A recently invented blood examination for Alzheimer’s disease not only assists in identifying the neurodegenerative disorder but also reveals the extent of its advancement, as indicated by a study from scholars at Washington University School of Medicine in St. Louis and Lund University in Sweden.
Multiple blood exams for Alzheimer’s disease are already available in clinical settings, including two that utilize technology licensed from WashU. These tests aid physicians in diagnosing the ailment in individuals displaying cognitive issues, yet they do not provide information regarding the clinical stage of the symptoms — specifically, the level of deterioration in cognition or memory linked to Alzheimer’s dementia. Current treatments for Alzheimer’s yield the best results in the initial phases of the disease, so an easy and dependable method for assessing the progression of the condition could guide doctors in determining which patients might gain from pharmacological intervention and to what degree. The newly developed test can also offer insights regarding whether an individual’s symptoms are more likely attributed to Alzheimer’s or another underlying cause.
The research findings are published March 31 in Nature Medicine.
In the investigation, the researchers discovered that concentrations of a protein named MTBR-tau243 in the bloodstream accurately represent the toxic buildup of tau aggregates within the brain and correlate with the severity of Alzheimer’s disease. By examining blood concentrations of MTBR-tau243 from a cohort of individuals experiencing cognitive decline, the researchers could differentiate between those with early or later stages of Alzheimer’s disease and distinctly separate both groups of Alzheimer’s patients from those whose symptoms stemmed from other conditions.
“This blood examination clearly identifies Alzheimer’s tau tangles, which serve as our most reliable biomarker for Alzheimer’s symptoms and dementia,” stated co-senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at WashU Medicine. “Presently in clinical practice, we lack straightforward and accessible measures for Alzheimer’s tangles and dementia, hence a tangle blood exam like this can furnish a far more accurate indication of whether the symptoms are related to Alzheimer’s, potentially aiding doctors in choosing the most appropriate treatments for their patients.”
Monitoring Alzheimer’s disease advancement via blood
Alzheimer’s disease is characterized by the accumulation of a protein, known as amyloid, which forms plaques in the brain, followed by the formation of tau protein tangles years later. Cognitive symptoms begin to manifest when tau tangles become detectable, with worsening symptoms as the tangles proliferate. The definitive method for staging Alzheimer’s disease involves positron emission tomography (PET) scans of the brain for amyloid plaques and tau tangles. Amyloid PET scans provide insights on the presymptomatic and early symptomatic stages, while tau scans are beneficial for tracking the later phases of the disease. Although PET brain scans are highly precise, they are costly, time-intensive, and often unavailable outside major research facilities, limiting their widespread use.
Bateman heads a team focused on developing blood tests for Alzheimer’s disease as a more accessible alternative to brain imaging. They have created two blood tests that closely correlate with the amyloid plaques present in the brain. Both tests are currently utilized by physicians to assist in diagnosis. However, until now, there hasn’t been a blood test that measures tau levels in the brain.
In a previous investigation, Bateman and colleagues — including co-first authors Kanta Horie, PhD, a research associate professor of neurology at WashU Medicine, and Gemma Salvadó, PhD, then a postdoctoral researcher at Lund University, along with co-senior author Oskar Hansson, MD, PhD, a neurology professor at Lund University — demonstrated that cerebrospinal fluid levels of MTBR-tau243 closely correspond to tau tangles in the brain. In the current research, the team expanded their analysis to include blood samples. A blood draw is much simpler to perform than collecting cerebrospinal fluid via a spinal tap.
The researchers devised a method for quantifying MTBR-tau243 levels in blood samples and compared these to the quantity of tau tangles present in their brains as determined by brain scans. They first implemented the approach using data from two cohorts: participants at WashU Medicine’s Charles F. and Joanne Knight Alzheimer Disease Research Center, which included 108 individuals, and a subset of 55 participants from the Swedish BioFINDER-2 cohort. To evaluate the generalizability of their method, they validated it using an independent dataset made up of an additional 739 individuals from the BioFINDER-2 cohort.
The individuals in both cohorts represented nearly all stages of Alzheimer’s disease spectrum, excluding the most severe cases, ranging from the presymptomatic phase when brain amyloid levels heighten yet cognition remains intact, through the early-stage disease characterized by mild cognitive impairments, to late symptomatic disease marked by full-blown dementia. For comparison, cognitively healthy individuals with normal amyloid levels and individuals exhibiting cognitive symptoms attributable to conditions besides Alzheimer’s disease were also included.
The researchers found that blood MTBR-tau243 levels mirrored the quantity of tau tangles in the brain with 92% accuracy. Normal MTBR-tau243 levels were observed in asymptomatic individuals, regardless of their amyloid status, meaning that blood MTBR-tau243 levels remain unchanged between healthy individuals and those at the presymptomatic stage of Alzheimer’s disease with amyloid plaques.
Among individuals exhibiting cognitive symptoms due to Alzheimer’s disease, MTBR-tau243 levels were significantly heightened for those in the mild cognitive impairment stage and markedly higher — up to 200 times — for patients in the dementia stage. These distinctions led to clear differentiation between individuals in early and late stages of Alzheimer’s disease. Simultaneously, MTBR-tau243 levels remained normal in individuals with cognitive symptoms stemming from conditions other than Alzheimer’s, illustrating the test’s efficacy in distinguishing Alzheimer’s dementia from other dementia types.
