Brain-related proteins as potential CSF biomarkers of Alzheimer's disease: A targeted mass spectrometry approach
Abstract
Alzheimer's disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline. The main disease hallmarks include amyloid beta aggregates and neurofibrillary tangles. Brain pathology is reflected in cerebrospinal fluid (CSF); the core biomarkers amyloid beta 1-42, total and phosphorylated tau protein levels are changed, relative to cognitively normal elderly. Still, there is a need for additional biomarkers which could identify disease more accurately and at an earlier stage, predict severity and be used in research settings. Here we evaluated 30 brain-related proteins as candidate biomarkers of AD. Proteins were quantified in CSF samples from cognitively healthy individuals (n = 23) and patients with mild cognitive impairment (MCI) due to AD (n = 20) or dementia due to AD (n = 10) using selected reaction monitoring mass spectrometry assays. APLP1 protein was increased in MCI relative to control (p < 0.001). The best discrimination between MCI vs. controls was observed with a model combining APLP1 and SPP1 proteins (area under the curve, AUC = 0.84). The strongest associations between protein abundance and disease severity were found for APLP1, CNTN2 and SPP1 proteins, which had a significant correlation with MMSE and CDR tests (p < 0.05). This study identifies new proteins with biomarker potential at various stages of AD severity.Significance The current study evaluated 30 brain-related, highly specific proteins as candidate biomarkers of AD diagnosis. Protein APLP1 showed promise as early AD biomarker; protein panel APLP1 and SPP1 had the best diagnostic potential in discriminating MCI from control group, while proteins APLP1, SPP1 and CNTN2 may be indicators of disease progression, demonstrating weak to moderate correlation with cognitive tests. This study therefore identifies new proteins with biomarker potential at early AD stage. If the performance of proposed biomarkers is further confirmed, these proteins may add value in the clinic or clinical trial settings as diagnostic biomarkers (alone or in combination with the existing biomarkers) of the prodromal AD stage, and in monitoring disease progression.
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Both Aβ and tau aggregates cause impaired synaptic plasticity and neuronal cell death.
“Both Aβ and tau aggregates and cause impaired synaptic plasticity and neuronal cell death [4].”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [4]
APLP1, SPP1 and CNTN2 showed discriminating potential for diagnosing cognitively impaired patients and MCI due to AD from controls.
“Amyloid beta precursor like protein 1 (APLP1), secreted phosphoprotein 1 (SPP1) and contactin 2 (CNTN2) showed discriminating potential for diagnosing cognitively impaired patients and MCI due to AD from controls.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [4]
Amyloid plaques are superabundant in ε4 carriers, with lower Aβ1-42 concentration in CSF and increased PiB binding to Aβ aggregates on PET imaging.
“Amyloid plaques are superabundant in ε4 carriers, with lower Aβ1-42 concentration in CSF, with increased Pittsburgh compound B (PiB) shown bound to Aβ aggregates on PET imaging [4].”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [4]
APLP1 was elevated in MCI patients.
“APLP1 was elevated in MCI patients.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [4]
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- Authors
- Begcevic, I., Brinc, D., Brown, M., Martinez-Morillo, E., Goldhardt, O., Grimmer, T., Magdolen, V., Batruch, I., & Diamandis, E. P.
- Affiliations
- Mount Sinai Hospital (CA)
- Fred Hutch Cancer Center (US)
- TUM Klinikum (DE)
- Corresponding author
- Diamandis, Eleftherios P.
- ORCID
- Venue
- Journal of Proteomics
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 182
- Pages
- 12-20
- ISSN
- 1874-3919 (ISSN-L)
- OpenAlex
- W2799293472
- Cited by
- 81
- References
- 42
- Citations by year
- 2026: 1 · 2025: 9 · 2024: 12 · 2023: 11 · 2022: 16 · 2021: 6 · 2020: 12 · 2019: 10 · 2018: 3 · 2013: 1
- FWCI
- 6.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Proteomics (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- Alzheimer's disease, cerebrospinal fluid biomarkers, APLP1, osteopontin, CNTN2, mild cognitive impairment, early diagnosis, disease progression, multiple reaction monitoring
- MeSH terms
- Alzheimer Disease, Brain Chemistry, Cerebrospinal Fluid Proteins, Dementia, Female, Humans, Male, Mass Spectrometry, Biomarkers, Case-Control Studies, Amyloid beta-Protein Precursor, Osteopontin, Contactin 2, Cognitive Dysfunction
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