Novel blood-based method diagnoses Alzheimer’s disease with high accuracy

Alzheimer's disease (AD) accounts for 60–80% of global dementia cases, with its core pathological feature being the misfolding and aggregation of β-amyloid (Aβ) proteins in the brain. These misfolded Aβ "seeds" can induce conformational changes in normal Aβ proteins in a prion-like manner, continuously propagating and amplifying, ultimately leading to neuronal damage and cognitive decline. Currently, definitive diagnosis of AD primarily relies on cerebrospinal fluid (CSF) testing or positron emission tomography (PET). However, these methods have limitations such as high invasiveness, expensive costs, or poor accessibility. Although blood biomarkers have shown promising results in recent years, research targeting the critical pathological process of Aβ aggregation seeding activity remains relatively limited.

Recently, a research team led by Professor Jianping jia from Xuanwu Hospital of Capital Medical University, China, published significant findings online in the Chinese Medical Journal on June 16, 2026. The team successfully developed a novel blood-based diagnostic method using real-time ultrasonic protein misfolding cyclic amplification (PMCA) technology. This method can accurately diagnose AD and mild cognitive impairment (MCI) due to AD by detecting plasma Aβ aggregation seeding activity, achieving a diagnostic accuracy exceeding 90% in the validation cohort.

The research team employed real-time ultrasonic PMCA technology, marking its first application in detecting plasma Aβ seeding activity. "Compared to traditional quaking-based methods, this ultrasonic technology can detect Aβ oligomers at concentrations as low as 1 femtomole," says Prof. Jia. This method integrates ultrasonic and fluorescence techniques, enabling real-time tracking of dynamic changes in Aβ aggregation during the amplification process and completing detection within 24 hours. The advantages of ultrasonic technology are attributed to its unique physical mechanisms: the spherical interfaces and energy generated by ultrasonic cavitation promote fibril formation, while the localized heat and shear forces induce the misfolding of normal Aβ proteins, thereby substantially enhancing amplification efficiency.

To ensure reliability, the study employed a rigorous two-stage design. The discovery phase included 120 participants to establish preliminary diagnostic efficacy, while the validation phase confirmed the method's stability in an independent cohort of 429 participants (comprising cognitively normal individuals, patients with MCI due to AD, AD patients, and non-AD dementia patients).

In the validation cohort, AD patients showed significantly higher plasma Aβ seeding activity compared to cognitively normal individuals and non-AD dementia patients (P < 0.001). Patients with MCI due to AD also exhibited significantly elevated seeding activity, revealing the method's capacity for early-stage identification. Furthermore, immunodepletion experiments confirmed that the detected seeding activity was indeed induced specifically by Aβ "seeds" in the plasma.

Receiver operating characteristic (ROC) curve analysis demonstrated the excellent diagnostic performance of plasma Aβ seeding activity. The area under the ROC curve (AUC) reached 0.93 for distinguishing AD from cognitively normal individuals, 0.91 for distinguishing AD from non-AD dementia, 0.92 for distinguishing MCI due to AD from cognitively normal individuals, and 0.90 for distinguishing MCI due to AD from non-AD dementia.

"The most important significance of this study lies in providing clinicians with a minimally invasive, efficient, and accurate AD diagnostic tool," says Prof. Jia. This method can facilitate large-scale screening in communities and primary healthcare facilities, promoting early detection and intervention of AD. It effectively differentiates AD from other types of dementia to avoid misdiagnosis, assesses disease severity, and monitors disease progression. Additionally, it provides an objective biomarker for subject screening and efficacy evaluation in clinical trials of AD drugs.

Moving forward, the research team plans to conduct larger-scale clinical validation studies and long-term follow-ups to assess the biomarker's ability to predict disease progression. This research marks a critical transition in AD diagnosis from relying on invasive examinations to minimally invasive blood testing, which is expected to bring earlier, more accurate diagnoses and more timely treatments to patients.