A polymorphism in RELN protects against amyloid‐driven tau pathology and cognitive decline in sporadic Alzheimer’s disease
Bibliographic record
Abstract
Abstract Background A rare reelin gene variant (RELN‐COLBOS mutation) delayed dementia onset in almost 30 years in an autosomal dominant Alzheimer’s disease (ADAD) carrier. This patient presented with high amyloid‐ß (Aß) plaque load, but low tau accumulation, suggesting that this single‐nucleotide polymorphism (SNP) in RELN conferred a resilience not only to cognitive decline but also to tauopathy in ADAD. However, whether RELN SNPs are also protective in sporadic Alzheimer’s disease (AD) is yet to be determined. Thus, we sought to examine the impact of RELN SNPs on AD pathophysiology and cognitive deterioration in sporadic AD. Method We assessed 198 individuals [105 cognitively unimpaired (CU) and 85 cognitively impaired (CI)] from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with available data on RELN SNPs and amyloid‐ and tau‐PET measures ([18F]‐florbetaben/florbetapir and [18F]‐flortaucipir, respectively), Aß1‐42 and ptau181 in the CSF, and neuropsychological testing (Clinical Dementia Rating Sum of Boxes). We analyzed the effect of RELN SNPs carriership in the association between amyloid and tau burden through linear regression analysis and on cognitive decline according to CSF AT status through linear mixed‐effect model correcting for age, sex, and ApoEe4 status (Bonferroni’s adjusted p‐value < 0.05). Result We performed linear regression analysis in all the 235 RELN SNPs available on ADNI (Fig.1). We found RELN rs802787 protected against amyloid‐driven tau pathology (adj. p‐value < 0.001, Fig.2). Dividing individuals according to the CSF AT status, we observed that RELN rs802787 did not impact the rate of decline in cognition in A‐T‐ and A‐T+ individuals (Fig.3A‐B). By contrast, RELN rs802787 CSF A+T‐ individuals presented a slower cognitive decline (Fig.3C), which was not observed in A+T+ individuals (Fig.3D). Conclusion Here, we show RELN rs802787 carriers presenting high amyloid load have lower tau accumulation than non‐carriers. In addition, CSF A+T‐ RELN carriers presented a slower cognitive decline compared to non‐carriers. Our results suggest that RELN rs802787 carriership protects against amyloid‐driven tau pathology and cognitive deterioration in sporadic AD individuals. To the best of our knowledge, this is the first RELN SNP found to be protective against non‐familial AD.
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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 | 0.000 | 0.000 |
| 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) | 0.001 | 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".