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Peer-reviewedCC BY 4.0Alzheimer's Research & Therapy

A CSF NPTX2-based residual metric captures prognostic heterogeneity within a proposed compensatory framework in prodromal Alzheimer’s disease

  • Federico Massa1,2
  • Anastasia Lechiara3
  • Francesca De Cesari1
  • Virginia Pelagotti1
  • Alessia Panza1,4
  • Giulia Bozzo1
  • Martina Urbinati1
  • Mattia Losa1
  • Stefano Raffa2
  • Emanuela Maria Mobilia3
  • Federica Maria Bozzano3
  • Davide Visigalli1,2
10 more authors
  • Luigi Lorenzini1,5
  • Andrea Brugnolo1,2
  • Nicola Girtler1,2
  • Dario Arnaldi1,2
  • Angelo Schenone1,2
  • Antonio Uccelli1,2
  • Gianmario Sambuceti6
  • Silvia Morbelli7,8
  • Giampaola Pesce3
  • Matteo Pardini1,2
8 affiliations
  1. 1Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Largo Daneo 3, Genoa, 16132 Italy
  2. 2AOM - IRCCS Ospedale Policlinico San Martino, Genoa, Italy
  3. 3Autoimmunology Laboratory, AOM - IRCCS Ospedale Policlinico San Martino, Genoa, Italy
  4. 4Department of Neuroscience Rita Levi-Montalcini, University of Turin, Turin, Italy
  5. 5Department of Radiology and Nuclear Medicine, Amsterdam UMC, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, Netherlands
  6. 6Department of Health Science (DISSAL), University of Genoa, Genoa, Italy
  7. 7Department of Medical Sciences, University of Turin, Turin, Italy
  8. 8Nuclear Medicine Unit, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
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Abstract

Background: In Alzheimer’s disease(AD), core CSF biomarkers incompletely predict clinical progression. Synaptic biomarkers may add prognostic information by capturing distinct biological dimensions, from synaptic injury to adaptive network function. Although correlated, neurogranin (Ng) is interpreted as a marker of post-synaptic injury, whereas neuronal pentraxin-2(NPTX2) is more closely related to circuit homeostasis. We tested whether CSF NPTX2 contains a specific component statistically associated with a putative adaptive network signal, interpreted within a hypothesized compensatory framework, using clinical progression and brain metabolism as convergent readouts.

Methods: We retrospectively studied 104 patients with typical MCI-AD. CSF core AD biomarkers, NPTX2 and Ng were measured with commercial immunoassays. Early and late MCI stages were defined by proximity to dementia conversion (LMCI ≤ 2 years; EMCI > 2 years or stable). A residual NPTX2 measure(Res_NPTX2) was derived by regressing z-transformed NPTX2 on Ng, an index of AD burden based on tau/amyloid ratio, and age. Associations with MMSE and time-to-conversion were tested using linear and survival models. In all patients, brain [18F]FDG PET was analyzed with voxel-based methods to identify metabolic correlates of NPTX2 and Res_NPTX2 relative to AD-related hypometabolic regions.

Results: Ng correlated strongly with NPTX2 (ρ = 0.67,p < 0.001). Res_NPTX2 was higher in EMCI than LMCI (p = 0.0006), associated with better baseline MMSE (p = 0.008), and predicted less MMSE decline over time (p = 0.002). During follow-up, 55/104 patients(52.9%) progressed to dementia. Higher Res_NPTX2 predicted lower progression risk (HR = 0.63,p = 0.007), including after accounting for baseline MMSE. Kaplan–Meier curves differed across Res_NPTX2 tertiles, with the strongest separation within 2 years (high vs. low: HR = 0.18,p = 0.008). On [18F]FDG PET, LMCI showed more marked left-sided posterior hypometabolism than EMCI. CSF NPTX2 and Res_NPTX2 were associated with distinct metabolic patterns centered on prominently left posterior parietal and right fronto-striatal regions, respectively.

Conclusions: In prodromal AD, CSF NPTX2 contains clinically relevant information beyond Ng and core biomarker burden. The proposed residualization approach provides a statistical strategy to isolate an NPTX2-related component associated with better cognition, lower short-term progression risk, and a precise right fronto-striatal metabolic signature. Within a hypothesized compensatory framework, this statistically isolated component may index a putative adaptive network capacity and help characterize clinically meaningful heterogeneity in early AD.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13195-026-02160-y.

