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. 2010 Jan;9(1):119-28.
doi: 10.1016/S1474-4422(09)70299-6.

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

Clifford R Jack Jr  1 , David S Knopman, William J Jagust, Leslie M Shaw, Paul S Aisen, Michael W Weiner, Ronald C Petersen, John Q Trojanowski
Affiliations

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

Clifford R Jack Jr et al. Lancet Neurol. 2010 Jan.

Abstract

Currently available evidence strongly supports the position that the initiating event in Alzheimer's disease (AD) is related to abnormal processing of beta-amyloid (Abeta) peptide, ultimately leading to formation of Abeta plaques in the brain. This process occurs while individuals are still cognitively normal. Biomarkers of brain beta-amyloidosis are reductions in CSF Abeta(42) 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 Abeta biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegenerative biomarkers become abnormal later, and correlate with clinical symptom severity.

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Conflict of interest statement

Conflicts of interest

CRJ is an investigator in clinical trials sponsored by Pfizer and Baxter, and consults for Elan and Lilly. DSK has served on a data and safety monitoring board for Lilly, has been a consultant for GlaxoSmithKline, and receives grant funding for clinical trials by Baxter, Elan, and Forest. WJJ has consulted for Genentech, Synarc, Elan Pharmaceuticals, Ceregene, Schering Plough, Merck & Co, and Lilly. LMS has consulted for Pfizer. PSA has consulted for Elan, Wyeth, Eisai, Neurochem, Schering-Plough, Bristol-Myers-Squibb, Lilly, Neurophase, Merck, Roche, Amgen, Genentech, Abbott, Pfizer, Novartis, and Medivation, has stock options with Medivation and Neurophase, and has received grant support from Pfizer, Baxter, and Neuro-Hitech. MWW has been on the scientific advisory boards for the Alzheimer’s Study Group, Bayer Schering Pharma, Lilly, CoMentis, Neurochem, Eisai, Avid, Aegis, Genentech, Allergan, Bristol-Myers Squibb, Forest, Pfizer, McKinsey, Mitsubishi, and Novartis, has received travel funding from Nestlé, honoraria from BOLT International, commercial research support from Merck and Avid, and has stock options in Synarc and Elan. RCP has been a chair, member of the safety monitoring committee, and consultant for Elan, has chaired a data monitoring committee for Wyeth, and has been a consultant for GE Healthcare. JQT has received lecture honoraria from Wyeth, Pfizer, and Takeda.

Figures

Figure 1
Figure 1. Illustration of biomarker staging of Alzheimer’s disease
Three elderly individuals are placed in order from left to right by use of our proposed biomarker staging scheme. (A) A cognitively normal individual with no evidence of Aβ on PET amyloid imaging with PiB and no evidence of atrophy on MRI. (B) A cognitively normal individual who has no evidence of neurodegenerative atrophy on MRI, but has significant Aβ deposition on PET amyloid imaging. (B) An individual who has dementia and a clinical diagnosis of Alzheimer’s disease, a positive PET amyloid imaging study, and neurodegenerative atrophy on MRI. Aβ=β-amyloid. PiB=Pittsburgh compound B.
Figure 2
Figure 2. Dynamic biomarkers of the Alzheimer’s pathological cascade
Aβ is identified by CSF Aβ42 or PET amyloid imaging. Tau-mediated neuronal injury and dysfunction is identified by CSF tau or fluorodeoxyglucose-PET. Brain structure is measured by use of structural MRI. Aβ=β-amyloid. MCI=mild cognitive impairment.
Figure 3
Figure 3. Staging Alzheimer’s disease with dynamic biomarkers
Disease stage based on biomarkers is described by the magnitude of the biomarker abnormality and its rate of change at a given point in time (t). This is illustrated by the following terms: A(t)=magnitude of the Aβ plaque biomarker at time t; SA(t)=slope of the Aβ plaque function at time t; N(t)=tau-mediated neuron injury at time t; SN(t)=slope of N(t); M(t)=MRI at time t; SM(t)=slope of M(t). Aβ=β-amyloid.
Figure 4
Figure 4. Anatomical imaging information
For simplicity in other figures, imaging biomarkers have been shown as individual curves. However, anatomical variation exists in the time courses within each imaging mode. For example, in FDG-PET, one would expect abnormalities to appear in the following order: precuneus/posterior cingulate, lateral temporal, and frontal lobe much later. Similarly, in structural MRI, one would expect abnormalities to appear in the following order: medial temporal, lateral temporal, and frontal lobe later. FGD=fluorodeoxyglucose.
Figure 5
Figure 5. Modulators of biomarker temporal relationships
(A,B) Relative to a fixed age (here, 65 years), the hypothesised effect of APOE ε4 is to shift β-amyloid plaque deposition and the neurodegenerative cascade both to an earlier age compared with ε4 non-carriers. (C) The hypothesised effect of the presence of different diseases and genes on cognition: C−=cognition in the presence of comorbidities (eg, Lewy bodies or vascular disease) or risk amplification genes; C+=cognition in patients with enhanced cognitive reserve or protective genes; Co=cognition in individuals without comorbidity or enhanced cognitive reserve.
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