Elsevier

The Lancet Neurology

Volume 9, Issue 1, January 2010, Pages 119-128
The Lancet Neurology

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Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade

https://doi.org/10.1016/S1474-4422(09)70299-6Get rights and content

Summary

Currently available evidence strongly supports the position that the initiating event in Alzheimer's disease (AD) is related to abnormal processing of β-amyloid (Aβ) peptide, ultimately leading to formation of Aβ plaques in the brain. This process occurs while individuals are still cognitively normal. Biomarkers of brain β-amyloidosis are reductions in CSF Aβ42 and increased amyloid PET tracer retention. After a lag period, which varies from patient to patient, neuronal dysfunction and neurodegeneration become the dominant pathological processes. Biomarkers of neuronal injury and neurodegeneration are increased CSF tau and structural MRI measures of cerebral atrophy. Neurodegeneration is accompanied by synaptic dysfunction, which is indicated by decreased fluorodeoxyglucose uptake on PET. We propose a model that relates disease stage to AD biomarkers in which Aβ biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegenerative biomarkers become abnormal later, and correlate with clinical symptom severity.

Introduction

As recently as 2 to 3 decades ago, a compartmentalised model of Alzheimer's disease (AD) was widely accepted. The view at that time was that people either had AD pathological changes, in which case they had dementia, or they did not have such changes and were cognitively normal. In the meantime, a revised view of the disease has been developed, in which both AD pathological processes and clinical decline occur gradually, with dementia representing the end stage of many years of accumulation of these pathological changes. An additional feature of the current view of AD is that these changes begin to develop decades before the earliest clinical symptoms occur.

Biomarkers, both chemical and imaging, are indicators of specific changes that characterise AD in vivo. Evidence suggests that these AD biomarkers do not reach abnormal levels or peak simultaneously but do so in an ordered manner. Measurement of these biomarkers in longitudinal observational studies is now commonplace, enabling investigators to establish the correct ordering of the relevant biomarkers and their relationships to clinical symptoms.

For biomarkers of AD to be used effectively for disease staging, the time-dependent ordering of biomarkers must be thoroughly understood. This is particularly true since the introduction of clinical trials of disease-modifying therapies in which disease biomarkers play an increasingly important part both as outcome measures and as inclusion criteria. We will review the five most well validated AD biomarkers. We then propose a hypothetical model of the time-dependent ordering of onset and maxima of these biomarkers. The purpose of this paper is to offer this model as a conceptual construct within which research studies from different disciplines can relate to one another through a common framework. The model suggests a series of testable hypotheses from which a clearer picture of the time-dependent trajectories of AD biomarkers relative to clinical disease stage and to each other can be derived.

Section snippets

AD clinical features and pathological changes

Dementia is the clinically observable result of the cumulative burden of multiple pathological insults in the brain. Most elderly patients with dementia have multiple pathological changes underlying their dementia; however, the most common pathological substrate is AD.1, 2

The clinical disease stages of AD have been divided into three phases. First is a pre-symptomatic phase in which individuals are cognitively normal but some have AD pathological changes. To some extent, labelling these

Biomarkers of AD

Biomarkers are variables (physiological, biochemical, anatomical) that can be measured in vivo and that indicate specific features of disease-related pathological changes. We have used the term “biomarker” to denote both imaging and biospecimen (ie, CSF) measures. We will focus on the five most widely studied biomarkers of AD pathology, based on the current literature: decreased CSF Aβ42, increased CSF tau, decreased fluorodeoxyglucose uptake on PET (FDG-PET), PET amyloid imaging, and

Temporal ordering of biomarker abnormalities

A crucial element of biomarker-based staging of AD is the notion of temporal ordering of different biomarkers. The model that we propose, which relates pathological stage to AD biomarkers, is based on a largely biphasic view of disease progression.61, 62 In this model, biomarkers of Aβ deposition become abnormal early, before neurodegeneration and clinical symptoms occur. Biomarkers of neuronal injury, dysfunction, and neurodegeneration become abnormal later in the disease. Cognitive symptoms

Use of biomarkers to stage AD in vivo

Autopsy studies have been, and will continue to be, essential in uncovering the biological basis of the clinical symptoms in AD. However, by definition, autopsy studies are unable to provide clinical–histological correlations during life, when pathological changes actually occur, resulting in an inability to isolate relationships between time-dependent histological changes and clinical/cognitive consequences. This point underlies the value of using biomarkers in the staging of disease.

On the

Clinical trials

Our proposed model has implications for clinical trials. For example, it is rational to select patients for inclusion in trials of anti-Aβ therapies on the basis of biomarker evidence of the presence of Aβ in the brain by use of either amyloid PET imaging or CSF Aβ42. Although biomarkers of neurodegeneration correlate with clinical and pathological severity, they are not specific for AD and thus should not take precedence over Aβ biomarkers as inclusion criteria for patients in anti-amyloid

Conclusions

Our main objective was to provide a framework for hypothesis testing that relates temporal changes in AD biomarkers to clinical disease stage and to each other. The temporal relationships among the biomarkers and with clinical disease stage constitute an array of testable hypotheses. For example, carriers of APOE ɛ4 have an earlier age of onset of dementia than non-carriers,109 and we hypothesise that APOE ɛ4 carriers will have a leftward (earlier in time) shift of both the Aβ-plaque and

Search strategy and selection criteria

References for this paper were identified through searches of PubMed between 1984 and October, 2009, with combinations of the search terms “Alzheimer's disease”, “dementia”, “MCI”, “imaging”, “PET”, “PiB”, “amyloid imaging”, “MRI”, and “biomarker”. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed.

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