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Alzheimer disease blood biomarkers: considerations for population-level use

  • Review Article
  • Published:

From Nature Reviews Neurology

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Abstract

In the past 5 years, we have witnessed the first approved Alzheimer disease (AD) disease-modifying therapy and the development of blood-based biomarkers (BBMs) to aid the diagnosis of AD. For many reasons, including accessibility, invasiveness and cost, BBMs are more acceptable and feasible for patients than a lumbar puncture (for cerebrospinal fluid collection) or neuroimaging. However, many questions remain regarding how best to utilize BBMs at the population level. In this Review, we outline the factors that warrant consideration for the widespread implementation and interpretation of AD BBMs. To set the scene, we review the current use of biomarkers, including BBMs, in AD. We go on to describe the characteristics of typical patients with cognitive impairment in primary care, who often differ from the patient populations used in AD BBM research studies. We also consider factors that might affect the interpretation of BBM tests, such as comorbidities, sex and race or ethnicity. We conclude by discussing broader issues such as ethics, patient and provider preference, incidental findings and dealing with indeterminate results and imperfect accuracy in implementing BBMs at the population level.

Key points

  • Numerous studies have demonstrated the clinical utility and accuracy of plasma measures of the amyloid-β42:40 ratio and phosphorylated tau (p-tau) 181 and p-tau217 levels for the detection of Alzheimer disease (AD) pathology among clinically well-characterized patients.

  • Most AD blood-based biomarker (BBM) studies focused on specialty clinic populations are not generalizable to typical patients with dementia, and an urgent need exists to test the BBMs at the population level.

  • Chronic kidney disease, obesity and cardiovascular conditions or medication can elevate or lower AD BBM levels and need to be taken into consideration to avoid false-positive or false-negative diagnoses; understanding how to interpret AD BBM levels in the context of multiple chronic conditions is crucial for diagnosing AD among older adults in the population.

  • Other factors that might influence AD BBM levels include sex and race or ethnicity, although findings on these associations have been inconsistent to date.

  • A positive BBM test might indicate the presence of AD pathology but could be an incidental finding; the test must be considered in the context of all other symptoms and with the potential for co-pathologies.

  • Policies must be developed to protect patients who have AD BBM results added to their medical records so that they do not lose access to insurance or to disability or other rights.

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Fig. 1: Chronic conditions in typical patients presenting with cognitive impairment.

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Acknowledgements

M.M.M. and N.R.F. acknowledge support from the National Institute on Aging and the NIH (grants U24 AG082930, RF1 AG077386, RF1 AG079397, RF1 AG69052 and P30 AG07247).

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Authors and Affiliations

  1. Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Michelle M. Mielke

  2. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Nicole R. Fowler

  3. Indiana University Center for Aging Research, Indianapolis, IN, USA

    Nicole R. Fowler

  4. Regenstrief Institute, Inc., Indianapolis, IN, USA

    Nicole R. Fowler

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M.M.M. researched data for the article and wrote the article. Both authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Michelle M. Mielke.

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Competing interests

M.M.M. has served on scientific advisory boards and/or has consulted for Acadia, Biogen, Eisai, LabCorp, Lilly, Merck, PeerView Institute, Novo Nordisk, Roche, Siemens Healthineers and Sunbird Bio. N.R.F. declares no competing interests.

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Mielke, M.M., Fowler, N.R. Alzheimer disease blood biomarkers: considerations for population-level use. Nat Rev Neurol 20, 495–504 (2024). https://doi.org/10.1038/s41582-024-00989-1

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