References for this paper were identified through searches of PubMed for articles published between January, 1984, and October, 2012, with combinations of the search terms “Alzheimer's disease”, “MCI”, “PiB”, “amyloid imaging”, “PET AND Alzheimer's”, “MRI AND Alzheimer's”, and “Alzheimer's biomarkers”. The search also included papers presented at the 2011 and 2012 Alzheimer's Association International Conference. Articles were also identified through searches of the authors' own files. Only
Personal ViewTracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers
Introduction
We proposed a model of Alzheimer's disease (AD) biomarkers that was intended to be a framework for in-vivo staging of the disease. The model focused on the five most well established biomarkers of AD, which we propose can be divided into two major categories: measures of brain amyloid β (Aβ) deposition and measures of neurodegeneration—defined as a progressive loss of neurons or their processes (axons and dendrites) with a corresponding progressive impairment in neuronal function. Brain Aβ deposition is assessed by measures of CSF Aβ421, 2, 3, 4, 5 and by PET amyloid imaging.6, 7, 8 Increased concentrations of CSF total tau (t-tau) and phosphorylated tau (p-tau),2, 4, 5, 9 hypometabolism on fluorodeoxyglucose (FDG) PET,10 and atrophy on structural MRI11, 12, 13, 14, 15, 16 are measures of neurodegeneration. FDG PET and MRI follow a modality-specific topology that is characteristic of AD.
The model was initially presented at the International Conference on Alzheimer's Disease in July, 2009,17 and published in January, 2010.18 It was based on evidence available at the time with the assumption that empirical assessment was needed. The purpose of this update is to review evidence addressing our model that has accumulated since its publication and to propose modifications to the original model based on these new data.
Section snippets
The original model
Our AD biomarkers model is predicated on the assumption that biomarkers are related to specific pathophysiological processes. This is supported by various biomarker–autopsy correlation studies. Low CSF Aβ4219, 20 and uptake of amyloid PET tracers21, 22, 23, 24 are associated with fibrillar Aβ deposits. Correlation of CSF tau and Aβ42 with neuropathology is difficult to disambiguate because, unlike with imaging, region-to-region correlations are not possible. Increases in t-tau20 and p-tau20, 25
Temporal ordering of biomarker abnormalities
Buchhave and colleagues26 followed up 137 individuals for an average of 9·2 years after baseline CSF analysis. All patients had been diagnosed with mild cognitive impairment at baseline and 72 (54%) progressed to AD. The investigators reported that CSF Aβ42 was fully abnormal 5–10 years or more before dementia diagnosis. By contrast, both CSF t-tau and p-tau became progressively more abnormal as the time to diagnosis of dementia decreased. p-tau and t-tau behaved identically over time (figure 2
Shapes of biomarker curves
In our 2010 model,18 we proposed that biomarkers curves assume a sigmoidal shape as a function of time. A sigmoid shape implies an initial period of acceleration and later deceleration. Our reasoning was based on imaging, biofluid,39, 56 and autopsy36 data available at the time. Since the publication of our model, several studies have assessed the shape of biomarker curve trajectories in different populations.
Caroli and Frisoni57 analysed cross-sectional data in 576 individuals from the ADNI.
Non-AD pathophysiological processes in elderly populations
Our hypothetical model18 was intended to model pure AD, which in late-onset disease is most likely an abstraction, because AD pathophysiology usually coexists with other pathophysiological changes, particularly cerebrovascular disease and synucleinopathy (although hippocampal sclerosis, TDP-43, and potentially non-AD tauopathies such as argyrophylic grain disease are also important contributors).63, 64, 65, 66, 67, 68 Non-AD pathophysiological processes present two closely related challenges to
Model revision
Figure 5 is a revised version of our original 2010 model (figure 1) that incorporates new findings and also addresses some of the shortcomings described in the preceding paragraphs. Although our revised model has many similarities with our 2010 model, differences do exist. Firstly, the horizontal axis in our revised model is expressed as time, not clinical disease stage. The absolute time in years needed to traverse the disease pathway from left to right and the specific age at which a person
Autopsy evidence that tau pathophysiology can precede Aβ deposition
Ours is a model of the temporal evolution of AD biomarkers in relation to each other and to the progression of clinical symptoms. Although biomarkers do reflect the specific pathophysiological processes that they measure, the sensitivity of histopathological assays is almost certainly greater than that of in-vivo biomarkers. This Personal View addresses three different potential concepts that should be kept distinct: biomarkers of AD pathophysiology; histopathology that can be measured at
Model incorporating tau and Aβ pathology as independent processes
Two sets of evidence exist that on the surface seem contradictory. First, several independent sources of AD biomarker evidence in elderly people and in young autosomal-dominant mutation carriers suggest that the sequence of events depicted by these biomarkers is Aβ pathophysiology first, then tau-related neurodegeneration. However, autopsy data83 suggest that AD-like tauopathy precedes Aβ deposition. One way to integrate these apparently conflicting data into a coherent model of disease is a
Biomarkers that precede Aβ deposition
Biomarker research is advancing in the search for biomarker abnormalities that temporally precede Aβ biomarkers. Evidence exists that FDG PET hypometabolism in an AD-like pattern occurs in some APOE ɛ4 carriers in middle-aged and young adults.95, 96 The presumption is that this hypometabolism reflects an effect of APOE ɛ4 on glucose metabolism that temporally precedes amyloid deposition. This presumption must be tempered, however, with more recent data indicating that FDG PET is a
Conclusions and future directions
The discussion above emphasises the need for discovery of new biomarkers that would allow the testing of hypotheses that can currently be framed only in theoretical terms. This list includes CSF analytes or PET ligands that are sensitive to the AT8 tauopathy described in young people by Braak and Del Tredici83 and PET ligands that measure NFTs and soluble Aβ.114 Imaging and biofluid markers of TDP-43 and α-synuclein, and imaging detection of hippocampal sclerosis and microinfarctions are
Search strategy and selection criteria
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