The underlying technology of the blood test for tau aggregates has been licensed by WashU to C2N Diagnostics, a startup that developed the blood tests for amyloid. These amyloid tests include measurements of another tau variant known as p-tau217.
“I anticipate we will use blood-based p-tau217 to ascertain whether a person has Alzheimer’s disease, but MTBR-tau243 will serve as a highly valuable adjunct in both clinical environments and research trials,” remarked Hansson. “When both of these biomarkers yield positive results, the likelihood that Alzheimer’s is the root cause of a person’s cognitive symptoms increases significantly compared to instances where only p-tau217 is abnormal. This differentiation is vital for selecting the most suitable treatment for each individual patient.”
Blood tests may guide personalized Alzheimer’s therapy
The Food and Drug Administration (FDA) has approved two Alzheimer’s therapies aimed at slowing the disease’s progression, both functioning by reducing amyloid levels in the brain. Horie mentioned that the quantity and diversity of Alzheimer’s medications available may soon increase, as several investigational drugs targeting tau or other facets of Alzheimer’s disease are being developed. With blood tests available to diagnose and stage the condition, physicians would be apt to customize treatments to fit the specific disease state of the patient.
“We are on the verge of entering the era of
“Tailored therapy for Alzheimer’s condition,” Horie stated. “In the initial phases marked by minimal tau aggregates, anti-amyloid treatments might prove more beneficial than during advanced stages. However, following the emergence of dementia accompanied by substantial tau aggregates, anti-tau interventions or one of the various other investigational methods may yield better results. Once we have a blood assessment available for staging the condition, alongside therapies effective at different stages of the ailment, healthcare providers will be better equipped to refine their treatment strategies to suit each patient’s distinct needs.”
Horie K, Salvadó G, Koppisetti RK, Janelidze S, Barthélemy NR, He Y, Sato C, Gordon BA, Jiang H, Benzinger TLS, Erik Stomrud E, Holtzman DM, Mattsson-Carlgren N, Morris JC, Palmqvist S, Ossenkoppele R, Schindler SE, Hansson O, Bateman RJ. Plasma MTBR-tau243 detects tau aggregate pathology in Alzheimer’s condition. Nature Medicine. March 31, 2025. DOI: 10.1038/s41591-025-03617-7.
This research was backed by the Charles F. and Joanne Knight Alzheimer Disease Research Center; the Tracy Family SILQ Center; the National Institutes of Health (NIH), grant number R01AG070941; the Alzheimer’s Association’s Zenith Award; the Hope Center for Neurological Disorders; and the Department of Neurology at WashU Medicine. The Swedish BioFINDER-2 study was funded by the U.S. National Institute on Aging, grant number R01AG083740, the European Research Council, grant number ADG-101096455; the Alzheimer’s Association, grant numbers ZEN24-1069572 and SG-23-1061717; the GHR Foundation; the Swedish Research Council, grant numbers 2022-00775, 2021-02219, and 2018-02052; ERA PerMed, grant number ERAPERMED2021-184; the Knut and Alice Wallenberg foundation, grant number 2022-0231; the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s Disease) at Lund University; the Swedish Alzheimer Foundation, grant numbers AF-980907, AF-994229, and AF-994075; the Swedish Brain Foundation, grant numbers FO2021-0293, FO2023-0163 and FO2022-0204; the Wallenberg AI, Autonomous Systems and Software Program (WASP) and the SciLifeLab and Wallenberg National Program for Data-Driven Life Science (DDLS) joint call for research projects, grant number WASP/DDLS22-066; the Parkinson foundation of Sweden, grant number 1412/22; the Cure Alzheimer’s fund; the Rönström Family Foundation; the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse; the Skåne University Hospital Foundation, grant number 2020-O000028; the Regionalt Forskningsstöd, grant number 2022-1259; and the Swedish federal government under the ALF agreement, grant numbers 2022-Projekt0080 and 2022-Projekt0107. Gemma Salvadó secured funding through the European Union’s Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie action grant agreement number 101061836; the Alzheimer’s Association, fellowship number AARF-22-972612; the Alzheimerfonden, grant number AF-980942; BrightFocus Foundation, fellowship number A2024007F; Greta och Johan Kocks; and the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s Disease) at Lund University.
The information expressed is solely the authors’ responsibility and does not necessarily reflect the official perspectives of the NIH.
About Washington University School of Medicine
WashU Medicine stands as a premier institution in academic medicine, encompassing biomedical research, patient service, and educational initiatives with 2,900 academic staff. Its National Institutes of Health (NIH) research funding portfolio ranks as the second largest among U.S. medical schools and has expanded by 56% over the past seven years. In conjunction with institutional funding, WashU Medicine allocates well over $1 billion each year to basic and clinical research advancement and education. Its faculty practice frequently ranks among the top five nationally, comprising over 1,900 physician faculty serving at 130 locations and who also constitute the medical teams of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine boasts a rich tradition in MD/PhD education, recently dedicating $100 million towards scholarships and curriculum enhancement for its medical students, and fosters excellent training programs across all medical specialties as well as physical therapy, occupational therapy, and audiology and communication sciences.
Originally published on the WashU Medicine webpage
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