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

Abstract

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 Aβ 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 Aβ biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegenerative biomarkers become abnormal later, and correlate with clinical symptom severity.

Relationships between cardiorespiratory fitness, hippocampal volume, and episodic memory in a population at risk for Alzheimer's disease

“…Specifically, individuals with parental family history of AD are three times more likely to develop the disease compared to those with no familial history (Duijn et al., 1991). Further, there is a strong genetic component, with those at greatest risk being carriers of APOE‐e4 (Jack et al., 2010). If the APOE‐e4 allele is inherited, the chance of developing AD doubles (Vardarajan et al., 2014).…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Frequency‐specific quantitative electroencephalographic (EEG) measures of NREM sleep, particularly those in the <1 Hz signature range, may therefore represent an early biomarker of Aβ burden. Compared with other established biomarkers, sleep EEG may significantly contribute to identifying an individual's risk for developing AD years or even decades before onset of clinical symptoms (Jack et al, 2010). …”

Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain

“…Despite decades of intense research, existing biomarkers of AD, such as CSF and plasma measurements of pathogenic proteins A β and Tau, are imperfect as they do not exhibit dynamic changes across the entire course of the disease15 and provide a classification accuracy below what would be accepted for clinical diagnosis. For this reason, they have been adopted in research, but not in clinical practice 16.…”