P4‐089: Candidate gene study in the endosome‐to‐Golgi retrieval pathway reveals association of retromer genes with Alzheimer's disease
Bibliographic record
Abstract
Recent genetic and cell biological studies have implicated the retromer complex in regulating the localization and processing of amyloid precursor protein (APP), establishing it as a key player in the pathogenesis of Alzheimer's disease (AD). We analyzed the association of AD with 451 SNPs in 15 genes encoding retromer or retromer-associated proteins in a sample of 8,309 AD cases and 7,366 controls. We employed VEGAS, a gene-based significance test, to test association of individual genes. Based on these results, the interaction of Snx3 with the retromer complex was tested using a yeast two-hybrid system (Y2H). We also investigated whether Snx3 and Rab7 act together or independently to regulate retromer association using SNX3 or Rab7A siRNA knockdown HeLa cells stably expressing GFP-Snx3 and GFP-Rab7a. In four of 15 retromer-related genes (KIAA1033, RAB7A, SNX1 and SNX3), 50% or more of the SNPs were significantly associated with AD at P = 0.05. Two SNPs in SNX3 were significant after multiple testing correction (best P = 0.0056 for rs12524840) and two SNPs in RAB7A nearly met gene-based significance (rs9831813, P = 0.0058; rs7631994, P = 0.0059). VEGAS analysis revealed significant association of AD with RAB7A, KIAA1033 and SNX1 at the gene level and suggestive evidence with SNX3 (P = 0.06). Analysis of Snx3 interactions with retromer components and retromer-associated proteins using the Y2H system revealed association only between Snx3 and Vps25. We also demonstrated that GFP-Snx3 co-immunoprecipitates Vps26 and Vps35 proteins. The Rab7A KD in GFP-Snx3 cells caused a reduction in Vps26 staining but there was an increase of Snx3 expression in Rab7A knockdown cells. Snx3 KD in GFP-Rab7A cells resulted in reduced GFP-Rab7A expression along with loss of expression in Vps26. In addition, we observed that elevated expression of Rab7A cannot compensate for loss of Snx3 expression. SNX3 and RAB7A provided the most compelling evidence of association with AD. Consistent with recent reports we confirmed Sxn3 interaction with the retromer. We also demonstrated that Snx3 and Rab7A regulate retromer membrane association through distinct mechanisms. These data implicate additional AD risk genes in the retromer pathway and demonstrate a direct link between the activity of the retromer complex and AD.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".