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Cite

BibTeXRIS
BibTeX
@article{massa2026nptx2based,
  title = {{A CSF NPTX2-based residual metric captures prognostic heterogeneity within a proposed compensatory framework in prodromal Alzheimer’s disease}},
  author = {Federico Massa and Anastasia Lechiara and Francesca De Cesari and Virginia Pelagotti and Alessia Panza and Giulia Bozzo and Martina Urbinati and Mattia Losa and Stefano Raffa and Emanuela Maria Mobilia and Federica Maria Bozzano and Davide Visigalli and Luigi Lorenzini and Andrea Brugnolo and Nicola Girtler and Dario Arnaldi and Angelo Schenone and Antonio Uccelli and Gianmario Sambuceti and Silvia Morbelli and Giampaola Pesce and Matteo Pardini},
  journal = {Alzheimer's Research \& Therapy},
  year = {2026},
  month = aug,
  doi = {10.1186/s13195-026-02160-y},
  url = {https://doi.org/10.1186/s13195-026-02160-y},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A CSF NPTX2-based residual metric captures prognostic heterogeneity within a proposed compensatory framework in prodromal Alzheimer’s disease
AU  - Federico Massa
AU  - Anastasia Lechiara
AU  - Francesca De Cesari
AU  - Virginia Pelagotti
AU  - Alessia Panza
AU  - Giulia Bozzo
AU  - Martina Urbinati
AU  - Mattia Losa
AU  - Stefano Raffa
AU  - Emanuela Maria Mobilia
AU  - Federica Maria Bozzano
AU  - Davide Visigalli
AU  - Luigi Lorenzini
AU  - Andrea Brugnolo
AU  - Nicola Girtler
AU  - Dario Arnaldi
AU  - Angelo Schenone
AU  - Antonio Uccelli
AU  - Gianmario Sambuceti
AU  - Silvia Morbelli
AU  - Giampaola Pesce
AU  - Matteo Pardini
PY  - 2026
DA  - 2026/08/11
JO  - Alzheimer's Research & Therapy
DO  - 10.1186/s13195-026-02160-y
UR  - https://doi.org/10.1186/s13195-026-02160-y
AB  - Background: In Alzheimer’s disease(AD), core CSF biomarkers incompletely predict clinical progression. Synaptic biomarkers may add prognostic information by capturing distinct biological dimensions, from synaptic injury to adaptive network function. Although correlated, neurogranin (Ng) is interpreted as a marker of post-synaptic injury, whereas neuronal pentraxin-2(NPTX2) is more closely related to circuit homeostasis. We tested whether CSF NPTX2 contains a specific component statistically associated with a putative adaptive network signal, interpreted within a hypothesized compensatory framework, using clinical progression and brain metabolism as convergent readouts.  Methods: We retrospectively studied 104 patients with typical MCI-AD. CSF core AD biomarkers, NPTX2 and Ng were measured with commercial immunoassays. Early and late MCI stages were defined by proximity to dementia conversion (LMCI ≤ 2 years; EMCI > 2 years or stable). A residual NPTX2 measure(Res_NPTX2) was derived by regressing z-transformed NPTX2 on Ng, an index of AD burden based on tau/amyloid ratio, and age. Associations with MMSE and time-to-conversion were tested using linear and survival models. In all patients, brain [18F]FDG PET was analyzed with voxel-based methods to identify metabolic correlates of NPTX2 and Res_NPTX2 relative to AD-related hypometabolic regions.  Results: Ng correlated strongly with NPTX2 (ρ = 0.67,p < 0.001). Res_NPTX2 was higher in EMCI than LMCI (p = 0.0006), associated with better baseline MMSE (p = 0.008), and predicted less MMSE decline over time (p = 0.002). During follow-up, 55/104 patients(52.9%) progressed to dementia. Higher Res_NPTX2 predicted lower progression risk (HR = 0.63,p = 0.007), including after accounting for baseline MMSE. Kaplan–Meier curves differed across Res_NPTX2 tertiles, with the strongest separation within 2 years (high vs. low: HR = 0.18,p = 0.008). On [18F]FDG PET, LMCI showed more marked left-sided posterior hypometabolism than EMCI. CSF NPTX2 and Res_NPTX2 were associated with distinct metabolic patterns centered on prominently left posterior parietal and right fronto-striatal regions, respectively.  Conclusions: In prodromal AD, CSF NPTX2 contains clinically relevant information beyond Ng and core biomarker burden. The proposed residualization approach provides a statistical strategy to isolate an NPTX2-related component associated with better cognition, lower short-term progression risk, and a precise right fronto-striatal metabolic signature. Within a hypothesized compensatory framework, this statistically isolated component may index a putative adaptive network capacity and help characterize clinically meaningful heterogeneity in early AD.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13195-026-02160-y.
SN  - 1758-9193
ER  -