Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders
Open accessAbstract
The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral A β amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis -Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10 −3 ), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10 −5 ) and plasma tau concentration (0.06 log 2 (ng l −1 ) 95%CI 0.03; 0.08, p = 4.55 × 10 −6 ). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.
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CPHPC efficiently reduces SAP concentration in serum (58.5% reduction) and bone marrow (95% reduction) in aged mice.
“Our data demonstrated that CPHPC (miridesap), developed by Pepys’ team at University College London90–92, efficiently reduces SAP concentration in serum (58.5% reduction) and bone marrow (95% reduction) in aged mice.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [90]
The Discussion (page unavailable) identifies CPHPC as miridesap and reports effective SAP depletion, including a reduction of more than 95% in plasma while the drug is administered. It does not report a 58.5% serum reduction or a 95% bone-marrow reduction in aged mice; those figures are presented as the citing authors’ own data. (LLM, conf=0.88)
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Cites
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“The presence of SAP in all cerebral A β plaques and on most neurofibrillary tangles in AD, long known from immunohistochemical studies, has recently been shown to strongly discriminate between AD brains and cognitively normal brains [55].”
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“It is therefore interesting that, unrelated to its contribution both to A β amyloid formation and persistence, human SAP is itself directly neurotoxic to cerebral neurones in vitro [13 – 16] and in animal models in vivo [17].”
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“Furthermore, the association of dementia with SAP content was independent of Braak stage, Thal phase and all other classical neuropathological hallmarks of dementia [18].”
InfluentialSelf-citationEfflux transport of serum amyloid P component at the blood-brain barrier
Veszelka, S., Laszy, J., Pázmány, T., Németh, L., Obál, I., Fábián, L., Szabó, G., Ábrahám, C. S., Deli, M. A., & Urbányi, Z. (2013) · European Journal of Microbiology and Immunology · doi:10.1556/eujmi.3.2013.4.8 · Cited by 8 · cited 2× · see citing works
“Normally, the brain is strongly protected against exposure to SAP by the BBB and by active transport back to the plasma of any SAP that leaks through [4], so that the CSF SAP concentration is about one thou-sandth of that in the plasma [2,3].”
BackgroundGenome-Wide Association Analysis of Neonatal White Matter Microstructure
Zhang, J., Xia, K., Ahn, M., Jha, S. C., Blanchett, R., Crowley, J. J., Szatkiewicz, J., Zou, F., Hongtu Zhu, B., Styner, M. A., et al. (2020) · Cerebral Cortex · doi:10.1093/cercor/bhaa266 · Cited by 5 · cited 1× · see citing works
“GWAS Catalog look-ups for the effects of genetic variants in APCS identified a previously reported association with white-matter microstructure [51] (electronic supplementary material, figure S3 and table S9).”
Serum amyloid P component accumulates and persists in neurones following traumatic brain injury
Yip, P. K., Liu, Z.-H., Hasan, S., Pepys, M., & Uff, C. E. G. (2023) · Open Biology · doi:10.1098/rsob.230253 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
9 of the 71 references couldn’t be matched to a known paper.
Research works printed but not linked: 5
- [6]Pepys MB, Dyck RF, de Beer FC, Skinner M, Cohen AS. 1979 Binding of serum amyloid P-component (SAP) by amyloid fibrils. Clin. Exp. Immunol. 38, 284- 293. 118839 PMC1537850
- [12]Couzin-Frankel J. 2023 FDA approves new antibody to slow Alzheimer's disease, even as safety concerns linger. Science, AAAS. See https://www.science.org/content/article/fda-approves-new-antibody-slow-alzheimer-s-disease-even-safety-concerns-linger (accessed 15 June 2023).
- [21]Pepys MB, Dash AC, Markham RE, Thomas HC, Williams BD, Petrie A. 1978 Comparative clinical study of protein SAP (amyloid P component) and C-reactive protein in serum. Clin. Exp. Immunol. 32, 119- 124. 668189 PMC1541304
- [64]Pepys MB, Lanham JG, de Beer FC. 1982 C-reactive protein in SLE. Clin. Rheum. Dis. 8, 91- 103. (10.1016/S0307-742X(21)00201-0) 6749401 · DOI
- [70]Schmidt AF, Finan C, Chopade S, Ellmerich S, Rossor MN, Hingorani AD, Pepys MB. 2024 Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders. Figshare. (10.6084/m9.figshare.c.7308163) PMC11251762 39013416 · DOI
Cited by
Sorted by citations
Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis
Kumar, S., Song, K., Wang, J., Baghel, M. S., Zeng, Y., Shen, K., Zheng, J., Crane, J., Demehri, S., Gao, P., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-00924-z · Cited by 16 · see citing works
“Our data demonstrated that CPHPC (miride-sap), developed by Pepys’ team at University College London 90–92 , efficiently reduces SAP concentration in serum (58.5% reduction) and bone marrow (95% reduction) in aged mice.”
