Plasma Biomarker Predicts Tau, Amyloid Brain Changes in Down Syndrome

Plasma levels of tau phosphorylated at threonine 217 (p-tau217) in persons with Down syndrome reflected tau aggregation in the brain, a cross-sectional study found.

Among 300 people with Down syndrome, plasma p-tau217 accurately distinguished people with abnormal tau positron emission tomography (PET) scans from those with normal scans, especially when combined with age, reported Benjamin Handen, PhD, of University of Pittsburgh in Pennsylvania, and co-authors in JAMA Neurology.

The results mirrored earlier findings for p-tau217 in Alzheimer’s disease (AD).

"Plasma p-tau217 is a very accurate blood-based biomarker of both tau and amyloid β (Aβ) pathological brain changes in Down syndrome that could help guide screening and enrichment strategies for inclusion of individuals with Down syndrome in future AD clinical trials, especially when it is combined with age as a covariate," Handen and colleagues wrote.

"Considering that the costs of PET are high, it is likely that future clinical trials will include initial screening with plasma biomarkers to enroll individuals who are more likely to have brain tau pathology and rule out those who do not need to undergo additional procedures," the researchers continued. "However, relations between tau-PET imaging and plasma biomarkers (including plasma p-tau) in Down syndrome are at present unknown, and understanding these relations is important to facilitate future inclusion of individuals with Down syndrome in clinical trials of AD."

Among people with Down syndrome, duplication of the amyloid precursor protein (APP) gene on chromosome 21 is associated with the aggregation of both amyloid β and tau proteins in the brain and dementia by age 40 in 90% or more.

Elevation of plasma tau has been demonstrated in people with early Alzheimer disease. Phosphorylated tau candidates include p-tau181 as well as p-tau217; a recent direct comparison found small but significant differences favoring p-tau217 in predicting amyloid and tau PET signals.

In their study, Handen and co-authors assessed plasma measurements of p-tau217, glial fibrillary acidic protein (GFAP), amyloid β42/40, neurofilament light (NfL), and total tau (t-tau). Brain PET characterized tau and Aβ.

Their analysis showed:

• Plasma p-tau217 and total tau were significantly increased in people with Down syndrome who had both Aβ and tau positive PET results (A⁺T⁺) compared with A⁺T^- or A^-T^- PET results. The A⁺T^- group had significantly increased levels of both plasma proteins compared with the A^-T^- group.
• Combined p-tau217 and age performed best when detecting tau-PET abnormality in temporal and neocortical regions, with an area under the curve (AUC) range of 0.96-0.99.
• The best models for Aβ-PET status included p-tau217, t-tau, and age (AUC range 0.93-0.95).

Study participants were drawn from the Alzheimer’s Biomarker Consortium–Down Syndrome study and were enrolled between 2016 and 2019. The cohort included 300 people with Down syndrome and 37 siblings without Down syndrome. Mean age of the cohort was 45 and 49.6% were men.

Down syndrome participants were classified as cognitively stable (n=212), having mild cognitive impairment (n=40), having AD (n=33), or not determined (n=15). Compared with data from non-Down syndrome siblings used as controls, cognitively stable Down syndrome participants’ plasma p-tau217, GFAP, and NfL were increased, with further increases seen in the mild cognitive impairment and dementia subgroups.

Among people with Down syndrome, the A⁺T⁺ group, but not the A⁺T^- group, had elevated GFAP levels compared to the A^-T^- group.

"In this study, we show, for the first time to our knowledge, that in participants with DS, p-tau217 and GFAP but not other plasma AD biomarkers (i.e., Aβ42/Aβ40, t-tau, and NfL) were associated with tau-PET status when accounting for age," Handen and colleagues noted.

On secondary cognitive outcomes, higher p-tau217 levels were associated with worse performance on the Down syndrome Mental Status Examination (β −0.24, 95% CI −0.36 to −0.12, P<0.001) and the Cued Recall Test (β −0.40, 95% CI −0.53 to −0.26, P<0.001).

Head-to-head comparison of different p-tau isoforms in the same cohorts of participants with Down syndrome may be warranted, Handen and co-authors noted. However, it is "unlikely that another plasma p-tau variant will greatly outperform the current p-tau217 assay because it performed very well in Down syndrome, with AUCs above 0.9 for both tau- and Aβ-PET," they wrote.

"The excellent performance of plasma p-tau217 in the present study indicates that it could be used even as a stand-alone blood-based biomarker enabling selection and inclusion of adults with Down syndrome in anti-AD clinical trials," Handen and colleagues added.

Prior research showed an association with NfL levels and cognitive scores among people with Down syndrome. However, "we did not find significant associations between plasma NfL and cognitive scores when controlling for the association of p-tau217 with cognition, possibly because of the cross-sectional nature of the present study," Handen and co-authors noted,

Limitations of the study included its lack of longitudinal data. In addition, cohort size was relatively small.

This study was supported by the Swedish Research Council, Knut and Alice Wallenberg Foundation, Marianne and Marcus Wallenberg Foundation, Strategic Research Area MultiPark at Lund University, Swedish Alzheimer Foundation, Swedish Brain Foundation, Parkinson Foundation of Sweden, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Skåne University Hospital Foundation, Regionalt Forskningsstöd, and Swedish federal government. The Alzheimer’s Biomarker Consortium–Down Syndrome is funded by the National Institute on Aging (NIA) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Handen reported grants from the NIA and Eunice Kennedy Shriver National Institute of Child Health and Human Development during the conduct of the study, and grants from Autism Speaks and Roche outside the submitted work.

Janelidze S, et al "Detection of brain tau pathology in Down syndrome using plasma biomarkers" JAMA Neurol 2022; DOI: 10.1001/jamaneurol.2022.1740.