Exploring Blood‐Based Biomarkers in a Comparative Study of Amyloid‐Negative and Amyloid‐Positive Clinical Alzheimer's Syndrome
Bibliographic record
Abstract
BACKGROUND: It has been documented, 25-33% of individuals clinically diagnosed with Alzheimer's syndrome, commonly referred to as the Alzheimer's phenotype, do not exhibit amyloid plaques in the brain upon autopsy. While non-Alzheimer pathologies are suspected to contribute to misdiagnosis and cognitive decline observed in these patients, pathological distinctions between amyloid-positive (Aβ+) and amyloid-negative (Aβ-) individuals remain poorly understood. Further investigation into these differences using blood-based biomarkers may provide valuable insights into the underlying pathophysiology of the amyloid-negative subgroup. Our objective was to compare blood-based biomarkers between Aβ- and Aβ+ subgroups diagnosed with clinical Alzheimer's syndrome. METHOD: Participants were recruited from the screening phase of clinical trials investigating anti-amyloid agents. A retrospective chart review was conducted to collect demographic, clinical, imaging, biomarker, and neuropsychological data. Amyloid-beta (Aβ) status was assessed through cerebrospinal fluid (CSF) analysis using the Roche-Elecsys β-Amyloid (1-42) CSF II assay or positron emission tomography (PET) imaging. Plasma samples were analyzed on the Quanterix Simoa HD-X platform, employing neurology-4-plex-E, p-tau-181, p-tau-217, and TDP-43 assays. Statistical analyses were performed using the Mann-Whitney U test for continuous variables and Fisher's exact test for categorical variables to compare group differences. RESULT: Of n = 45 patients, n = 25 (56%) were classified as Aβ+, and n = 20 (44%) were classified as Aβ-. No significant differences were found between groups in terms of age, sex, duration of illness or cognitive presentation. Groupwise analysis revealed significantly elevated concentrations of phosphorylated tau (p-tau) proteoforms in the Aβ+ group, including p-tau 181 (4.32 vs 2.93 pg/mL, p = 0.0058) and p-tau 217 (1.36 vs 0.46 pg/mL, p <0.0001), as well as glial fibrillary acidic protein (GFAP) (223 vs 123 pg/mL, p = 0.0265) and neurofilament light chain (NfL) (31.8 vs 19.1 pg/mL, p = 0.0068), relative to the Aβ- group. Although no significant differences were observed for Aβ42/40 (0.0548 vs 0.0567 pg/mL, p = 0.1466) or TDP-43 (2219 vs 359 pg/mL, p = 0.0607), the Aβ- group exhibited markedly higher TDP-43 concentrations compared to the Aβ+ group. CONCLUSION: These findings highlight distinct biomarker profiles between Aβ+ and Aβ- individuals, offering insights into the pathophysiology of clinical Alzheimer's syndrome.
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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 | 0.002 | 0.005 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".