<i>RELN</i> SNP rs802787 protects against Aβ‐driven tau pathology, counteracts <i>APOE</i> ε4 effects, and slows cognitive decline in sporadic late‐onset Alzheimer's disease
Bibliographic record
Abstract
BACKGROUND: A rare reelin gene variant (RELN-COLBOS mutation) delayed dementia onset by 30 years in an autosomal dominant Alzheimer's disease (ADAD) mutation carrier. Despite a high amyloid-β (Aβ) load, the brain had low tau accumulation, suggesting that this mutation conferred resilience against tau pathology and cognitive decline. However, whether RELN variants protect against sporadic late-onset Alzheimer's disease (LOAD) remains unknown. Here, we evaluated the impact of RELN single nucleotide polymorphisms (SNPs) on AD pathophysiology and cognitive decline in LOAD. METHOD: , APOEε4 status, neuropsychological tests (CDRSB and MMSE), and clinical diagnosis. We investigated the impact of RELN carriership on the association between Aβ and tau burden through regional- and voxel-wise linear regressions, and on cognitive decline based on AT biomarker profile with a linear mixed-effect model. We also analyzed the interaction effects between RELN and APOEε4 carriership on tau pathology (Bonferroni's adjusted p-value < 0.05). RESULT: Of the RELN SNPs available in ADNI (Figure 1A), RELN rs802787 protected against Aβ-driven tau pathology (β = -0.603, adj. p-value = 0.0002; Figure 1B). At the voxel level, this protection was mostly associated with the temporal lobe (Figure 1C). Also, RELN rs802787 carriers exhibited a reduced APOEε4-related tau burden (β = -0.572, p-value = 0.035; Figure 2). Stratifying individuals by AT status revealed that RELN rs802787 carriership did not affect cognitive decline in Aβ- groups (Figure 3). In contrast, A+T- carriers showed a slower change in CDRSB (β = -0.45, p-value = 0.007) and MMSE (β = +0.3, p-value = 0.001) scores over the months, an effect absent in individuals with high tau burden (A+T+; Figure 3). CONCLUSION: Our findings suggest that RELN rs802787 confers resilience against Aβ-driven tau pathology and cognitive deterioration in LOAD. The reduced APOEε4-associated tau burden suggests a potential mechanism by which RELN could modulate tau accumulation. To our knowledge, this is the first RELN variant identified as protective in LOAD. Our results suggest that reelin signaling is an important player in AD pathophysiology, underscoring it as a promising target for AD therapeutics.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| 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) | 0.004 | 0.001 |
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".