Scientists have taken another major stride toward the long-sought goal of diagnosing Alzheimer’s disease with a simple blood test after researchers reported that a blood test was significantly more accurate than doctors’ interpretation of cognitive tests and CT scans in signalling the condition.
The study found that about 90% of the time the blood test correctly identified whether patients with memory problems had Alzheimer’s.
Dementia specialists using standard methods that did not include expensive PET scans or invasive spinal taps were accurate 73% of the time, while primary care doctors using those methods got it right only 61% of the time.
The findings were published in JAMA Neurology.
“Not too long ago measuring pathology in the brain of a living human was considered just impossible,” said Dr Jason Karlawish, a co-director of the Penn Memory Centre at the University of Pennsylvania who was not involved in the research. “This study adds to the revolution that has occurred in our ability to measure what’s going on in the brain of living humans.”
The New York Times reports that the results, presented at the Alzheimer’s Association International Conference in Philadelphia, are the latest milestone in the search for affordable and accessible ways to diagnose Alzheimer’s, a disease that afflicts nearly 7m Americans and more than 32m people worldwide.
Medical experts say the findings bring the field closer to a day when people might receive routine blood tests for cognitive impairment as part of primary care check-ups, similar to the way they receive cholesterol tests.
“Now, we screen people with mammograms and PSA or prostate exams and other things to look for very early signs of cancer,” said Dr Adam Boxer, a neurologist at the University of California, San Francisco, who was not involved in the study. “And I think we’re going to be doing the same thing for Alzheimer’s disease and hopefully other forms of neurodegeneration.”
In recent years, several blood tests have been developed for Alzheimer’s. They are currently used mostly to screen participants in clinical trials and by some specialists like Boxer to help pinpoint if a patient’s dementia is caused by Alzheimer’s or another condition.
The new research was conducted in Sweden, and experts cautioned that, for use in the United States, the results should be confirmed in a diverse American population.
Experts emphasised that blood tests should be only one step in a screening process and, most importantly, should be used only for people with memory loss and other symptoms of cognitive decline – not for people who are cognitively healthy to predict if they will develop Alzheimer’s.
“If you would detect Alzheimer’s disease pathology in the person without cognitive impairment, there would be no therapies to offer,” said Dr Oskar Hansson, a professor of clinical memory research at Lund University in Sweden and the senior author of the study.
The pathology of Alzheimer’s disease can begin developing about 20 years before any symptoms, but sometimes dementia does not develop, or people die from other causes before it does. Given that, Hansson said, there is a “risk of anxiety and other reactions, psychological reactions, to such a test result”.
Testing recommendations could change if scientists find drugs that can delay or halt Alzheimer’s pathology in people who have not yet developed cognitive problems. But for now, said Boxer, “most of us feel it would not be ethical to use it in people who don’t yet have symptoms, unless it’s in the context of a research study”.
Medical experts also said that blood tests should be performed only after administering tests that assess memory and thinking abilities, and CT scans that seek alternative causes like strokes or brain tumours.
And blood test results should be confirmed by one of the gold-standard methods: PET scans or spinal taps to measure a protein, amyloid, that accumulates and forms plaques in the brains of patients with Alzheimer’s.
In the wake of the recent approval of the drugs Leqembi and Kisunla, which attack amyloid, blood tests may also help identify patients who are eligible for the medications: those in mild stages of the disease who have amyloid in their brains. For such patients, the drugs may modestly slow cognitive decline, but also carry risks of swelling and bleeding in the brain.
The recent study used a blood test that focuses on a form of the tau protein that sprouts into tangles in the brains of people with Alzheimer’s.
Measuring that form, called ptau-217, was found to give the most accurate assessment of Alzheimer’s pathology in a comparison of various Alzheimer’s blood tests that will also be presented at the Alzheimer’s Association conference.
Tau is more closely linked to cognitive decline than amyloid, and tau tangles form later than amyloid plaques in Alzheimer’s patients. The test in the study also tracks amyloid.
Tests like this are available in the US for use by doctors, not consumers. Last year, a test that measures only amyloid was marketed directly to consumers, raising concerns among Alzheimer’s experts who believe that until preventative treatments are available, doctors should decide who is eligible for such tests.
That company has since stopped marketing the test to consumers.
The new study included about 1 200 patients with mild memory problems. About 500 of them visited primary care physicians; the rest sought specialist care at memory clinics. Dr Sebastian Palmqvist, an associate professor of neurology at Lund University who led the study with Hansson, said that first, about 300 patients in each group were given the blood test, and results were compared with spinal taps or PET scans.
Then the researchers wanted to see how the blood test compared with the judgment of doctors after they administered cognitive tests and CT scans.
“We started asking both the primary care physicians and our own dementia specialists: after the standard evaluation, do you think your patient has Alzheimer’s disease?” Palmqvist said.
