GWAS
Can blood markers and genes diagnose Alzheimer’s?
Open access · cc by · source: Europe PMC
In 1,439 AD cases and 508 older controls, combining plasma Aβ40/42, P-tau181, NfL, GFAP with APOE and PRS reached AUC 0.81; case-only GWAS linked Aβ42/Aβ40 to WWOX and COPG2.
How this study connects
Role on claims
Each row is a claim on a concept or method page where this paper supports, challenges, or qualifies the statement. Roles are hand-checked — not a model guess.
Blood GFAP and NfL associate with higher later dementia risk years before diagnosis.
In UK Biobank adults with baseline plasma measures, higher GFAP and NfL associated with roughly doubled hazards of incident all-cause dementia over ~13 years, with elevations detectable up to about 15 years before diagnosis and incremental prediction beyond demographic risk scores.
Scope note — clinic case-control discrimination with a multi-marker + APOE/PRS panel — not UK Biobank incident-dementia prognosis
Limits the claim's scope: a different population, assay, or outcome.
A clinic plasma panel plus genetics can discriminate clinical AD from older controls without being autopsy-confirmed diagnosis.
In the AD Cardiff Cohort (1,439 clinical AD cases, 508 older controls), plasma Aβ40/42, P-tau181, NfL, and GFAP plus APOE-ε4 and polygenic risk reached AUC 0.81. Aβ-related peptides were lower in cases; P-tau181, NfL, and GFAP were higher. Case-only GWAS linked the Aβ42/Aβ40 ratio to WWOX and COPG2. Authors note ~25% of clinical AD lack AD pathology at autopsy.
Evidence for the claim as stated.
Pathogenic tau can sit in retinal ganglion cells in MCI and AD, with substantial RGC loss.
In 41 donor eyes, MCI-due-to-AD and AD retinas showed pS396-tau and oligomeric tau inside RGCs, hypertrophic somas and death-pathway markers, about 50% RGC loss, and correlations with brain AD pathology, stage, and cognition.
Scope note — blood protein discrimination in clinic cases — not postmortem RGC counts
Limits the claim's scope: a different population, assay, or outcome.
Plasma p-tau217 can match CSF p-tau217 for PET amyloid/tau status in a memory clinic.
In 114 Geneva memory-clinic patients, plasma p-tau217 identified amyloid/tau PET positivity with mean AUC 0.96, outperforming plasma p-tau181/231 (AUC 0.76/0.79) and similar to CSF p-tau217 (AUC 0.95). CSF n was only 36.
Scope note — Cardiff clinical AD vs controls with a multi-marker panel — not PET-defined positivity
Limits the claim's scope: a different population, assay, or outcome.
Clinic plasma+genetics discrimination, biobank GFAP/NfL prognosis, cortical tau PET, and postmortem retinal tau are related Alzheimer’s biology at different compartments, time horizons, and confirmation standards. They do not yield one interchangeable “accuracy number.”
Evidence for the claim as stated.
Open questions
Tensions this paper is part of
From concept pages' “where studies disagree.” Disagreement means the same question; scope means different assays, populations, or outcomes.
Clinic plasma+genetics discrimination, biobank GFAP/NfL prognosis, cortical tau PET, and postmortem retinal tau are related Alzheimer’s biology at different compartments, time horizons, and confirmation standards. They do not yield one interchangeable “accuracy number.”
History
When this study was placed
Dated entries from the concept change log — when this paper was added or removed as support, challenge, or qualifier on a claim.
Placed as a scope qualifier on Alzheimer’s and MCI markers
In UK Biobank adults with baseline plasma measures, higher GFAP and NfL associated with roughly doubled hazards of incident all-cause dementia over ~13 years, with elevations detectable up to about 15 years before diagnosis and incremental prediction beyond demographic risk scores.
Placed as supporting evidence on Alzheimer’s and MCI markers
In the AD Cardiff Cohort (1,439 clinical AD cases, 508 older controls), plasma Aβ40/42, P-tau181, NfL, and GFAP plus APOE-ε4 and polygenic risk reached AUC 0.81. Aβ-related peptides were lower in cases; P-tau181, NfL, and GFAP were higher. Case-only GWAS linked the Aβ42/Aβ40 ratio to WWOX and COPG2. Authors note ~25% of clinical AD lack AD pathology at autopsy.
Placed as a scope qualifier on Alzheimer’s and MCI markers
In 41 donor eyes, MCI-due-to-AD and AD retinas showed pS396-tau and oligomeric tau inside RGCs, hypertrophic somas and death-pathway markers, about 50% RGC loss, and correlations with brain AD pathology, stage, and cognition.
Placed as supporting evidence on Alzheimer’s and MCI markers
Clinic plasma+genetics discrimination, biobank GFAP/NfL prognosis, cortical tau PET, and postmortem retinal tau are related Alzheimer’s biology at different compartments, time horizons, and confirmation standards. They do not yield one interchangeable “accuracy number.”
Placed as a scope qualifier on Alzheimer’s and MCI markers
In 114 Geneva memory-clinic patients, plasma p-tau217 identified amyloid/tau PET positivity with mean AUC 0.96, outperforming plasma p-tau181/231 (AUC 0.76/0.79) and similar to CSF p-tau217 (AUC 0.95). CSF n was only 36.
Study at a glance
- Design
- Case-control — AD Cardiff Cohort cases vs screened elderly controls; Simoa plasma biomarkers plus GWAS/PRS; clinical diagnosis not CSF/PET-confirmed.
- N
- N=1947 · 1,439 AD cases (mean age 68) and 508 controls (mean age 82); 1,947 with APOE and genome-wide genotypes.
- Population
- Early- and late-onset sporadic Alzheimer’s disease cases and screened elderly controls from the Alzheimer’s Disease Cardiff Cohort.
- Outcome
- Discrimination of clinical AD (AUC) by plasma Aβ40/42, P-tau181, NfL, GFAP plus APOE/PRS, and GWAS of biomarkers.
Structured fields used in claim comparison tables when every cited study has a complete layer.
Inspect source passages
Can blood markers and genes diagnose Alzheimer’s?
These passages occur verbatim in the stored paper text. They support the points listed below; they do not verify every statement in the explanation.
1,439 cases and 508 controls.
We used plasma samples collected from 1439 early and late onset sporadic AD cases and 508 screened elderly controls.
Biomarkers + APOE + PRS AUC = 0.81.
The prediction accuracy of Alzheimer’s disease clinical diagnosis by the combination of all biomarkers, APOE and polygenic risk score reached area under receiver operating characteristic curve (AUC) = 0.81
Key findings
Aβ-related peptides were lower in cases; P-tau181, NfL, and GFAP were higher. All markers associated with age. Combined biomarkers + APOE + PRS AUC=0.81 (drivers: ε4, Aβ40/42, GFAP, NfL). ε4 associated with all markers except NfL. P-tau181 variance was largely captured by ε4. Case-only GWAS found WWOX and COPG2 for the Aβ42/Aβ40 ratio.
Methodology
Measured five Simoa plasma biomarkers in the AD Cardiff Cohort, related them to age at onset/duration, built prediction models with APOE-ε4 and polygenic risk, and ran case-control and case-only GWAS.
Limitations
AD diagnosis was clinical, not CSF/PET/autopsy-confirmed (~25% clinical AD lack pathology at autopsy, as the authors note); controls were older than cases; novel GWAS hits need replication and are not a screening program.
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