Blood tests improve Alzheimer's detection in Down syndrome patients

New blood tests that detect early changes associated with Alzheimer's disease are making diagnosis easier and accessible to more patients, since they are less invasive than the brain scans or spinal taps typically used for a definitive diagnosis. Identifying the condition in its earlier stages means drugs that slow progression may have the chance to provide greater benefit. 

However, one group of people at elevated risk is rarely included in testing advances. 

Alzheimer's incidence is dramatically higher in people with Down syndrome. Yet Lumipulse G p-tau217/β-Amyloid 1-42, the blood test approved by the Food and Drug Administration in 2025 to aid in the diagnosis of Alzheimer's disease, is not available to them because it hasn't been studied in that population.

Scientists at the USC Epstein Family Alzheimer's Therapeutic Research Institute aim to change that. A new USC-led study in the journal Communications Medicine is the first to engage participants with Down syndrome to evaluate Lumipulse G p-tau217 and PrecivityAD2, a second blood test already in wide use for research. The researchers found that both are effective in detecting Alzheimer's pathology in this population.

"These blood tests are revolutionizing the field," said corresponding author Michael Rafii, MD, PhD, professor of clinical neurology at the Keck School of Medicine of USC and medical director of the USC Epstein Family Alzheimer's Therapeutic Research Institute. "Our work is one step toward making them available to people with Down syndrome. We're encouraging clinicians to use the tests to help families understand the basis for symptoms they might be observing."

The link between Alzheimer's disease and Down syndrome

In Alzheimer's disease, protein clumps called amyloid cause chemical changes in the tau proteins that act as brain cells' scaffolding and transport system. These changes damage the tau proteins, causing them to clump together and tangle, leading to nerve cell death. 

Down syndrome is caused by duplicated genetic material, and that same duplication also causes higher levels of amyloid plaques. By age 40, almost all people with Down syndrome have amyloid plaques in their brain. Not all will develop Alzheimer's, but lifetime risk exceeds 90%. The disease is also the leading cause of death in people with Down syndrome over 35.

Because of these connections, some of our fundamental understanding of Alzheimer's surfaced in research about Down syndrome.

"Being inclusive of this group is not only a scientific imperative, but also an ethical one," said Rafii, director of medical safety for the Alzheimer's Clinical Trials Consortium and co-director of the clinical core for the Alzheimer's Disease Neuroimaging Initiative. "This population taught us so much about the biology of Alzheimer's. It's sad, and wrong, to see them excluded from clinical trials."

Investigating blood tests for Alzheimer's in people with Down syndrome

The study, done in collaboration with scientists at the University of Madison–Wisconsin and C2N Diagnostics, which makes PrecivityAD2, involved 39 participants with Down syndrome. 

Blood from each participant was tested with both the Lumipulse G ptau-217 and the PrecivityAD2 blood tests, which measure amyloid buildup and an altered form of tau protein, known as p-tau217, that is associated with Alzheimer's disease. Each participant also underwent positron-emission tomography (PET), an imaging scan that is considered the gold standard for Alzheimer's diagnosis. 

The investigators found both blood tests accurately detected the presence of abnormal levels of amyloid plaques in the brain.

Applying advanced statistical techniques to their findings, the investigators established preliminary thresholds for people with Down syndrome that differentiated between those with or without Alzheimer's pathology in the brain - and did so with nearly the same accuracy as in the general population.

An easier path to an Alzheimer's disease diagnosis

Currently, there are two Alzheimer's diagnostics available for people with Down syndrome: One is an amyloid PET scan, which is typically offered only at larger or specialized medical centers and involves minor exposure to radiation. The other involves evaluating the fluid that circulates between the brain and the spine, which is gathered through lumbar puncture.

"The blood test is much more accessible as a screening test," said first author Zinayida Schlachetzki, MD, PhD, clinical research program administrator at the USC Epstein Family Alzheimer's Therapeutic Research Institute. "It is easier to perform, less expensive and readily scalable, and it places substantially less burden on patients."

In individuals from the general population, positive blood-based results are confirmed with amyloid PET imaging. These findings suggest that a similar approach could be applied to people with Down syndrome, as the blood tests showed a very low rate of false-negative results.

"There's a huge value to families in ruling out Alzheimer's disease," Rafii said. "Doctors can then search after some other cause for the symptoms, such as untreated depression or undiagnosed sleep apnea."

Making clinical trials for Alzheimer's disease more inclusive

The researchers plan to evaluate the blood tests and diagnostic thresholds in a larger Down syndrome cohort. 

In the meantime, the current results will have immediate impact on research. Next month, the investigators will launch a clinical trial of an FDA-approved Alzheimer's treatment, donanemab, in people with Down syndrome, and blood testing for elevated brain amyloid will be used to select eligible participants.

"We're excited to bring leading-edge science to this population," Rafii said. "If you have a family member with Down syndrome, know that there's hope on the horizon for an accurate blood test to help discern whether any symptoms they show are because of Alzheimer's disease or something else."

About the study

Other study co-authors are Oliver Langford, Michael Donohue, Xiaoyu Zhou, Sonal Sukreet, Sara Abdel-Latif and Robert Rissman, all of USC; Matthew Zammit of the University of Wisconsin–Madison; and Joel Braunstein of C2N Diagnostics.

The study was supported by the National Institutes of Health [R61AG066543].