Osteopontin exhibits a bidirectional relationship with Alzheimer’s disease pathology in asymptomatic individuals with a parental history of sporadic Alzheimer’s disease
Bibliographic record
Abstract
Abstract Background Osteopontin (OPN) is a secreted protein that plays pivotal roles in the recruitment and activation of immune cells, cell survival, and tissue repair following injury. OPN has been demonstrated to be increased in the cerebrospinal fluid (CSF) and brains of individuals with Alzheimer’s disease (AD). However, in order to elucidate the role of OPN in the asymptomatic stage of sporadic AD, we analyzed data from the PREVENT‐AD cohort, which consists of asymptomatic individuals with a parental or multi‐sibling history of AD. Method The Olink Proximity Extension Assay was used to measure CSF levels of OPN. CSF levels of amyloid beta (Aβ1‐42), and total Tau (t‐Tau) were measured by enzyme‐linked immunosorbent assay (Fujirebio). Participants were staged as CSF Aβ1‐42 or t‐Tau positive according to specified thresholds of 989 pg/mL and 336 pg/mL, respectively. CSF levels of synaptic proteins, including GAP43, SYT1, SNAP25 and NRGN were measured by immunoprecipitation followed by mass spectrometry. Tau and Aβ positron emission tomography (PET) burdens were measured using 18F‐AV1451 and 18F‐NAV4694. Result Aβ(+)/Tau(‐) individuals displayed a reduction in CSF OPN levels, relative to Aβ(‐)/Tau(‐) individuals (p = 0.001). Furthermore, Aβ(+)/Tau(+) individuals exhibited a significant increase in CSF OPN levels relative to Aβ(+)/Tau(‐) individuals (p < 0.001), and at a trend level, to Aβ(‐)/Tau(‐) individuals (p = 0.069). In addition, CSF OPN levels were positively correlated with synaptic markers in the CSF, including GAP43 (p < 0.001), SYT1 (p = 0.001), SNAP25 (p < 0.001) and NRGN (p = 0.004). Finally, in PET imaging analyses, CSF OPN levels were positively correlated with pTau burden in the entorhinal cortex (p = 0.009), fusiform gyrus (p = 0.030) and lingual gyrus (p = 0.003). However, CSF OPN levels were not correlated with global cortical Aβ burden (p = 0.374). Conclusion Our results suggest that early Aβ pathology dampens OPN levels in asymptomatic individuals with a family history of AD. Furthermore, our data provide compelling evidence that OPN plays a critical role in the compensatory response to neurofibrillary tangle formation, neuronal loss and synaptic dysfunction. Finally, our findings reveal that OPN may be a valuable therapeutic target.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".