Effect of reduction in brain amyloid levels on change in cognitive and functional decline in randomized clinical trials: an updated instrumental variable meta-analysis
Bibliographic record
Abstract
ABSTRACT Objective To update a recently published analysis exploring the causal association between positron emission tomography (PET)-measured change in brain β-amyloid plaque and cognitive decline in patients with Alzheimer’s disease (AD) enrolled in randomized clinical trials (RCTs). Design Updated instrumental variable meta-analysis. Setting Sixteen RCTs were included in this updated meta-analysis versus 14 in the original publication by Ackley et al . 1 Data sources were ClinicalTrials.org, Alzheimer Research Forum ( alzforum.org ), PubMed and clinical study reports from 2015 to March 1, 2022. Three researchers extracted data from the data sources independently and subsequently resolved any discrepancy. Population RCTs that evaluated β-amyloid targeting therapies and enrolled adult patients with AD dementia or mild cognitive impairment due to AD with data on β-amyloid as measured by PET and clinical outcome measures. Main outcome measures An instrumental variable meta-analysis was performed to compute trial and drug-specific estimates and pooled estimates of the effect of change in PET β-amyloid standard uptake value ratio (SUVR) on cognitive and functional decline with 95% confidence intervals (CIs) and associated p-values. This analysis updated and expanded a prior meta-analysis by Ackley et al . 1 using the same methodology and clinical outcome measures: Clinical Dementia Rating–Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), and Mini-Mental State Examination (MMSE). Results The reduction of PET-measured β-amyloid induced a statistically significant reduction in cognitive and functional decline. The effect size was characterized by an estimated change (95% CI) of 0.09 (0.034, 0.15) on the CDR-SB; 0.33 (0.12, 0.55) on the ADAS-Cog; and 0.13 (0.017, 0.24) on the MMSE for each decrease of 0.1-unit in PET β-amyloid SUVR. Conclusion This updated instrumental variable meta-analysis of 16 RCTs provides statistically significant evidence of a causal relationship between the reduction in brain β-amyloid plaque and the reduction in cognitive and functional decline in patients with Alzheimer’s disease.
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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 | 0.078 | 0.147 |
| Meta-epidemiology (narrow) | 0.005 | 0.002 |
| Meta-epidemiology (broad) | 0.022 | 0.076 |
| Bibliometrics | 0.008 | 0.006 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.006 | 0.004 |
| Open science | 0.004 | 0.003 |
| Research integrity | 0.003 | 0.004 |
| Insufficient payload (model declined to judge) | 0.004 | 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".