In evaluations of about 200 patients, primary care doctors who thought patients had Alzheimer’s were wrong 36% of the time. And when they thought patients did not have Alzheimer’s, they were wrong 41% of the time. Memory specialists who evaluated about 400 patients did somewhat better – they were wrong 25% of the time when they thought patients had Alzheimer’s and wrong 29% of the time when they thought patients didn’t.
The blood test was wrong only about 10% of the time.
The blood test’s accuracy was highest with patients who had already progressed to dementia, and was slightly lower with patients in a pre-dementia stage called mild cognitive impairment, Palmqvist said.
It was not very accurate with the earliest stage, called subjective cognitive decline, when patients begin to perceive their memory to be failing. Hansson said that lower accuracy probably occurred because many people with subjective cognitive decline do not turn out to have Alzheimer’s.
In the study, patients who visited primary doctors were older and had fewer years of education than those who visited memory specialists. Primary care patients were also more likely to have other medical conditions, like diabetes and cardiovascular disease.
Experts said it was significant that the blood test performed well in people with such conditions, especially patients with kidney disease, which can cause high ptau-217 levels that are not linked to Alzheimer’s.
One remaining hurdle, Boxer and Karlawish said, is for blood test analysis to be easily integrated into hospital laboratory systems rather than requiring outside labs. The hope, they said, is that if primary care doctors can eventually use these tests, it will increase access to screening, especially for people from racial and ethnic minorities and low-income and rural communities.
Study details
Blood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Care
Sebastian Palmqvist, Pontus Tideman, Oskar Hansson et al.
Published in JAMA Neurology on 28 July 2024
Abstract
Importance
An accurate blood test for Alzheimer disease (AD) could streamline the diagnostic workup and treatment of AD.
Objective
To prospectively evaluate a clinically available AD blood test in primary care and secondary care using predefined biomarker cutoff values.
Design, setting, and participants
There were 1213 patients undergoing clinical evaluation due to cognitive symptoms who were examined between February 2020 and January 2024 in Sweden. The biomarker cutoff values had been established in an independent cohort and were applied to a primary care cohort (n = 307) and a secondary care cohort (n = 300); 1 plasma sample per patient was analysed as part of a single batch for each cohort. The blood test was then evaluated prospectively in the primary care cohort (n = 208) and in the secondary care cohort (n = 398); 1 plasma sample per patient was sent for analysis within 2 weeks of collection.
Exposure
Blood tests based on plasma analyses by mass spectrometry to determine the ratio of plasma phosphorylated tau 217 (p-tau217) to non-p-tau217 (expressed as percentage of p-tau217) alone and when combined with the amyloid-β 42 and amyloid-β 40 (Aβ42:Aβ40) plasma ratio (the amyloid probability score 2 [APS2]).
Main outcomes and measures
The primary outcome was AD pathology (determined by abnormal cerebrospinal fluid Aβ42:Aβ40 ratio and p-tau217). The secondary outcome was clinical AD. The positive predictive value (PPV), negative predictive value (NPV), diagnostic accuracy, and area under the curve (AUC) values were calculated.
Results
The mean age was 74.2 years (SD, 8.3 years), 48% were women, 23% had subjective cognitive decline, 44% had mild cognitive impairment, and 33% had dementia. In both the primary care and secondary care assessments, 50% of patients had AD pathology.
When the plasma samples were analyzed in a single batch in the primary care cohort, the AUC was 0.97 (95% CI, 0.95-0.99) when the APS2 was used, the PPV was 91% (95% CI, 87%-96%), and the NPV was 92% (95% CI, 87%-96%); in the secondary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 83%-93%), and the NPV was 87% (95% CI, 82%-93%). When the plasma samples were analysed prospectively (biweekly) in the primary care cohort, the AUC was 0.96 (95% CI, 0.94-0.98) when the APS2 was used, the PPV was 88% (95% CI, 81%-94%), and the NPV was 90% (95% CI, 84%-96%); in the secondary care cohort, the AUC was 0.97 (95% CI, 0.95-0.98) when the APS2 was used, the PPV was 91% (95% CI, 87%-95%), and the NPV was 91% (95% CI, 87%-95%). The diagnostic accuracy was high in the 4 cohorts (range, 88%-92%). Primary care physicians had a diagnostic accuracy of 61% (95% CI, 53%-69%) for identifying clinical AD after clinical examination, cognitive testing, and a computed tomographic scan vs 91% (95% CI, 86%-96%) using the APS2. Dementia specialists had a diagnostic accuracy of 73% (95% CI, 68%-79%) vs 91% (95% CI, 88%-95%) using the APS2. In the overall population, the diagnostic accuracy using the APS2 (90% [95% CI, 88%-92%]) was not different from the diagnostic accuracy using the percentage of p-tau217 alone (90% [95% CI, 88%-91%]).
Conclusions and relevance
The APS2 and percentage of p-tau217 alone had high diagnostic accuracy for identifying AD among individuals with cognitive symptoms in primary and secondary care using predefined cutoff values. Future studies should evaluate how the use of blood tests for these biomarkers influences clinical care.
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