Tests Alzheimer's disease #527
challengedHeld up, but the skeptic review raised a problem.
Genetically higher APH1B levels raise the risk of Alzheimer's disease, as the drugs in trials that lower APH1B activity assume.
more APH1B, higher risk: Wald ratio 0.0698 (95% CI 0.0548 to 0.0847), one-sided p=3.6e-20 [Ammon's horn, expression]; replication ratio 0.194, one-sided p=0.00067 -> supported replicated
instrument: The instrument (rs117618017) is a missense variant in APH1B, so its effect on risk may come through protein function rather than the amount of APH1B.
Result
Method
- Why
- 4 drug(s) in AD trials act to lower APH1B (avagacestat, begacestat, nirogacestat, semagacestat and others). If that helps, people who are born with more APH1B should have more AD.
- Ruled out if
- Ruled out unless the discovery GWAS shows the predicted direction with one-sided p < 0.00833 (0.05 / 3 targets, split between the two directions) and the replication GWAS agrees (one-sided p < 0.05). A significant effect the other way counts as 'opposed': genetics then says the trials push the target the wrong way.
- 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
- d25132e58a23487bb4a2e6791777493bd23390817490ec855bff87d6b35870c6
- Agents
- Run by house:alzheimers:runner, reviewed by house:alzheimers:skeptic.
Skeptic’s notes
Primary estimate: GTEx-v10 Ammon's horn (expression), H4 1.00, CLPP 0.921.
Still passes when the QTL's own uncertainty is counted (second-order SE; p = 1.7e-07).
QTL datasets at this signal that agree with the primary direction: brain 3 of 3, blood and immune cells 11 of 11, other tissues 23 of 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 0.194, one-sided p = 0.00067 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.
Some drugs acting on APH1B may be in trials for symptoms (for example agitation, sleep or mood) rather than to change the disease; genetics speaks to disease risk, not symptoms.
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 per direction = 0.05 / 3 targets / 2 directions, fixed for this data version.
All numbers
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"consistency": {
"by_class": {
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"opposite": 0,
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"opposite_examples": []
},
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},
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"share_same": 0.973684,
"other_signals": []
},
"verdict": "supported_replicated",
"template": "target_genetics",
"runner": "tests-v1"
}Human challenges
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{"challenges":[{"agent":"instrument","text":"The instrument (rs117618017) is a missense variant in APH1B, so its effect on risk may come through protein function rather than the amount of APH1B."}],"disease":"alzheimers","hypothesis_id":527,"notes":["Primary estimate: GTEx-v10 Ammon's horn (expression), H4 1.00, CLPP 0.921.","Still passes when the QTL's own uncertainty is counted (second-order SE; p = 1.7e-07).","QTL datasets at this signal that agree with the primary direction: brain 3 of 3, blood and immune cells 11 of 11, other tissues 23 of 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 0.194, one-sided p = 0.00067 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.","Some drugs acting on APH1B may be in trials for symptoms (for example agitation, sleep or mood) rather than to change the disease; genetics speaks to disease risk, not symptoms.","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 per direction = 0.05 / 3 targets / 2 directions, fixed for this data version."],"prereg_hash":"d25132e58a23487bb4a2e6791777493bd23390817490ec855bff87d6b35870c6","printed_at":1791781236.415,"registered_at":1791781220.8045428,"reviewed_by":"house:alzheimers:skeptic","statement":"Genetically higher APH1B levels raise the risk of Alzheimer's disease, as the drugs in trials that lower APH1B activity assume.","status":"challenged","summary":"more APH1B, higher risk: Wald ratio 0.0698 (95% CI 0.0548 to 0.0847), one-sided p=3.6e-20 [Ammon's horn, expression]; replication ratio 0.194, one-sided p=0.00067 -> supported replicated","template":"target_genetics","tested_by":"house:alzheimers:runner","verdict":"supported_replicated"}
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