are redefining the association between amyloid beta (Aβ) and Alzheimer’s disease. Aβ, a misfolded protein not unique to Alzheimer’s patients, forms amyloid plaques that have been blamed for the onset and progression of Alzheimer’s. “What happens is this amyloid protein–a normal protein we all have that circulates in our fluids–starts to change,” said Claudio Soto from UT. “And it makes this protein more prone to interact and aggregate, binding to other amyloid proteins bound together.” However, the frame of focus on Aβ has changed. “Now it seems clear that the aggregates are not the main culprits, it’s their precursors, so-called beta amyloid oligomers,” said Soto. What’s more, “those beta amyloid oligomers may be circulating in the body for years if not decades before cognitive symptoms arise.”
Soto used this notion to develop a method of detection for the misfolded protein aggregates in the cerebrospinal fluid of patients. The technology, protein misfolding cyclic amplification (PMCA) can detect extremely low concentrations of amyloid oligomers because it amplifies existing misfolded proteins from cerebrospinal fluid samples and breaks them into smaller pieces. These smaller pieces are then used to “seed” amyloid aggregates similar to those found in the Alzheimer’s brain.
As reported by Soto and colleagues in Cell Reports, a Cell Press journal, PMCA predicted Alzheimer’s disease with 90% sensitivity and 92% specificity. Although this level of detection was made possible through tests on cerebrospinal fluid, Soto is planning to adapt the technology for use with blood or urine samples, which are obtained through less invasive methods. If further testing validates the efficacy of PMCA, an FDA-approved test may be on the market in as few as three years, according to Soto.
A test such as PMCA could be used to slow the onset of Alzheimer’s by identifying patients who need early intervention. “What we really need in this field is to know [whether a] person is on the way to Alzheimer’s,” said Soto. “Knowing that, we can start safe treatment [early] that will delay progression of the disease, so much so that people will maybe die from other conditions at old age and not from the disease itself. That’s really the main goal.” Other groups have developed methods to test the blood of patients to determine the level of biomarkers associated with Alzheimer’s. Soto is more optimistic about PMCA because it analyzes the protein linked to dementia: “They measure lipids, not proteins…. We work with the molecule that is supposed to be one of the causes of brain damage; it’s the earliest event in the development of Alzheimer’s.”