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Charting the Next Road Map for CSF Biomarkers in Alzheimer’s Disease and Related Dementias

  • Review
  • Published:
Neurotherapeutics

Abstract

Clinical prediction of underlying pathologic substrates in people with Alzheimer’s disease (AD) dementia or related dementia syndromes (ADRD) has limited accuracy. Etiologic biomarkers — including cerebrospinal fluid (CSF) levels of AD proteins and cerebral amyloid PET imaging — have greatly modernized disease-modifying clinical trials in AD, but their integration into medical practice has been slow. Beyond core CSF AD biomarkers (including beta-amyloid 1–42, total tau, and tau phosphorylated at threonine 181), novel biomarkers have been interrogated in single- and multi-centered studies with uneven rigor. Here, we review early expectations for ideal AD/ADRD biomarkers, assess these goals’ future applicability, and propose study designs and performance thresholds for meeting these ideals with a focus on CSF biomarkers. We further propose three new characteristics: equity (oversampling of diverse populations in the design and testing of biomarkers), access (reasonable availability to 80% of people at risk for disease, along with pre- and post-biomarker processes), and reliability (thorough evaluation of pre-analytical and analytical factors influencing measurements and performance). Finally, we urge biomarker scientists to balance the desire and evidence for a biomarker to reflect its namesake function, indulge data- as well as theory-driven associations, re-visit the subset of rigorously measured CSF biomarkers in large datasets (such as Alzheimer’s disease neuroimaging initiative), and resist the temptation to favor ease over fail-safe in the development phase. This shift from discovery to application, and from suspended disbelief to cogent ingenuity, should allow the AD/ADRD biomarker field to live up to its billing during the next phase of neurodegenerative disease research.

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Data Availability

Data available through ADNI or through reasonable requests.

Abbreviations

ACTH:

Adrenocorticotropic hormone

AD:

Alzheimer’s disease

ADNC:

Alzheimer’s disease neuropathologic changes

ADRD:

Alzheimer’s related disorders including FTLD, LBD, and vascular dementia

ADNI:

Alzheimer’s disease neuro-imaging initiative

AgRP:

Agouti-related peptide

ALS:

Amyotrophic lateral sclerosis

BACE1:

Beta-site amyloid precursor protein cleaving enzyme 1

BDNF:

Brain-derived neurotrophic factor

CAH:

Critical access hospital

CIED:

Cardiac implantable electronic device

CSF:

Cerebrospinal fluid

EDTA:

Ethylenediaminetetraacetic acid

FDA:

Food and Drug Administration

FTLD:

Frontotemporal lobar degeneration

HIV:

Human immunodeficiency virus

IL:

Interleukin

IP-10:

Interferon response protein 10

LBD:

Lewy body disease

LP:

Lumbar puncture

MCI:

Mild cognitive impairment

MCP1:

Monocyte chemoattractant protein 1

MS:

Multiple sclerosis

QALY:

Quality-adjusted life years

NfL:

Neurofilament light chain

NIH:

National Institute of Health

PD:

Parkinson’s disease

PET:

Positron emission tomography

TDP-43:

TAR DNA binding protein of 43 kD

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Funding

This work is supported by NIH R01 AG054046 and NIH RF1 AG054991.

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  1. Department of Neurology, Rutgers Biomedical and Health Sciences, Rutgers-Robert Wood Johnson Medical School, 125 Paterson Street, Suite 6200, New Brunswick, NJ, 08901, USA

    William T. Hu, Ashima Nayyar & Milota Kaluzova

  2. Center for Innovation in Health and Aging Research, Institute for Health, Health Care Policy, and Aging Research, Rutgers Biomedical and Health Sciences, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA

    William T. Hu

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Contributions

WTH conceived and designed the study; WTH and MK analyzed and interpreted the biomarker data; WTH and AN analyzed and interpreted the clinical, pathologic, and biomarker literature; WTH performed the statistical analysis; WTH and AN drafted a significant portion of the manuscript; MK revised the manuscript critically for important intellectual content. All authors read and approved the submission.

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Correspondence to William T. Hu.

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Competing Interests

WTH has patents on CSF-based diagnosis of FTLD-TDP, prognosis of very mild AD, and prognosis of spinal muscular atrophy following treatment; consulted for Apellis Pharmaceuticals, Biogen, Fujirebio Diagnostics, Hoffman-LaRoche; and received research support from Fujirebio Diagnostics and Linus Health.

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Hu, W.T., Nayyar, A. & Kaluzova, M. Charting the Next Road Map for CSF Biomarkers in Alzheimer’s Disease and Related Dementias. Neurotherapeutics 20, 955–974 (2023). https://doi.org/10.1007/s13311-023-01370-8

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