InfluentialLipke, P. (2025) · mBio · doi:10.1128/mbio.00203-25 · Cited by 7 · see citing works
Functional Amyloids in Adhesion of Non-albicans Candida Species
Garcia-Sherman, M. C., Hamid, S. A., Jackson, D., Thomas, J. D., & Lipke, P. (2025) · Pathogens · doi:10.3390/pathogens14080723 · Cited by 5 · see citing works
Is the Relationship Between Cardiovascular Disease and Alzheimer’s Disease Genetic? A Scoping Review
Moore, A. K., & Ritchie, M. D. (2024) · Genes · doi:10.3390/genes15121509 · Cited by 4 · see citing works
The landscape of plasma proteomic links to human organ imaging
Fan, Z.-R., Chirinos, J., Yang, X.-C., Shu, J., Li, Y.-J., O'Brien, J. M., Witschey, W., Rader, D., Gur, R., & Zhao, B.-X. (2025) · medRxiv · doi:10.1101/2025.01.14.25320532 · Cited by 2
“APCS is cytotoxic to cerebral neurons, promotes Aβ amyloid formation, highlighting an inter-organ proteomic relationship in disease pathology 109,110 .”
Wang, Z., Xia, K., Huang, X., Dongsheng, F., & Yang, Q. (2025) · Journal of Alzheimer s Disease Reports · doi:10.1177/25424823251403565 · Cited by 2 · see citing works
Ren, B., Ma, Y.-Y., Mao, W.-J., & Wu, X.-K. (2026) · Frontiers in Neurology · doi:10.3389/fneur.2026.1977360
The landscape of plasma proteomic links to human organ imaging
Fan, Z.-R., Chirinos, J., Yang, X.-C., Shu, J., Li, Y.-J., O'Brien, J. M., Witschey, W., Rader, D. J., Gur, R., & Zhao, B.-X. (2026) · Nature Communications · doi:10.1038/s41467-026-74715-4
“APCS is cytotoxic to cerebral neurons, promotes A β amyloid formation, highlighting an inter-organ proteomic relationship in disease pathology 108,109 .”
Proteomic profile of bone in patients with acromegaly: new insights from a pilot exploratory study
Demarchis, L., Chiloiro, S., Mattogno, P., Cicchinelli, M., Giambò, P., Valeri, F., Panizzi, E., Angelini, F., Giampietro, A., Vodola, E., et al. (2026) · Journal of Endocrinological Investigation · doi:10.1007/s40618-026-02936-x
“It is involved in neurodegenerative diseases and amyloidosis [ 65– 68 ].”
Molecularly Imprinted Membranes: From Protein Recognition to Refolding Activity
Mallegni, N., Barbani, N., Rossino, D., Cicogna, F., & Cristallini, C. (2026) · Polymers · doi:10.3390/polym18121482
“A common feature of these disorders is the presence of amyloid deposits stabilized by serum amyloid P protein (SAP), a circulating glycoprotein capable of binding to amyloid fibrils and protecting them from proteolytic degradation [3].”
Zhou, H., Dong, S., Pan, A., Xu, H., Tang, X., Wang, X., Xie, L., & Li, Y. (2025) · Journal of Chromatography B · doi:10.1016/j.jchromb.2025.124906
- Authors
- Schmidt, A. F., Finan, C., Chopade, S., Ellmerich, S., Rossor, M. N., Hingorani, A. D., & Pepys, M. B.
- Affiliations
- Utrecht University (NL)
- British Heart Foundation (GB)
- Wolfson Drug Discovery Unit, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK
- UCL Queen Square Institute of Neurology (GB)
- The Royal Free Hospital (GB)
- Corresponding author
- Schmidt, A. Floriaan
- ORCID
- Venue
- Open Biology
- Publisher
- The Royal Society
- Published
- 2024-07
- Volume
- 14
- Issue
- 7
- Pages
- 230419-230419
- ISSN
- 2046-2441 (ISSN-L)
- PMC
- PMC11251762
- OpenAlex
- W4400672758
- Cited by
- 11
- References
- 71
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3
- FWCI
- 0.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Open Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion, cc-by)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- UKRI/NIHR Multimorbidity Fund Mechanism and Therapeutics Research Collaborative (MR/V033867/1)
- BHF (AA/18/6/34223, PG/18/5033837, PG/22/10989)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- serum amyloid P component, Alzheimer's disease, dementia with Lewy bodies, neurodegeneration, dementia, amyloid-beta, neurofibrillary tangles, plasma tau, genetic association, Mendelian randomization, neuroprotection, therapeutic target
- MeSH terms
- Alzheimer Disease, Serum Amyloid P-Component, Female, Humans, Male, Biomarkers, tau Proteins, Neurodegenerative Diseases, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Lewy Body Disease, Genome-Wide Association Study, Mendelian Randomization Analysis
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