Alzheimer’s biomarkers show a tantalizing hint of utility for trail prevention

PHILADELPHIA – Blood tests for Alzheimer’s disease biomarkers may not only be useful for clinical diagnosis, but may also allow preventive therapies to be tested in people who have not yet shown any signs of the condition, they said. the researchers.

In a prospectively followed cohort of elderly people with normal cognition and a low burden of amyloid-β (Aβ) plaque in their brain, baseline plasma levels of tau and Aβ protein species predicted speed at a which Aβ plaques accumulated in 5 years of follow-up. according to Oskar Hansson, MD, PhD, of Skåne University Hospital in Malmö, Sweden, and colleagues.

In particular, participants with a low proportion of two forms of Aβ amino acid (Aβ42/40) and a high ratio of tau217 phosphorylation (ie, tau with a phosphate molecule attached to the threonine-217 residue, % p -tau217) showed dramatically faster plaque accumulation. , the researchers reported in JAMA Neurology. The study was also to be presented at the Alzheimer’s Association International Conference (AAIC).

The report followed one of several by the same researchers, also presented at the AAIC, indicating that a model based on this same pair of biomarkers outperformed human doctors in diagnosing Alzheimer’s disease in people with deficits cognitive

For people without such symptoms, or even with substantial Aβ plaque loads, the findings could pave the way for “primary prevention” trials to identify drugs or other therapies that prevent Aβ from accumulating in the brain. These will be aimed at individuals who, due to family history, genetic characteristics, or other factors, are thought likely to develop Alzheimer’s disease.

Such trials, which must necessarily enroll people without cognitive deficits and low plaque loads, are currently not feasible. If the participants were randomly selected from the general population, either large numbers or decades of follow-up would be needed to determine whether a particular therapy effectively prevents plaque build-up and, hopefully, Alzheimer’s disease.

But if a subpopulation could be identified that can undergo a rapid accumulation of Aβ, then such trials could be shorter and would not require so many participants to confirm an effect. This is where the Aβ42/40 and %p-tau217 blood test comes in.

The study drew mainly from the so-called BioFINDER-2 ongoing cohort study in Sweden, which enrolled cognitively normal seniors from 2017 to 2022 and followed them with tests including periodic PET scans to assess brain Aβ plaque load. Overall, the cohort included 495 people, among whom 384 had low plaque burdens (<40 centiloid). The median age in this latter group was 65 (IQR 54–76). An average of 2.7 years passed from the baseline PET scan to the last.

Faster plaque accumulation was observed in people with low (defined below the median) Aβ42/40 and high (above the median) % p-tau217 at baseline, as opposed to the three other groups with different combinations of high vs. low ratios. The low Aβ42/40, high % p-tau217 group also had the highest mean plaque burden at baseline. This group then saw the accumulation of brain Aβ increase during 5 years of follow-up, while it did not change dramatically in the other three groups. Participants with high baseline Aβ42/40 and low % p-tau217 did not show a mean increase at all brain plaque levels.

Hansson and colleagues also looked at the basis of Aβ42/40 and %p-tau217 individually. As expected, participants with low Aβ42/40 showed faster plaque accumulation than those with high baseline levels. The same was found for high versus low %p-tau217. In both cases, however, the rate of accumulation was lower than with the combination of low Aβ42/40 and high % p-tau217.

That is, the correlation of low baseline Aβ42/40 and high %p-tau217 with subsequent plaque accumulation produced a R² value of 0.48, which means a very strong relationship.

To verify these findings, the researchers performed the same analyzes on two other prospective cohorts: a previous Swedish study now called BioFINDER-1 and another conducted at the Washington University Alzheimer’s Disease Research Center in St. The same pattern of results was seen in these groups, including 205 and 283 initially cognitively normal individuals, respectively, Hansson’s group said.

Importantly, however, many participants – close to half – with low baseline Aβ42/40 and high % p-tau217 did not show particularly rapid plaque accumulation. And a receiver operating characteristic analysis failed to show a significant difference in predictive ability between the combination of two markers and %p-tau217 alone, although both were superior to Aβ42/40. That led the authors to express caution about the immediate application of their results to the designs of prevention trials.

“Future studies in a larger sample and using highly accurate approaches for the quantification of plasma p-tau217 and Aβ42/40 (such as, for example, assays on fully automated platforms) are needed,” they wrote.