Scientific advances in the understanding of Alzheimer's disease (AD), coupled with the release of various technologies, enable the early detection of biomarkers. This knowledge is reshaping the paradigm for treatment, potential diagnosis, and classification of the disease by offering new hope for more personalized approaches in medicine. In this interview, we cover the current thoughts and trends in pathophysiology and disease diagnosis, research on diagnostic testing tools, and the role of clinically relevant biomarkers for AD.
Neurodegeneration, the underlying mechanism of AD, is challenging to identify. A definitive diagnosis requires confirmation of neuropathological changes in the brain. The gold standard test is post-mortem tissue studies. Research indicates, however, that pathological changes in the brain occur decades before cognitive symptoms appear. The goal of new generation biomarker-based tests is to detect these changes earlier to inform more targeted treatments for AD and any co-occurring neurological conditions. Importantly, a validated biomarker must be proven reliable across clinical settings and institutions (Lucs, 2013).
What is Alzheimer's disease?
Alzheimer's disease is the leading cause of dementia in older adults, accounting for almost 70% of dementia cases. AD is considered the sixth-leading cause of death in the United States. Approximately 5.8 million Americans are living with AD. Caring for those with dementia costs $305 billion in 2020, which is projected to rise to $1.1 trillion in 2050 (Alzheimer's Association, 2020).
A diagnosis of probable AD is based on a pattern of memory loss and behavioral changes when there is no evidence of other reversible causes. Imaging techniques such as magnetic resonance imaging (MRI) or positron emission tomography (PET), used as part of a clinical assessment, can detect specific protein aggregates (National Institute on Aging, 2017a; Small, 2008). Analysis of biomarkers in cerebrospinal fluid (CSF) aids diagnosis, especially in the early stages, and helps to discriminate AD from non-AD dementia patients (Sutphen, 2014). CSF biomarkers that support the diagnosis of AD include Aβ42, Aβ40, total tau (T-tau), and phosphorylated tau (P-tau) (Blennow, 2010).
A biomarker is defined as "any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease" (Strimbu, 2010). As a molecular indication of disease, proteins offer valuable feedback for treatment planning, while also informing research on clinical trial design and recruitment.
Treatment of Alzheimer's disease
"It's the utmost priority for researchers in the United States, as well as globally, to identify a disease-modifying therapy for Alzheimer's disease," said Iswariya Venkataraman, PhD, Scientific Affairs Lead, EUROIMMUN US. With no treatments yet effective in reversing or arresting AD's progression, current treatment strategies focus on managing symptoms by regulating neurotransmitters. Therapies can improve memory, attention, reason, language, and the ability to perform simple tasks.
The US Food and Drug Administration (FDA) has approved three types of treatments for AD:
- Acetylcholinesterase inhibitors, which include donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Razadyne®).
- An NMDA receptor antagonist, memantine (Namenda®) (National Institutes of Health, 2019).
- A combination of donepezil and memantine.
"Researchers are continuing to understand the pathophysiology of the disorder to identify a suitable treatment," said Dr. Venkataraman. "But we are hoping for a breakthrough in the near future." According to Dr. Venkataraman, recent progress in understanding the disease's biological constructs points to underlying protein pathology as a potential new treatment target.
Pathophysiology of Alzheimer's disease
In 2011, the National Institute on Aging and Alzheimer's Association (NIA-AA) released a new research framework for AD that focused on the disease's pathology (Jack, 2018). Abnormal protein deposits are characteristic of AD. Amyloid fibrils, which form from the breakdown of the protein amyloid β, clump together to form pathogenic plaques that can block neurons and disrupt cell function (Jack, 2018). Neurofibrillary tangles are formed of aggregated tau protein. After phosphorylating, tau detaches from microtubules as paired filaments that form tangles inside neurons, blocking synaptic communication (Jack, 2018). Researchers suspect interplay between amyloid β and tau (Nisbet, 2015). Rising levels of amyloid β may trigger the rapid spread of tau (National Institute on Aging, 2017b).
