The use biomarkers for Alzheimer's disease (AD) in clinical settings is regulated relatively loosely compared, for example, to requirements for introducing new drugs. In 2001, the framework used for drugs validation was adapted to design a strict and systematic validation procedure for oncology biomarkers. This work aims to adapt the oncology framework to AD specific biomarkers.


      The 5-phases framework by Pepe et al (Journal of the National Cancer Institute, 93(14), 2001) was adapted to meet the specificity of validation studies of biomarker for AD. Adaptations were made to: specific terms; types of studies design; context of use; target population. Limitations of these adaptations were thoroughly considered.


      The adaptation led to Incidental and Substantial differences of the 'AD', compared to the ‘oncology', framework. Incidental differences relate to target tissue (brain vs tumor), specific outcomes (disability, morbidity, institutionalization, quality of life, caregivers burden vs mortality), and study designs (prospective vs retrospective). Substantial differences relate to the target population and to the possible use of biomarkers within the two frameworks. As to target population, this validation framework is restricted to the MCI population, due to the need of early detection of clinical disease, to the fact that clinical criteria do not recommend preclinical diagnosis for ethical reasons, and to the possibility to use ‘conversion to dementia' as a gold standard for diagnosis (in the lack of pathology data). The resulting 5 sequential phases were: 1) pilot studies, 2) clinical assay development for clinical disease, 3) prospective longitudinal repository studies, 4) prospective diagnostic studies, and 5) disease control studies (Table). Because of the required adaptations, biomarkers for AD can be used for biomarker-based diagnoses and not yet for screening purposes.


      The adaptation of the oncology framework to AD aims to systematize the validation of AD biomarkers. The important limitations restrict the generalizability of results to the general population and the use of such biomarkers for screening purposes. This initiative should be considered as a first, although necessary, step to the definition of a systematic validation of biomarkers for AD.
      Tabled 1Phases for the development of biomarkers as adapted from the oncology framework (Pepe et al., J Natl Cancer Inst 2001) to the case of the pre-dementia diagnosis of Alzheimer's disease.
      Phase 1
      Pilot StudiesPrimary AimsTo identify leads for potentially useful biomarkers and prioritize identified leads.
      Phase 2
      Clinical AssayPrimary AimTo estimate the true and false positive rate or ROC curve and assess its ability to distinguish subjects with and without the disease.
      Development for Clinical Disease
      Secondary Aim 1To optimize procedures for performing the assay and to assess the reproducibility of the assay within and between laboratories.
      Secondary Aim 2To determine the relationship between biomarker tissue measurements made on tissue (phase 1) and the biomarker measurements made on the noninvasive clinical specimen (phase 2).
      Secondary Aim 3To assess factors (e.g. sex, age, etc.), associated with biomarker status or level in control subjects. If such factors affect the biomarker, thresholds for test positivity may need to be defined separately for target subpopulations.
      Secondary Aim 4To assess factors associated with biomarker status or level in diseased subjects—in particular, disease characteristics.
      Phase 3
      Prospective LongitudinalPrimary Aim 1To evaluate the capacity of the biomarker to detect the earliest disease stages.
      Repository StudiesPrimary Aim 2To define criteria for a biomarker positive test in preparation for phase 4.
      Secondary Aim 1To explore the impact of covariates on the discriminatory abilities of the biomarker before clinical diagnosis.
      Secondary Aim 2To compare markers with a view to selecting those that are most promising.
      Secondary Aim 3To develop algorithms for positivity based on combinations of markers.
      Secondary Aim 4To determine a biomarker testing interval for phase 4 if repeated testing is of interest.
      Phase 4
      Prospective Diagnostic StudiesPrimary AimTo determine the operating characteristics of the biomarker-based test in a relevant population by determining the detection rate and the false referral rate. Studies at this stage involve testing people and lead to diagnosis and treatment.
      Secondary Aim 1To describe the characteristics of disease detected by the biomarker test—in particular, with regard to the potential benefit incurred by early detection.
      Secondary Aim 2To assess the practical feasibility of implementing the diagnostic program and compliance of test-positive subjects with work-up and treatment recommendations.
      Secondary Aim 3To make preliminary assessments of the effects of biomarker testing on costs and mortality associated with the disease.
      Secondary Aim 4To monitor disease occurring clinically but not detected by the biomarker testing protocol.
      Phase 5
      Disease Control StudiesPrimary AimTo estimate the reductions in disease-associated mortality, morbidity.
      and disability afforded by biomarker testing.
      Secondary Aim 1To obtain information about the costs of biomarker testing and treatment and the cost per life saved or per quality-adjusted life year.
      Secondary Aim 2To evaluate compliance with testing and work-up in a diverse range of settings.
      Secondary Aim 3To compare different biomarker testing protocols and/or to compare different approaches to treating test positive subjects in regard to effects on mortality and costs.