Abnormal increases in the levels of certain proteins are warning signs of dementia. Studies have found that people with higher baseline GFAP are 2.32 times more likely to develop dementia in the future than ordinary people. As early as 15 years before the diagnosis of AD, the levels of GFAP, NEFL and GDF15 in patients’ plasma began to deviate significantly from normal values. Compared with healthy people, the GFAP and NEFL levels of patients with all-cause dementia rise faster over time.
“Even using blood sample data from more than ten years before the diagnosis of dementia patients, the algorithm successfully predicted three common dementias, including AD, with an accuracy rate of about 90%.” Yu Jintai said, “Blood testing is a more accessible detection method that can be used in routine physical examination scenarios, and it is of great significance for screening and early intervention of high-risk groups.”
A week after Nature Aging published the research of Yu Jintai’s team, on February 19, the Hong Kong University of Science and Technology also announced that the team of Professor Ye Yuru of the school had successfully developed a new blood test that can identify AD early by simultaneously detecting changes in the levels of 21 blood biomarkers, with an accuracy rate of 96%.
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Immediately afterwards, on February 22, the New England Journal of Medicine published the research of Professor Jia Jianping’s team from Xuanwu Hospital. Through a 20-year study of the Chinese population, the team revealed for the first time the dynamic changes in cerebrospinal fluid and imaging biomarkers in AD patients from asymptomatic to symptomatic stages.
Studies have shown that, taking the Aβ (β-amyloid protein) target as an example, the time when the Aβ level difference between AD patients and normal people can be traced back to 18 years before the onset of the disease, while NFL (neurofilament light chain) began to increase 9 years before diagnosis. After these changes occurred, patients began to experience hippocampal atrophy and cognitive decline.
Is blood testing reliable?
Because of its convenience, high efficiency and low trauma, blood tests for Alzheimer’s disease have gradually become a hot research direction in academia and are believed to open a new era of AD diagnosis and treatment.
In 2022, Japanese regulators approved the country’s first AD blood test kit, which only requires 10-30ml of blood and can complete the test in 17 minutes; the US FDA has successively granted several AD blood test kits breakthrough medical device certification; the British Alzheimer’s Association announced at the end of last year that it would launch a £5 million project with the goal of being able to determine whether someone has AD in a few seconds with a drop of blood.
Yu Jintai’s team also said that if the follow-up progress of this study goes smoothly, it can be applied to clinical testing in half a year to screen out people at high risk of AD.
But early detection has also caused concern in academia. A study published by Dutch scholars in 2015 estimated that more than 10% of cognitively normal 50-year-olds tested positive for Aβ in cerebrospinal fluid, and 23% of those aged 70 and above, and most of these people will never suffer from dementia in their lifetime.
“The key is to find an accurate marker that has a strong direct correlation with the onset of dementia and has clear intervention measures, otherwise early screening will cause panic.” Yu Jintai said, “Previous studies have focused on Aβ targets. In recent years, it has been gradually found that the reliability of peripheral blood Aβ in predicting the onset of AD is not high.”
Price is also a key consideration. Yu Jintai said that currently recognized peripheral blood biomarkers with high specificity and promising prospects include pTau 217 and GFAP. Data show that the detection price of pTau 217 is about US$200-500.
“The problem with p-tau217 is that the detection cost is too high. GFAP is cheap, but its specificity is slightly inferior. To find a golden detection indicator with high accuracy and high accessibility like ‘diagnosis of diabetes by blood sugar’, there is still a lot of research work to be done.”
But Yu Jintai believes that with the development and progress of biotechnology, these are only a matter of time. “Once there is a major breakthrough in early diagnosis, combined with innovative therapies, Alzheimer’s disease is expected to become a disease that can be conquered.” Yu Jintai said.
Alzheimer’s disease is preventable and treatable
On February 12 and February 22 this year, Nature and the New England Journal of Medicine published commentary articles respectively, affirming the research results of Yu Jintai and Jia Jianping’s team. The New England Journal of Medicine said, “Determining the nodes of this series of physiological events is crucial to providing the start time for AD prevention and treatment in the future.” “Timing is everything. The importance of the work of Jia Jianping and others cannot be overemphasized.” The reason why this series of
studies has attracted great attention, Yu Jintai said, “is that for a long time to be foreseeable, the effectiveness of global AD prevention, control and treatment will be strongly linked to the time of initial intervention for patients.”
Due to the hidden onset of AD, pathological changes in the brain far earlier than the onset of symptoms, and the long-term lack of specific drugs, it has been regarded by the public as an “immortal disease” that seems to be left to fate. “But this is a cognitive misunderstanding.” Yu Jintai said.
The occurrence and development of AD can be divided into three periods. Including “preclinical period”, that is, pathological changes have occurred in the brain, but the patient has no symptoms, “mild cognitive impairment period” and “dementia period”, the whole course of the disease can exceed 20 years. It is currently recognized that the intervention methods that can effectively prevent the onset of AD are concentrated in the preclinical and mild cognitive impairment stages.
In 2020, after five years of collaborative research with 17 top expert teams at home and abroad, Yu Jintai’s team took the lead in formulating the world’s first international guideline for evidence-based prevention of AD. The guideline can prevent at least 40% of AD incidence through 21 methods including vascular risk factor control and weight, blood pressure, sleep, exercise, and diet management.
When entering the dementia stage, “common symptomatic treatment drugs include cholinesterase inhibitors, NMDA receptor antagonist therapeutic agents, etc., which can significantly improve cognitive symptoms in the early stage and improve the quality of daily life. At the same time, the combination of some low-dose psychotropic drugs can also solve the emotional and mental behavioral problems that may occur in dementia patients.” Yu Jintai said.
In the field of specific drugs, innovative Aβ disease-modifying therapies represented by Lencanel and Donetuzumab were recognized as breakthrough therapies by the FDA (U.S. Food and Drug Administration) in 2023. The former was approved by China’s Food and Drug Administration on January 9 this year. The latter has also been applied for in China. Phase III clinical trials show that nearly half of early symptomatic AD patients (47%) did not show disease progression within one year after taking the drug.
“But the earlier these treatments are used, the better the effect.” Yu Jintai said that he sees more than 4,000 AD patients every year, about 80% of whom are in the middle and late stages, and have obvious symptoms such as cognitive impairment. “At this time, drug treatment and lifestyle intervention can also improve symptoms to a certain extent, but it can no longer prevent the development of the disease. Most patients will inevitably experience worsening symptoms after one year.”
According to a report from the American Alzheimer’s Association, early diagnosis of Alzheimer’s disease may save trillions of dollars in medical costs. However, due to the high price, cumbersome operation, and invasiveness, people with no symptoms or mild symptoms will not easily accept examinations including PET scans and spinal punctures.
“In recent years, the role of blood biomarkers in AD diagnosis has received more and more attention, and many markers with excellent diagnostic performance prospects have been developed and clinically verified.” Yu Jintai said, “But the accuracy of related peripheral blood tests remains to be seen. Including stable verification in different clinical cohorts, distinguishing between “positive” and “negative” blood biomarker cutoff values is also a difficulty in current research.”
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