— Research Identifies Biomarkers Linked to Rate of Amyloid Plaque Growth

PHILADELPHIA — Blood tests for Alzheimer’s-related biomarkers are emerging as not only tools for diagnosis, but also as potential aids in testing preventive interventions for individuals who may not yet show symptoms, according to recent findings from researchers.

In a study focusing on older adults with healthy cognitive function and minimal amyloid-β (Aβ) plaque buildup in their brains, initial plasma levels of specific tau and Aβ proteins were found to predict how quickly Aβ plaques accumulated over a 5-year period. The study, conducted by Oskar Hansson, MD, PhD, from Skåne University Hospital in Malmö, Sweden, and colleagues, provides new insights into Alzheimer’s disease progression.

The results point out that participants with a low Aβ42/40 ratio (two forms of the Aβ protein) and elevated phosphorylated tau217 (a form of tau protein with a phosphate molecule at the threonine-217 residue), also known as %p-tau217, experienced significantly faster plaque buildup, according to the report published in JAMA Neurology. These findings were additionally presented at the Alzheimer’s Association International Conference (AAIC).

This research builds on a previous study presented by many of the same researchers at the AAIC, which demonstrated that a biomarker-based model outperformed traditional clinical diagnosis in identifying Alzheimer’s in patients already experiencing cognitive decline.

The implications go beyond diagnosis — for individuals who are asymptomatic or who already have notable plaque buildup, these findings could pave the way for preventive trials. These "primary prevention" trials would focus on discovering interventions that could stop Aβ buildup in the brain before cognitive symptoms manifest, especially in individuals with a high genetic risk or those with a family history of Alzheimer’s disease.

Currently, trials involving participants with low cognitive impairment and minimal Aβ plaques face logistical challenges. Enrolling participants from the general population means studies would require either an extremely large sample size or decades-long monitoring. This makes it difficult to determine whether a therapy is effective in preventing plaque accumulation, and by extension, Alzheimer’s disease.

However, identifying at-risk subgroups where plaques are expected to grow more rapidly could significantly streamline these trials, making them shorter and requiring fewer participants. That’s where the blood tests for Aβ42/40 and %p-tau217 come into play.

The study primarily relied on data from the BioFINDER-2 study in Sweden. This study followed cognitively healthy older adults from 2017 to 2022, employing regular PET scans to monitor Aβ plaque levels. Of the 495 participants, 384 had low Aβ plaque levels at the start (defined as under 40 centiloid units), with a median age of 65 (interquartile range 54-76). The average follow-up between the first and last PET scans was 2.7 years.

The most rapid plaque accumulation during follow-up occurred in participants who had a low Aβ42/40 ratio and high %p-tau217 at baseline. This group, which also had higher initial plaque levels, experienced a sharp increase in brain Aβ over five years. In contrast, other groups with varying combinations of these biomarkers showed little to no change. Those with high baseline Aβ42/40 and low %p-tau217, for example, exhibited no overall increase in plaque levels.

When examining the Aβ42/40 and %p-tau217 markers separately, the researchers found that lower baseline Aβ42/40 ratios and higher %p-tau217 levels predicted faster plaque growth. However, the rate of plaque increase was less dramatic when compared to the combination of both markers.

To put this in perspective, the correlation between low Aβ42/40, high %p-tau217 at baseline, and subsequent plaque buildup yielded an R-squared (R2) value of 0.48, indicating a strong correlation.

To verify these findings, the researchers replicated the analyses using two additional cohorts: BioFINDER-1, an earlier study in Sweden, and a cohort from Washington University's Knight Alzheimer Disease Research Center in St. Louis. These studies, which involved 205 and 283 participants respectively, found similar patterns of results, further validating the results.

However, the researchers advised caution. Nearly half of the participants with low Aβ42/40 and high %p-tau217 did not demonstrate the rapid buildup in plaques that the biomarkers suggested. Moreover, when comparing the predictive accuracy, %p-tau217 alone was comparable to the combined markers, though both methods were more reliable than Aβ42/40 alone. As a result, researchers suggested that more work is needed before these biomarkers are implemented in prevention trial designs.

"Future research with larger sample sizes and improved testing methods, such as automated assays, is necessary to further evaluate these findings," the authors noted.

Disclosures

The research was supported by a variety of funding sources, including government grants from the U.S. and Europe, along with nonprofit foundations. No involvement from pharmaceutical or diagnostic companies was recorded.

Several authors disclosed industry relationships that were unrelated to this study. Certain study authors also reported intellectual property interests related to Aβ and tau diagnostics. One author is employed by C2N Diagnostics.

Primary Source

JAMA Neurology

Source Reference: Janelidze S, et al. "Plasma phosphorylated tau 217 and Aβ42/40 to predict early brain Aβ buildup in people without cognitive impairment" JAMA Neurol 2024; DOI: 10.1001/jamaneurol.2024.2619.