Neuronal Pentraxin 2 predicts medial temporal atrophy and memory decline across the Alzheimer’s disease spectrum
Open accessAbstract
Chronic neuroinflammation is thought to potentiate medial temporal lobe (MTL) atrophy and memory decline in Alzheimer's disease (AD). It has become increasingly important to find novel immunological biomarkers of neuroinflammation or other processes that can track AD development and progression. Our study explored which pro- or anti-inflammatory cerebrospinal fluid (CSF) biomarkers best predicted AD neuropathology over 24months. Using Alzheimer's Disease Neuroimaging Initiative data (N=285), CSF inflammatory biomarkers from mass spectrometry and multiplex panels were screened using stepwise regression, followed up with 50%/50% model retests for validation. Neuronal Pentraxin 2 (NPTX2) and Chitinase-3-like-protein-1 (C3LP1), biomarkers of glutamatergic synaptic plasticity and microglial activation respectively, were the only consistently significant biomarkers selected. Once these biomarkers were selected, linear mixed models were used to analyze their baseline and longitudinal associations with bilateral MTL volume, memory decline, global cognition, and established AD biomarkers including CSF amyloid and tau. Higher baseline NPTX2 levels corresponded to less MTL atrophy [R 2=0.287, p<0.001] and substantially less memory decline [R 2=0.560, p<0.001] by month 24. Conversely, higher C3LP1 modestly predicted more MTL atrophy [R 2=0.083, p<0.001], yet did not significantly track memory decline over time. In conclusion, NPTX2 is a novel pro-inflammatory cytokine that predicts AD-related outcomes better than any immunological biomarker to date, substantially accounting for brain atrophy and especially memory decline. C3LP1 as the microglial biomarker, by contrast, performed modestly and did not predict longitudinal memory decline. This research may advance the current understanding of AD etiopathogenesis, while expanding early diagnostic techniques through the use of novel pro-inflammatory biomarkers, such as NPTX2. Future studies should also see if NPTX2 causally affects MTL morphometry and memory performance.
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Both NPTX2 and NPTXR correlated positively with MMSE scores, indicating a possible association with cognitive decline.
“Both NPTX2 and NPTXR correlated positively with MMSE scores, as has been previously shown by other groups [69, 70], indicating a possible association with cognitive decline.”
NPTX2 correlates with medial temporal atrophy, hippocampal volume and cognitive impairment.
“This was further sustained by studies that found NPTX2 correlating with medial temporal atrophy, hippocampal volume and cognitive impairment (Nilsson et al. 2021; Swanson et al. 2016; Xiao et al. 2017).”
From Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration (2022) · cites this paper as Swanson et al. 2016
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- Authors
- Swanson, A., & Willette, A. A.
- Affiliations
- Iowa State University (US)
- University of Iowa (US)
- Corresponding author
- Willette, A.A.
- ORCID
- Willette, A.A.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 58
- Pages
- 201-208
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC5349324
- OpenAlex
- W2506432941
- Cited by
- 79
- References
- 45
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 8 · 2023: 7 · 2022: 19 · 2021: 9 · 2020: 8 · 2019: 5 · 2018: 4 · 2017: 2
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 346 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Brain Behavior and Immunity (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alzheimer's Disease Neuroimaging Initiative
- National Institute on Aging
- Alzheimer's Drug Discovery Foundation
- Alzheimer's Association
- Iowa State University
- National Institute of Biomedical Imaging and Bioengineering
- National Institutes of Health (U01-AG-024904, AG047282)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, NPTX2, YKL-40, cerebrospinal fluid biomarkers, neuroinflammation, medial temporal lobe atrophy, memory decline, microglial activation, amyloid, tau protein
- MeSH terms
- Chitinase-3-Like Protein 1, Pentraxins, Aged, Alzheimer Disease, Atrophy, C-Reactive Protein, Encephalitis, Female, Humans, Male, Nerve Tissue Proteins, Neuropsychological Tests, Temporal Lobe, Biomarkers, Amyloid beta-Peptides, tau Proteins
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