Biomarkers: Our Path Towards a Cure for Alzheimer Disease

Abstract

Over the last decade, biomarkers have significantly improved our understanding of the pathophysiology of Alzheimer disease (AD) and provided valuable tools to examine different disease mechanisms and their progression over time. While several markers of amyloid, tau, neuronal, synaptic, and axonal injury, inflammation, and immune dysregulation in AD have been identified, there is a relative paucity of biomarkers which reflect other disease mechanisms such as oxidative stress, mitochondrial injury, vascular or endothelial injury, and calcium-mediated excitotoxicity. Importantly, there is an urgent need to standardize methods for biomarker assessments across different centers, and to identify dynamic biomarkers which can monitor disease progression over time and/or response to potential disease-modifying treatments. The updated research framework for AD, proposed by the National Institute of Aging- Alzheimer’s Association (NIA-AA) Work Group, emphasizes the importance of incorporating biomarkers in AD research and defines AD as a biological construct consisting of amyloid, tau, and neurodegeneration which spans pre-symptomatic and symptomatic stages. As results of clinical trials of AD therapeutics have been disappointing, it has become increasingly clear that the success of future AD trials will require the incorporation of biomarkers in participant selection, prognostication, monitoring disease progression, and assessing response to treatments. We here review the current state of fluid AD biomarkers, and discuss the advantages and limitations of the updated NIA-AA research framework. Importantly, the integration of biomarker data with clinical, cognitive, and imaging domains through a systems biology approach will be essential to adequately capture the molecular, genetic, and pathological heterogeneity of AD and its spatiotemporal evolution over time.

News about the Role of Fluid and Imaging Biomarkers in Neurodegenerative Diseases

“…Up to now, however, the results of clinical trials to evaluate the state of the AD therapy have been disappointing. In the future, development should be based on multiple criteria, including the state of the disease, its progression, and the activity of biomarkers focused on critical processes [ 40 ].…”

“…Although incomplete, the present knowledge appears of interest to establish the properties of some AD heterogeneous forms, such as responses to treatments. The study of multiple biomarkers, identified during the last months, might be sufficient to characterize at clinical level various aspects of AD, including diagnosis and prognosis [ 38 , 39 , 40 ]. Heterogeneity exists also for tau.…”

Deciphering the links between psychological stress, depression, and neurocognitive decline in patients with Down syndrome

“…Historically, abnormal accumulation of fibrillar amyloid plaques in the extra-neuronal compartment – amyloidosis – has been the key lesion described in AD. Such amyloid plaques dysregulate neuronal connections, increase cerebral oxidative stress, enhance cerebral inflammation and cerebral amyloid angiopathy, and ultimately lead to neuronal apoptosis ( Tarawneh, 2020 ).…”

Biomarkers and Their Implications in Alzheimer’s Disease: A Literature Review

“…These biomarkers exhibit greater than 95% sensitivity and 85% specificity in regards to diagnosing AD. 2 Low quantities of Aβ42 in the CSF are observed in AD individuals compared to controls, 29 while elevated levels of hyper-phosphorylated tau and t-tau have been identified in the CSF in AD patients. 2, 30 Previous literature has shown that high t-tau and/or p-tau181 along with low Aβ42 in the CSF can be detected before patients with AD become symptomatic, and offer improved diagnostic accuracy of AD from other causes of dementia.…”

“…The most promising biomarkers associated with synaptic dysfunction in AD patients are the postsynaptic protein neurogranin (Ng) and the presynaptic proteins synaptosome-associated protein-25 (SNAP25) and synaptotagmin-1 (Syt1). 2 The overall neuronal specificity and abundant expression of Ng, SNAP25, and Syt1 allow these biomarkers to accurately reflect the degree of neuronal and synaptic injury. This is because the CSF level of these biomarkers correlate with damage to neuronal and synaptic structures, as well as with the release of neuronal or synaptic components into the extracellular compartment as neurodegeneration progresses.…”