The role of biologic markers in the diagnosis of Alzheimer's disease

The objective of this report is to establish consensus criteria for the use of biologic markers in the diagnosis of Alzheimer’s disease (AD). To address this issue, we will first provide background information concerning the significance of biologic AD markers, differences between genetic markers, genetic modifiers, and biologic markers, criteria for an ideal biologic marker, strengths and weaknesses of biologic markers currently available, and promising future research developments in AD biomarker discovery. Specific recommendations to primary care physicians and specialists will follow. 2. What is a biologic marker? A biologic marker of disease is a measurable change in the physical constitution of an organism that indicates the presence of the disease. Current biologic indices under investigation for the early diagnosis of AD include chemical markers detected in body fluids and brain volume or activity measurements derived from neuroimaging modalities such as magnetic resonance imaging (MRI) or positron emission tomography (PET) of relevant brain regions. Neuroimaging modalities are expensive, labor-intensive, and not universally available, prompting a search for reliable chemical biomarkers and other practical neurodiagnostic modalities. Chemical markers of AD can be conceptualized within three general categories: (1) genetic markers, (2) genetic modifiers, and (3) biologic markers. Genetic markers such as mutant forms of amyloid precursor protein (APP), presenilin-1, and presenilin-2 are excellent for predicting disease in rare kindreds with familial AD but are not useful in tracking disease progression or efficacy of therapeutic intervention in these subjects. Moreover, these genetic markers have little or no role to play in the management of patients with the far more common sporadic form of the illness. The presence of the apolipoprotein E (APOE) e4 allele, a genetic modifier, is a strong risk factor for the development of sporadic AD and predicts earlier onset of clinical dementia in AD patients. However, the presence of the e4 allele does not confer AD, and its absence does not exclude this disorder. Thus, testing for the e4 allele cannot be used as a diagnostic marker of sporadic AD. Unlike the genetic markers and modifiers, true biologic markers of AD are “state” indicators that inform of the presence or absence of AD at the time of measurement and are thus appropriate for use as diagnostic modalities for sporadic (and possibly familial) forms of this condition.