Plasma proteome‐wide analysis of dementia risk mechanistically implicates synaptic biomarkers
Bibliographic record
Abstract
BACKGROUND: Although numerous biological processes have been implicated in Alzheimer's disease (AD) pathogenesis, plasma biomarkers have been largely limited to measures of amyloid-b and p-tau. We used a large-scale plasma and brain tissue proteomic analyses to (i) identify early plasma biomarkers of AD and (ii) assess the mechanistic relevance of identified proteins. METHOD: We applied the SomaScan proteomic platform to measure the abundance of 4,877 plasma proteins among middle-aged adults in the ARIC study. Dementia was assessed over the subsequent 25-year period. Cox proportional hazards models adjusted for demographic characteristics and cardiovascular risk factors were used to relate each plasma protein to 25-year dementia risk. Using brain tissue proteomic results from the ROSMAP cohort, we (i) examined the extent to which identified proteins were differentially expressed in AD, (ii) identified brain tissue protein quantitative trait loci (pQTL), and (iii) used two-sample Mendelian randomization to assess the causal link between candidate plasma proteins and AD dementia. RESULT: In proteome-wide analyses of 10,981 adults (baseline age: 60 (SD 6); 21% Black; 54% women), we identified 32 plasma proteins associated with subsequent dementia risk, most of which were involved in biological processes such as proteostasis, immunity, extracellular matrix organization, and synaptic function (CPLX1, CPLX2, CBLN4). Synaptic proteins CPLX1 and CPLX2 were upregulated in plasma among those at risk for dementia over a 25-year follow-up period, whereas CBLN was down-regulated among individuals at risk for dementia over a 15-year follow-up period. While the majority of the 32 dementia-associated proteins were expressed across multiple tissue, synaptic proteins were primarily expressed in the central nervous system (CNS), and each synaptic protein was down-regulated in AD brains, compared to control brains. Brain tissue pQTLs were identified for CPLX1. Two-sample Mendelian randomization supported the causal link between brain CPLX1 levels and AD dementia (Z=2.13; p = 0.03). CONCLUSION: These results suggest that synaptic proteins are released from the CNS into the blood well before symptom onset. Synaptic proteins measured in blood, such as CPLX1, may represent mechanistically relevant biomarkers of AD dementia risk.
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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 | 0.001 | 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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".