Biomarkers, assays, and therapies for Alzheimer disease.

Abstract

Alzheimer disease (AD) is a devastating neurodegenerative disorder characterized by a progressive decline in cognitive function. In 2010, an estimated 36 million people worldwide had AD or a related dementia, with this number projected to double by 2030. The social and economic burden of AD is well documented and will be amplified by this increase in prevalence. The initial pathophysiologic changes of AD are found in the hippocampus region of the brain, disrupting memory and the ability to learn. AD progression is linked to nerve cell dysfunction and cell death due to the accumulation of 2 protein aggregates: β-amyloid (Aβ)5 and tau. In the cerebrospinal fluid (CSF), these proteins are biomarkers for AD. Cleavage of the amyloid precursor protein (APP) generates varying lengths of Aβ peptides (38–43 amino acids) that accumulate in the extracellular space. Of these monomers, Aβ-42 is the major form associated with AD. In addition, tau entanglement is also associated with AD and consists of insoluble hyperphosphorylated tau protein in the intracellular space. Both total tau (t-tau) and phosphorylated tau (p-tau) proteins are measured and associated with AD. Currently, clinical trials are testing therapies that target these proteins in hopes to delay or halt the cognitive decline in AD patients. In this Q&A, we discuss the current state and future direction of biomarkers, assays, and therapies for AD with 3 experts. Established Alzheimer biomarkers include β-amyloid and tau protein in CSF, as well as imaging techniques that involve MRI and positron emission tomography (PET). What are the limitations of these biomarkers that restrict them mostly to research purposes? Erik Portelius: In the recently updated diagnostic criteria for AD (the International Working Group-2 criteria), the CSF AD biomarkers (Aβ-42, t-tau, and p-tau) and neuroimaging with Pittsburgh compound B (PiB)-PET were included. Although MRI may mirror the disease …