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Blood Biomarkers to Detect Alzheimer's Disease in Primary and Secondary Care Settings
TAKE-HOME MESSAGE
- The present study assessed the diagnostic accuracy of a blood test for Alzheimer's disease based on plasma phosphorylated tau 217 levels and the plasma amyloid-β 42 and 40 ratio, known as the amyloid probability score 2 (APS2). The APS2 test demonstrated high diagnostic accuracy, with an area under the curve of 0.96 to 0.97, outperforming traditional clinical evaluations by primary care physicians and dementia specialists, which showed lower accuracy.
- These findings suggest that the APS2 blood test could significantly enhance the early and accurate diagnosis of Alzheimer's disease in both primary and secondary care settings.
abstract
This abstract is available on the publisher's site.
Access this abstract nowIMPORTANCE
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 analyzed 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 analyzed 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.
Additional Info
Disclosure statements are available on the authors' profiles:
Blood Biomarkers to Detect Alzheimer Disease in Primary Care and Secondary Care
JAMA 2024 Jul 28;[EPub Ahead of Print], S Palmqvist, P Tideman, N Mattsson-Carlgren, SE Schindler, R Smith, R Ossenkoppele, S Calling, T West, M Monane, PB Verghese, JB Braunstein, K Blennow, S Janelidze, E Stomrud, G Salvadó, O HanssonFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
A blood test for Alzheimer’s dementia
The first diagnosis of Alzheimer’s dementia was made at the autopsy of Dr. Alzheimer’s patient. Since then, we have questionnaires like the MMSE that can identify dementia, but these tests are not specific to Alzheimer’s dementia. CT imaging and MRI can identify atrophy, but again atrophy is not specific to Alzheimer’s disease. PET scans are useful, but they are expensive and not easily accessible, and you need to deal with radiative tracers. Finally, cerebral spinal fluid analysis for amyloid and tau proteins is the gold standard, but it is invasive, and not everyone has access to this test. So, basically, our current strategies of testing are not ideal for Alzheimer’s dementia.
The pathology of Alzheimer's dementia, as described in that autopsy, was the presence of plaques and tangles. The plaques were abnormal amyloid, which had clumped together and these were outside the neurons. The tangles were abnormal tau proteins inside the neurons. If we could measure these amyloid and tau proteins in the bloodstream, there would be no need for a lumbar puncture.
It makes sense to do this since the vascular system brings nutrients into the brain and carries out garbage, so some of those abnormal proteins could be in the bloodstream. The only problem is that amyloid and tau are also made by other tissues outside the brain. Therefore, we need to figure out what to measure that will best correlate with what is happening inside the brain. It turns out phosphorylated tau is the bad guy that we should measure. The tau protein normally wraps itself around the microtubules. These microtubules are like the subway system inside the neuron: everything travels in them. The phosphorylated tau clumps up and forms tangles. This also means the microtubules are no longer functional, and this might be one of the causes of Alzheimer’s dementia. Hence, comparing the amount of phosphorylated tau with that of normal tau would be a good measurement.
This comparison measurement can also be done with abnormal amyloid. By combining phosphorylated tau and abnormal amyloid numbers together, we can capture both abnormal protein systems. The researchers called this number the amyloid probability score 2, or the APS2 score. So, the question for this study is which of these numbers will be the best in identifying patients with Alzheimer’s disease. In addition, the authors could compare the test to how accurate physicians were in their diagnosis.
The study looked at 1213 patients in Sweden who were being assessed because of their cognitive symptoms. Some were assessed by primary care physicians and some were assessed by dementia specialists. All the patients had the blood test assessment. Of the patients assessed by primary care doctors, 61% were identified as having Alzheimer’s dementia. The specialist did better, identifying 73% of patients with Alzheimer's. However, the blood tests identified 91% of patients with Alzheimer’s disease.
When the authors compared the APS2 score with using only the phosphorylated tau percentage, there was no difference. Both parameters did equally well. So, perhaps in the future, to cut costs, we could just measure the phosphorylated tau as a percentage of normal tau and forget about measuring amyloid since it does not seem to contribute much. The researchers said they need to do more studies in more diverse populations to figure out what are the cut-offs for normal or abnormal.
The fact that adding amyloid numbers did not improve the test is interesting. Perhaps it might mean that the phosphorylated tau is driving the disease process. This makes sense because if the microtubules, the subway system, are not working, then that will lead to cell death. Perhaps future studies could look at longitudinal measurements of tau to see how it behaves.
Prior to this test, many people talked about the APOE4 gene, which is associated with a higher risk of Alzheimer’s dementia. However, the presence of this gene just signifies that an individual is at an increased risk of developing Alzheimer's, but it does not indicate if it is happening right now. This new test is telling us about phosphorylated tau — the bad guy. So, if the bad buy is there, then most likely, the tangles are in the neurons.
Another reason this test is very useful is that we have new treatments for Alzheimer's dementia. Monoclonal antibodies can grab onto the abnormal amyloid and remove it from the brain. This does not fix the tau tangle problem, but at least it corrects the amyloid plaque.
These new treatments would have the most benefit if given early on before the plaque kills off the neuron. And to find people in the early stages of Alzheimer's dementia is very difficult because we can’t wait for symptoms to develop. This is why this blood test is needed because we need to identify these patients early on so that they can be treated.
This blood test will change how we manage Alzheimer’s disease, especially in the earlier stages. When we look at all the results of these tests, we might also understand the role of phosphorylated tau protein in the disease process. Overall, this is a very positive day for patients with Alzheimer’s dementia.