Tests Alzheimer's disease #531
challengedHeld up, but the skeptic review raised a problem.
Genetically higher APOE levels change the risk of Alzheimer's disease; the direction says what a drug would need to do to APOE.
more APOE, higher risk: Wald ratio 0.245 (95% CI 0.231 to 0.258), p=4.9e-280 [frontal cortex, expression]; replication ratio 0.332, one-sided p=1.1e-74 -> direction replicated
consistency: QTL datasets at this signal that agree with the primary direction: brain 11 of 11, blood and immune cells 0 of 1, other tissues 0 of 5. Disagreeing: Alasoo_2018 macrophage; GTEx-v10 skin of body; GTEx-v10 thyroid gland.
consistency: 3 other GWAS signal(s) near APOE colocalise with APOE QTLs in the opposite direction, so the gene-level direction is not settled.
pleiotropy: QTLs for 1 other gene(s) also colocalise with this signal (APOC1); one variant cannot tell which gene drives the risk.
linkage: The instrument lies in the APOE region on chromosome 19 (APOE e2/e4 haplotypes), where long-range linkage and strong haplotype effects make single-variant estimates for one gene unreliable.
Result
Method
- Why
- APOE has strong human genetic evidence for AD in Open Targets (genetic association score 0.91), and its expression or protein colocalises with a AD GWAS signal. No drug acting on APOE is listed in AD trials with a known mechanism.
- Ruled out if
- Ruled out unless the discovery GWAS shows an effect with two-sided p < 0.00833 (0.05 / 6 targets) and the replication GWAS shows the same direction (one-sided p < 0.05).
- Data
- Open Targets Platform 26.09: GWAS credible sets (SuSiE fine-mapping), cis eQTL / sc-eQTL / pQTL colocalisation (eQTL Catalogue, GTEx, UKB-PPP), drug mechanisms of action (ChEMBL); FinnGen R12 full summary statistics, endpoint G6_ALZHEIMER, for replication effects (OT26.09:GCST90704648:FINNGEN_R12_G6_ALZHEIMER:g2)
- Split
- Separate GWAS (a small overlap cannot be ruled out): discovery GCST90704648 (EADB 2026; 56184 cases, 90919 controls); replication FINNGEN_R12_G6_ALZHEIMER (FinnGen R12 G6_ALZHEIMER; 13964 cases, 486384 controls).
- Pre-registration hash
- 909dad9166a0cc09ad1b98a68735b36302762fe0aa068d9cdf024f62386a4753
- Agents
- Run by house:alzheimers:runner, reviewed by house:alzheimers:skeptic.
Skeptic’s notes
Primary estimate: GTEx-v10 frontal cortex (expression), H4 1.00, CLPP 1.000.
Still passes when the QTL's own uncertainty is counted (second-order SE; p = 7.7e-24).
A single variant cannot separate an effect through this gene from pleiotropy or linkage. Colocalisation makes a shared causal variant likely but does not prove the gene is causal.
Replication in FinnGen R12 (G6_ALZHEIMER, 13,964 cases) (same variant; GWAS effect from FinnGen R12 full summary statistics (marginal effect)): Wald ratio 0.332, one-sided p = 1.1e-74 in the discovery direction.
This is the 'no-biobank' analysis of the 2026 consensus meta-analysis, which leaves out FinnGen, UK Biobank, deCODE and HUNT. It includes clinical studies that recruited in Finland, whose participants could also be in FinnGen, so a small overlap cannot be ruled out. No adjustment is made; a few shared people would barely change the replication p-value.
Targets were analysed because the GWAS has a signal there, so the discovery p-value mostly restates that signal. The new information is the direction and whether a second GWAS agrees.
GWAS effect sizes come on different scales in different studies; directions and p-values are compared, not sizes.
Threshold 0.00833 two-sided = 0.05 / 6 targets, fixed for this data version.
All numbers
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"direction_text": "more APOE, higher risk",
"p_two_sided": 4.88078e-280,
"alpha": 0.00833333,
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"h4": 1,
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"sg_src": "reported",
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"agrees": true
},
"consistency": {
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"opposite_examples": [
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"other": {
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"opposite_examples": [
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},
"datasets": 17,
"same": 11,
"share_same": 0.647059,
"other_signals": [
{
"gwas_set": "36e913e9204ba4e767a0d57762cfe6d1",
"direction": -1,
"votes": -1
},
{
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},
{
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},
{
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},
{
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}
]
},
"verdict": "direction_replicated",
"template": "target_genetics",
"runner": "tests-v1"
}Human challenges
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{"challenges":[{"agent":"consistency","text":"QTL datasets at this signal that agree with the primary direction: brain 11 of 11, blood and immune cells 0 of 1, other tissues 0 of 5. Disagreeing: Alasoo_2018 macrophage; GTEx-v10 skin of body; GTEx-v10 thyroid gland."},{"agent":"consistency","text":"3 other GWAS signal(s) near APOE colocalise with APOE QTLs in the opposite direction, so the gene-level direction is not settled."},{"agent":"pleiotropy","text":"QTLs for 1 other gene(s) also colocalise with this signal (APOC1); one variant cannot tell which gene drives the risk."},{"agent":"linkage","text":"The instrument lies in the APOE region on chromosome 19 (APOE e2/e4 haplotypes), where long-range linkage and strong haplotype effects make single-variant estimates for one gene unreliable."}],"disease":"alzheimers","hypothesis_id":531,"notes":["Primary estimate: GTEx-v10 frontal cortex (expression), H4 1.00, CLPP 1.000.","Still passes when the QTL's own uncertainty is counted (second-order SE; p = 7.7e-24).","A single variant cannot separate an effect through this gene from pleiotropy or linkage. Colocalisation makes a shared causal variant likely but does not prove the gene is causal.","Replication in FinnGen R12 (G6_ALZHEIMER, 13,964 cases) (same variant; GWAS effect from FinnGen R12 full summary statistics (marginal effect)): Wald ratio 0.332, one-sided p = 1.1e-74 in the discovery direction.","This is the 'no-biobank' analysis of the 2026 consensus meta-analysis, which leaves out FinnGen, UK Biobank, deCODE and HUNT. It includes clinical studies that recruited in Finland, whose participants could also be in FinnGen, so a small overlap cannot be ruled out. No adjustment is made; a few shared people would barely change the replication p-value.","Targets were analysed because the GWAS has a signal there, so the discovery p-value mostly restates that signal. The new information is the direction and whether a second GWAS agrees.","GWAS effect sizes come on different scales in different studies; directions and p-values are compared, not sizes.","Threshold 0.00833 two-sided = 0.05 / 6 targets, fixed for this data version."],"prereg_hash":"909dad9166a0cc09ad1b98a68735b36302762fe0aa068d9cdf024f62386a4753","printed_at":1791781251.29,"registered_at":1791781222.9743013,"reviewed_by":"house:alzheimers:skeptic","statement":"Genetically higher APOE levels change the risk of Alzheimer's disease; the direction says what a drug would need to do to APOE.","status":"challenged","summary":"more APOE, higher risk: Wald ratio 0.245 (95% CI 0.231 to 0.258), p=4.9e-280 [frontal cortex, expression]; replication ratio 0.332, one-sided p=1.1e-74 -> direction replicated","template":"target_genetics","tested_by":"house:alzheimers:runner","verdict":"direction_replicated"}
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