Blood Biomarkers for the Diagnosis of Alzheimer’s Disease

By Matthew E. Fink, MD, Editor

SYNOPSIS: In this population-based study of patients in Sweden with cognitive complaints, mild cognitive impairment, and dementia, the use of blood biomarkers, specifically, phosphorylated tau 217 and amyloid-beta 42/40 ratios, improved the diagnostic accuracy for pathological Alzheimer’s disease in primary care patients as well as patients seen by dementia specialists.

SOURCES: Palmqvist S, Tideman P, Mattsson-Carlgren N, et al. Blood biomarkers to detect Alzheimer disease in primary and secondary care. JAMA 2024; Jul 28. doi:10.1001/jama.2024.13855. [Online ahead of print].

Salloway S, Rowe C, Burns JM. Are blood tests for Alzheimer disease ready for prime time? JAMA 2024; Jul 28. doi:10.1001/jama.2024.12814. [Online ahead of print].

The prevalence of Alzheimer’s disease continues to rise as the population in the United States continues to age. We can expect about 15% of our population to eventually develop dementia from Alzheimer’s disease. At the same time, the general public is becoming aware of new therapies, particularly monoclonal antibodies that target amyloid, and is seeking medical care. Other new therapies will be coming along soon, and the demand for evaluation and treatment will continue to increase.

Our current number of practicing neurologists is being overwhelmed by appointments and other requests from patients who are developing memory disorders. We all are struggling to keep up with the demands for evaluation, diagnosis, and treatment. There already is a shortage of neurologists in the United States. The demand for services will continue to increase because of the increase in the prevalence of neurodegenerative diseases, particularly Alzheimer’s disease.

The diagnosis of Alzheimer’s disease also has changed dramatically with the development of biomarkers in the cerebrospinal fluid (CSF), and imaging biomarkers with amyloid positron emission tomography (PET) imaging. However, these studies are expensive and difficult to access for many people in the United States, let alone the rest of the world. Accurate and validated blood biomarkers would be a welcome advance to aid in the diagnosis of Alzheimer’s disease. The development of reliable blood biomarkers also would help to expand the number of physicians who could help in the evaluation, diagnosis, and treatment of these patients. Most patients first present to their primary care providers (PCPs) with memory complaints. Accurate biomarkers that can be requested easily by PCPs would aid in the diagnosis of these patients.

The investigators in this study, led by Palmqvist in Sweden, aimed to assess the value of blood biomarkers when used by both PCPs and secondary physicians to determine their sensitivity and accuracy in the diagnosis of Alzheimer’s disease.

A total of 1,213 patients who were undergoing clinical evaluation because of cognitive disorders were examined in Sweden from 2020 until 2024. Blood biomarkers were obtained in both a primary care cohort (307 patients) and a secondary care cohort (300 patients). One plasma sample per patient was analyzed. The blood biomarkers measured were the ratio of plasma phosphorylated tau 217 (p-tau217) to non-p-tau217, expressed as a percentage, and in combination with amyloid-beta 42 and amyloid-beta-40 plasma ratio, called the amyloid probability score 2 (APS2). The assays were performed in a single validated laboratory in the United States with plasma analysis by mass spectrometry. The patients were categorized into three clinical groups: subjective cognitive complaints without impairment, mild cognitive impairment, and dementia. The sensitivity of the physicians’ clinical diagnosis of Alzheimer’s disease and the sensitivity and specificity of the biomarker diagnosis for Alzheimer’s disease were compared to the pathological diagnosis of Alzheimer’s disease based on CSF biomarker studies and/or amyloid PET scans. The primary outcome was Alzheimer’s disease pathology. The secondary outcome was the clinical diagnosis of Alzheimer’s disease. The positive predictive value and negative predictive value, as well as the diagnostic accuracy of the blood biomarker tests, were calculated.

The mean age of the cohort was 74 years and 48% were women, with 23% having subjective cognitive complaints, 44% had mild cognitive impairment, and 33% had dementia. In both the primary care and the secondary care patient cohorts, 50% of the patients had Alzheimer’s pathology.

When plasma samples were analyzed in the primary care cohort using the APS2 biomarker panel, the positive predictive value for diagnosing Alzheimer’s disease was 91% and the negative predictive value was 92%. The clinical accuracy of a diagnosis based on neurological examination, cognitive testing, and computed tomography scan was only 61% compared to 91% when using biomarkers.

When the secondary cohort was analyzed using the APS2 biomarker panel, the positive predictive value was 88% and the negative predictive value was 87%. The clinical diagnostic accuracy of the dementia specialists was 73% compared to 91% using the blood biomarkers. In the overall population, the diagnostic accuracy using the APS2 biomarker panel was not different from the diagnostic accuracy using the percentage of p-tau217 alone.

The diagnostic accuracy of using blood biomarkers was robust in both patients with mild cognitive impairment and patients with dementia. However, in patients who had subjective cognitive complaints without measurable cognitive impairment, the results were less strong and only showed a positive predictive value of between 60% and 70%. This is a group that requires more careful evaluation and follow-up.

Commentary

In an accompanying editorial by Salloway and colleagues, the authors noted that blood biomarkers with p-tau217 have a high positive predictive value for diagnosing Alzheimer’s disease in patients who have cognitive impairment. They stress that the p-tau217 assay alone appears to be just as reliable as the combination with the beta-amyloid 42/40 ratio (APS2). The authors are urging that the U.S. Food and Drug Administration (FDA) approve these blood biomarker assays for general use, since they will not be reimbursed and covered by insurance companies or the Medicare program without FDA approval.

These blood biomarkers are most useful in patients who have mild cognitive impairment or dementia but are less useful in those who have subjective cognitive complaints. They should be integrated into the clinical evaluation of patients and certainly can be helpful for PCPs to make an early and rapid diagnosis of Alzheimer’s disease without the need to make referrals to dementia specialists.

The use of these biomarkers to identify people at risk for Alzheimer’s disease is less clear, but we know that amyloid plaques accumulate for at least 15 to 20 years before the onset of any cognitive impairment. How these biomarkers can be used to identify people at risk is uncertain at this time. We know that patients in midlife, between the ages of 50 and 60 years, who have blood biomarkers in the plasma, have an increased risk of developing late-life, all-cause dementia.¹ Other risk factors for late-life dementia include hypertension, diabetes, and being a carrier of the apolipoprotein E (APOE) 4 gene. Whether this information can be used to mitigate risk is uncertain. It also is unclear if treating patients at risk with anti-amyloid antibodies will provide any benefit and is not recommended at this time.

REFERENCE

1. Lu Y, Pike JR, Chen J, et al. Changes in Alzheimer’s disease blood biomarkers and associations with incident all-cause dementia. JAMA 2024; Jul 28. doi:10.1001/jama.2024.6619. [Online ahead of print].

Matthew E. Fink, MD, is Louis and Gertrude Feil Professor and Chair, Department of Neurology; Associate Dean for Clinical Affairs, NYP/Weill Cornell Medical College.