Biomarkers for the Early Detection and Progression of Alzheimer's Disease

Abstract

The recent failures of potential disease-modifying drugs for Alzheimer's disease (AD) may reflect the fact that the enrolled participants in clinical trials are already too advanced to derive a clinical benefit. Thus, well-validated biomarkers for the early detection and accurate diagnosis of the preclinical stages of AD will be crucial for therapeutic advancement. The combinatorial use of biomarkers derived from biological fluids, such as cerebrospinal fluid (CSF), with advanced molecular imaging and neuropsychological testing may eventually achieve the diagnostic sensitivity and specificity necessary to identify people in the earliest stages of the disease when drug modification is most likely possible. In this regard, positive amyloid or tau tracer retention on positron emission tomography imaging, low CSF concentrations of the amyloid-β 1-42 peptide, high CSF concentrations in total tau and phospho-tau, mesial temporal lobe atrophy on magnetic resonance imaging, and temporoparietal/precuneus hypometabolism or hypoperfusion on 18F-fluorodeoxyglucose positron emission tomography have all emerged as biomarkers for the progression to AD. However, the ultimate AD biomarker panel will likely involve the inclusion of novel CSF and blood biomarkers more precisely associated with confirmed pathophysiologic mechanisms to improve its reliability for detecting preclinical AD. This review highlights advancements in biological fluid and imaging biomarkers that are moving the field towards achieving the goal of a preclinical detection of AD.

Exosomal biomarkers in Down syndrome and Alzheimer's disease

“…The term “biomarker” refers to objective indications of a medical state that can be measured in a reproducible manner. Cerebrospinal fluid (CSF) biomarkers of AD include the Aβ peptides, Aβ 1-40 and Aβ 1-42 , different species of P-Tau, pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β, and pro-NGF, which have been detected decades prior to dementia onset in both the general population (Bayer-Carter et al 2011; Counts et al 2017; Jack et al 2012;) and in people with DS (Perluigi et al 2014; Prasher et al 2010). However, the use of CSF biomarkers is not always practical due to its invasiveness and potential risks for post-lumbar puncture (LP) headaches.…”

An Appraisal of Novel Biomarkers for Evaluating and Monitoring Neurologic Diseases: Editorial Introduction

“…Tau and amyloid are being imaged in ongoing clinical trials in Alzheimer's disease (AD) [6][7][8]; it remains to be seen whether changes in protein burden correlate well with changes in clinical phenotype. However, such imaging studies have already enhanced our understanding of the distribution of disease burden in patients with AD, as well as the potential for therapeutic agents to ameliorate accumulation.…”

“…However, such imaging studies have already enhanced our understanding of the distribution of disease burden in patients with AD, as well as the potential for therapeutic agents to ameliorate accumulation. Fludeoxyglucose positron emission tomography has also been used to assay pathway integrity in AD; it is still unknown whether sequential studies can measure disease progression more sensitively than currently used techniques [6].…”

“…With respect to fluid markers, rapid developments are occurring in ALS, AD, and inflammatory neurological diseases [6,7,14,15]. In ALS, markers under current development probably reflect cell death or response to stress rather than specific disease pathways.…”

Olfactory Response as a Marker for Alzheimer's Disease: Evidence from Perceptual and Frontal Oscillation Coherence Deficit

“…Mini-Mental State Exam (MMSE) and Mini-Cog are two examples of such tests, which are used by clinicians to evaluate the cognitive skills of the patients and decide upon further evaluation tests (7) (8) (9). Although no single protocol has been established for large-scale screening of AD, there are proposed frameworks for diagnosis based on a set of biomarkers such as those just mentioned (10). An update to the National Institute on Aging - Alzheimer’s Association (NIA-AA) Research Framework provides additional flexibility for introducing new biomarkers to allow the results of new measurement modality evaluations in observational studies to establish their value in the clinical assessment of AD (11).…”