Peripheral Biomarkers for Alzheimer’s Disease: Update and Progress

Abstract

In 1984, the NINDS-ADRDA published criteria stating that definite Alzheimer’s disease (AD) could only be confirmed by biopsy or autopsy [1]. This publication led to the widely held perception that AD diagnosis was a diagnosis of exclusion only. Since then, the field has evolved rapidly with the advent of cerebrospinal fluid (CSF) testing for AD with great sensitivity and specificity [2], and the development of amyloid positron emission tomography (PET), tau PET, and fluorodeoxyglucose PET. Amyloid PET has emerged as an added value test that could alter clinical management [3, 4]. Magnetic resonance imaging (MRI) is also evolving as a tool to measure regional volumes, particularly within the hippocampus, as a proxy measure of neurodegeneration. Many of these tests have excellent specificity and sensitivity but are limited by access/availability of such technologies as PET, the expense of tests, and the invasive quality of lumbar puncture. Ideally, a peripheral biomarker could be used as a screening tool, with the driver being the negative predictive value, similar to amyloid PET imaging. This type of biomarker would be advantageous for its minimal invasiveness and potentially lower cost. Specifically, a peripheral diagnostic tool with a normal value would reflect the absence of the target pathology, while an abnormal value would prompt further investigation using PET and MR imaging techniques, or CSF tests. It could be valuable as a screening tool in therapeutic and prevention trials and considerably reduce the costs of ruling out potential participants who do not have the target pathology. Screening tests also would be valuable in the primary care setting when disease-modifying therapies become available. Exploration into the development of peripheral biomarkers has accelerated rapidly in recent years. This acceleration is partly due to technological developments, with ultra-sensitive methods lowering the lower limit of quantification from the nanogram per liter range to the picogram per liter range. Thus, proteins previously thought to be undetectable in peripheral samples are now measurable. In this special issue, we include seven innovative and potentially scalable peripheral diagnostic tests currently in development. Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.10283069.