The journals of gerontology. Series A, Biological sciences and medical sciences · 2026
Substituting blood-based biomarkers for imaging measures in Alzheimer's disease studies: implications for sample size and bias.
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Ackley Sarah F, La Joie Renaud, Caunca Michelle, Mukherjee Shubhabrata, Choi Seo-Eun, Trittschuh Emily H, Crane Paul K, Hayes-Larson Eleanor, Alzheimer’s Disease Neuroimaging Initiative
Аннотация
BACKGROUND: Blood-based biomarkers for Alzheimer's disease (AD) pathology are appealing options in large population-based studies due to their low cost, minimal invasiveness, and feasibility of collection in non-clinical settings. Despite these benefits, blood-based biomarkers have lower test-retest reliability than neuroimaging measures like amyloid positron emission tomography (amyloid-PET) Centiloids; trade-offs in power and bias remain unexplored.
METHODS: We use data from Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) studies, which include both amyloid-PET and blood-based measures, to assess differences in statistical power, required sample size, and bias when replacing a neuroimaging measure with a blood-based measure. We use simulations parameterized based on these studies to show potential implications of using plasma p-tau 181 or p-tau 217, blood-based AD biomarkers, in place of Centiloids from amyloid-PET, when the biomarker is either the exposure or the outcome in an analysis of interest.
RESULTS: We demonstrated that substituting amyloid-PET Centiloids with a blood-based measure of p-tau can substantially reduce power, requiring 1.5-6.5 times the sample size to achieve 80% power compared to amyloid-PET. In addition, using a blood-based biomarker as the exposure can introduce significant regression dilution bias, attenuating estimated associations.
CONCLUSIONS: While blood-based biomarkers are lower cost and easier to collect than neuroimaging measures, their use as proxies for AD pathology may introduce substantial methodological challenges, depending on the p-tau isoform. Consideration of the sample sizes they necessitate and their potential for bias is critical for the design and interpretation of studies employing these biomarkers.
METHODS: We use data from Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) studies, which include both amyloid-PET and blood-based measures, to assess differences in statistical power, required sample size, and bias when replacing a neuroimaging measure with a blood-based measure. We use simulations parameterized based on these studies to show potential implications of using plasma p-tau 181 or p-tau 217, blood-based AD biomarkers, in place of Centiloids from amyloid-PET, when the biomarker is either the exposure or the outcome in an analysis of interest.
RESULTS: We demonstrated that substituting amyloid-PET Centiloids with a blood-based measure of p-tau can substantially reduce power, requiring 1.5-6.5 times the sample size to achieve 80% power compared to amyloid-PET. In addition, using a blood-based biomarker as the exposure can introduce significant regression dilution bias, attenuating estimated associations.
CONCLUSIONS: While blood-based biomarkers are lower cost and easier to collect than neuroimaging measures, their use as proxies for AD pathology may introduce substantial methodological challenges, depending on the p-tau isoform. Consideration of the sample sizes they necessitate and their potential for bias is critical for the design and interpretation of studies employing these biomarkers.