But in the absence of symptoms, it will not be possible to fulfill the conventional US Food and Drug Administration requirement for AD drug development: demonstration of efficacy on co-primary measures, specifically a cognitive performance test and a functional/global measure. It would require huge and lengthy studies to show slowing of cognitive and clinical progression or delay to diagnosis of dementia in subjects not yet showing any symptoms. To study interventions in this population, we will require validated surrogate markers.
A biomarker is any objectively measured characteristic that reflects normal or pathological processes, or responses to therapeutic intervention. As discussed above, biomarkers can be valuable in selecting subjects for clinical trials and for therapeutic interventions, for reducing unexplained variance and thus improving statistical power, and for establishing proof of concept in early phase drug development.
In rare cases, a biomarker can take the place of a clinical endpoint for establishing efficacy in a phase III clinical trial; that is, a biomarker can be validated as a surrogate endpoint. Examples of such surrogate markers include blood glucose and hgA1c in diabetes, blood pressure and cholesterol in cardiovascular disease, intraocular pressure in glaucoma, and lymphocyte subset ratios and viral load in HIV disease. To validate a biomarker as a surrogate endpoint, several issues must be addressed. There must be a well-accepted scientific framework connecting the biomarker to disease mechanisms and the prediction of clinical outcomes. Further, drug effects on the biomarker must be related to drug effects on clinical outcome; ideally, the biomarker should fully capture treatment effects, as confirmed by clinical trials of multiple interventions.
It is unlikely that an ideal surrogate for disease-modifying intervention in AD will become available in the foreseeable future. However, in consideration of the enormous clinical need, and the likelihood that the development of highly effective disease-modifying treatments will require the use of surrogate endpoints, it is reasonable to assume that regulatory agencies will consider acceptance of surrogates that are less than ideal.
A validated surrogate marker is essential for the study of AD interventions in asymptomatic or very mildly symptomatic individuals. It may be feasible to gain acceptance of a surrogate AD biomarker with a small number of trials demonstrating concordant treatment effects on the biomarkers and clinical symptoms. Even if the benefits of disease-modifying treatments in mild AD dementia are limited, they may well be sufficient to establish this concordance. Indeed, ongoing anti-amyloid trials that have incorporated biomarkers could provide this evidence. Consensus among clinical experts, based on robust data, that candidate biomarkers track disease progression at various stages of disease will strengthen the case for validation. A leading candidate surrogate marker is brain atrophy rate as measured by volumetric MRI; a huge body of evidence supports a link between regional brain atrophy and progression of AD pathobiology [32