Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 Feb;23(2):100721.
doi: 10.1016/j.mcpro.2024.100721. Epub 2024 Jan 20.

Alzheimer's Disease Biomarker Analysis Using Targeted Mass Spectrometry

Johan Gobom  1 , Ann Brinkmalm  2 , Gunnar Brinkmalm  3 , Kaj Blennow  2 , Henrik Zetterberg  4
Affiliations
Review

Alzheimer's Disease Biomarker Analysis Using Targeted Mass Spectrometry

Johan Gobom et al. Mol Cell Proteomics. 2024 Feb.

Abstract

Alzheimer's disease (AD) is characterized by several neuropathological changes, mainly extracellular amyloid aggregates (plaques), intraneuronal inclusions of phosphorylated tau (tangles), as well as neuronal and synaptic degeneration, accompanied by tissue reactions to these processes (astrocytosis and microglial activation) that precede neuronal network disturbances in the symptomatic phase of the disease. A number of biomarkers for these brain tissue changes have been developed, mainly using immunoassays. In this review, we discuss how targeted mass spectrometry (TMS) can be used to validate and further characterize classes of biomarkers reflecting different AD pathologies, such as tau- and amyloid-beta pathologies, synaptic dysfunction, lysosomal dysregulation, and axonal damage, and the prospect of using TMS to measure these proteins in clinical research and diagnosis. TMS advantages and disadvantages in relation to immunoassays are discussed, and complementary aspects of the technologies are discussed.

Keywords: Alzheimer's disease; amyloid; biomarkers; targeted mass spectrometry; tau.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest K. B. has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Julius Clinical, Lilly, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials, and participated in educational programs for Biogen, Eisai, and Roche Diagnostics; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this article. H.Z. has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, De nali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work).

Figures

None
Graphical abstract
Fig. 1
Fig. 1
Cellular origin of fluid biomarkers of Alzheimer’s disease (AD). The figure illustrates the main pathological changes affecting neural cells in AD and the proteins whose release into the cerebrospinal fluid (CSF) and plasma are altered as a result. The Aβ42/40 ratio in CSF and plasma is a direct marker of amyloid pathology, the earliest observed pathological change in AD. Affected neurons secrete total and multiply phosphorylated tau (t-tau and p-tau) at an increased rate, leading to higher concentrations of both proteins in CSF and increased pTau concentration in plasma. Axonal degeneration leads to leakage of neurofilament light polypeptide (NfL) and tau into the CSF and blood. Synaptic loss as well as synaptic hyperplasticity leads to changes in a host of synapse-associated proteins, including neurogranin, SNAP-25, and synaptotagmin-1. Dendritic spine loss is closely linked to synaptic dysfunction and results in the release of neurogranin into the CSF. Glial activation is part of the neuroinflammatory response to AD pathologies, leading to the release of TREM-2 from microglia and YKL-40 and GFAP from astroglia.
See this image and copyright information in PMC

References

    1. Alzheimer A., Stelzmann R.A., Schnitzlein H.N., Murtagh F.R. An English translation of Alzheimer's 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin. Anat. 1995;8:429–431. - PubMed
    1. Hardy J.A., Higgins G.A. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992;256:184–185. - PubMed
    1. McDade E., Cummings J.L., Dhadda S., Swanson C.J., Reyderman L., Kanekiyo M., et al. Lecanemab in patients with early Alzheimer's disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimers Res. Ther. 2022;14:191. - PMC - PubMed
    1. Mintun M.A., Lo A.C., Duggan Evans C., Wessels A.M., Ardayfio P.A., Andersen S.W., et al. Donanemab in early Alzheimer’s disease. N. Engl. J. Med. 2021;384:1691–1704. - PubMed
    1. Swanson C.J., Zhang Y., Dhadda S., Wang J., Kaplow J., Lai R.Y.K., et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Abeta protofibril antibody. Alzheimers Res. Ther. 2021;13:80. - PMC - PubMed