The Road Ahead to Cure Alzheimer\'s Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across All Stages and Target Populations

Abstract

Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aβ) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aβ 1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1- 40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for “prodromal AD” and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.

Precision pharmacology for Alzheimer’s disease

“…Novel biomarkers are currently investigated and may increase the utility of further stratification, e.g. tau PET imaging, biomarkers for neuroinflammation, blood or metabolic signatures [10,106,107,244,245]. Apart from that, epigenomics play an important role: for instance, APOE ε4 status may be used as one of the means of enrichment.…”

“…Combined downstream and upstream effects on different homeostatic key molecules and pathways are commonly shared on several biological networks which, in turn, underlie apparently unrelated diseases [10]. Pathway-based therapies are anticipated to support the development of novel interventions to treat several diseases which can show misleading clinical divergence.…”

A promising structural magnetic resonance imaging assessment in patients with preclinical cognitive decline and diabetes mellitus

“…Diffusion-tensor imaging (DTI) is a visible approach to examine the microstructure of white matter fibers in the human brain. DTI and advanced fiber tractography monitor the degree of fiber tracts and neural network disintegration (Cavedo et al, 2014). In SCD patients, the mean diffusion and fractional anisotropy values indicate significant difference in precuneus, calcarine, putamen, and left anterior cingulate (Wang et al, 2016).…”

The Relationship of Some Neurodegenerative Diseases with Endoplasmic Reticulum Stress and Histopathological Changes in These Diseases: An Overview

“…As we mentioned earlier, increased metabolic demand, infection, hypoxia, excessive lipid accumulation, genetic disorders, and various toxins can disrupt ER homeostasis and cause ER stress due to misfolded or unfolded protein accumulation [6]. To reduce ER stress, a signaling pathway called the unfolded protein response (UPR) is activated, which slows protein synthesis and increases protein degradation [7,8]. Activated UPR creates a stress response via protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) [9,10], inositol-requiring enzyme 1 (IRE-1) [10][11][12], and activating transcription factor 6 (ATF-6) [13,14].…”

“…Neurodegenerative diseases are very diverse and affect human health negatively [6]. In addition, the first is an attractive topic because the treatment of neurodegenerative diseases is limited [7]. Parkinson's, Alzheimer's, and Huntington's are among these harvests [8,9].…”