A Blood Test to Detect Amyloid in the Brain: A Step Forward in Alzheimer’s Screening for People With Down Syndrome

For adults with Down syndrome, Alzheimer’s disease is not a distant risk of old age. Having an extra copy of chromosome 21 also increases the dosage of the amyloid precursor protein gene located on it, often causing related brain pathology to emerge earlier. However, confirming whether amyloid has accumulated in the brain still generally relies on expensive and not readily accessible positron emission tomography (PET). An exploratory study led by the University of Southern California suggests that measuring phosphorylated tau 217 (p-tau217) in blood could become a more accessible first-line screening tool.

The study included 39 adults from the U.S. Down Syndrome Trial-Ready Cohort Study, ranging in age from 25 to 55, none of whom had been diagnosed with dementia at the time. The team measured plasma p-tau217 using Fujirebio’s Lumipulse immunoassay platform and C2N Diagnostics’ PrecivityAD2 mass spectrometry platform, then compared the results with amyloid PET findings. A PET burden above 18 centiloids was classified as positive, and eight participants ultimately met this criterion.

The areas under the curve for distinguishing PET-positive from PET-negative participants were 0.94 for Lumipulse and 0.91 for C2N, with overall accuracy of 90% and 92%, respectively. Both tests had a sensitivity of 88%, while specificity was 90% and 94%, respectively. In this group of participants, both tests had a negative predictive value of 97%, suggesting that they may be particularly suitable for initially ruling out people without substantial amyloid accumulation in the brain and reducing unnecessary PET scans during clinical trial recruitment.

The study also indicated that candidate cutoffs derived for people with Down syndrome cannot be directly based on standards for sporadic Alzheimer’s disease in the general population. In this analysis, the Lumipulse p-tau217 cutoff was 0.21 picograms per milliliter, and the C2N p-tau217 cutoff was 1.77 picograms per milliliter; the candidate cutoff for the PrecivityAD2 APS2 score was 20.5. Using existing cutoffs for sporadic Alzheimer’s disease increased specificity but missed more PET-positive participants, reflecting that the timing and rate of pathological progression in Down syndrome may require different interpretive thresholds.

Another signal came from plasma amyloid. In the study, Aβ42, Aβ40, and their ratio showed no clear association with PET results, and including Aβ42/40 in a composite score did not improve classification performance. This makes p-tau217 alone appear more promising, but the findings are not sufficient to conclude that it can replace imaging. At this stage, a more reasonable use would be as a preliminary screen for clinical trials, helping research teams identify suitable participants within the limited window for therapeutic intervention.

These findings remain preliminary evidence. The study had a cross-sectional design, included only 39 participants and eight PET-positive participants, lacked a neurotypical control group, and could not determine whether blood values can predict subsequent tau deposition or cognitive decline. All candidate cutoffs were also derived from the same small sample, meaning the accuracy and negative predictive values may be overestimated. Until these blood tests have been externally validated in a larger, more diverse Down syndrome population with long-term follow-up, they should not be regarded as standalone diagnostic tools.