"We are seeing the diseases more like biological constructs,” said Britta Brix, PhD, Department of Neurodegeneration Lead, EUROIMMUN Medical Laboratory Diagnostics AG, Lübeck, Germany. “What we try to do now is not to identify, let's say Alzheimer's disease, but we want to identify patients with amyloid pathology, we want to identify patients with tau pathology."
NIA-AA proposed a pathophysiological construct called AT(N) to classify amyloid β, tau, and neurodegenerative biomarker profiles using imaging and biofluids (Jack, 2018). N represents neurodegeneration based on abnormal imaging using MRI or PET that shows injury or atrophy. Each component of AT(N) is scored as positive or negative (i.e., A+/-, T+/-, and (N)+/-). A population-based study in 2019 used the AT(N) framework to investigate cognitive aging (Jack, 2019). The A+T+(N)+ group had the highest cognitive impairment, but rapid memory decline was also found in the A+T+(N)− and A+T−(N)+ groups (Jack, 2019).
"What we want to do is to treat amyloid pathology or, in a patient who only has tau pathology, we treat tau pathology. This paradigm shift is from seeing it as a disease to looking into the biological construct to treat that, rather than the disease," said Dr. Brix.
The AT(N) classification helps identify patients along a continuum from early to late-stage disease. Abnormal amyloid β and pathologic tau should be considered as potential biomarker definitions of AD. Amyloid β biomarkers represent the earliest evidence of AD neuropathologic change, serving as the first inclusion criteria on the AD continuum. The pathologic tau biomarker then evaluates the stage of disease on that continuum.
Molecular pathophysiology is being used to identify other pathways and processes of neurodegeneration in AD. A precursor protein of amyloid β, β-secretase 1 (BACE1) has been identified as a potential biomarker for predicting mild cognitive decline in AD (Hampel, 2018). Though not specific to AD, the axonal protein neurofilament light (NFL) is another possible biomarker; studies have shown elevated levels of NFL in those with NDD, including those with amyloid β-positive PET scans (Hampel, 2018).
The potential of a new era in AD detection and treatment has sparked increases in fluid biomarker research. "Many groups have blood-based biomarkers, and there are many research groups that have started focusing on an ideal candidate blood-based biomarker, specifically for Alzheimer's disease," said Dr. Venkataraman, "We definitely hope to have such a marker in the near future."
Testing for Alzheimer's disease
Physicians use a differential diagnosis to rule out other causes for presenting symptoms. Neurological tests are used to assess memory, problem-solving, attention, and language. In addition, probable diagnoses can be made by analyzing amyloid β and tau levels in CSF.
Optimally, a biomarker would be safe and easy to gather using a non-invasive procedure while also being reliable, stable, and cost-effective to analyze in a clinical laboratory. Toward that end, the field has focused on developing blood-based assays, with plasma offering the most potential for measuring protein and peptides (Hampel, 2018). Mass spectrometry can detect changes in protein concentrations; immunoassays can accurately identify specific proteins (Hampel, 2018).
Companies are rapidly developing blood-based assays for AD. According to Dr. Venkataraman, "It's important for these plasma markers to show good correlation to CSF markers because ultimately, you want a reliable diagnostic marker that can help detect the disease early-on."
In the clinic, a reliable blood-based assay could be a convenient and cost-effective way to screen for AD or as the first step in a diagnostic workup. Positive results could be followed up by more invasive and rigorous testing.
Brain imaging, such as PET, can be used to look for deposits of amyloid β. A new PET radiotracer approved by the FDA in May of 2020, called flortaucipir F18 or (Tauvid™), estimates the density and distribution of aggregated tau neurofibrillary tangles in adult patients with cognitive impairment. However, PET scans can be cost-prohibitive and not necessarily easily accessible to patients.
Role of biomarkers in clinical care and research
"It is better to target what protein pathology is present in these patients, not to get rid of it, but to resolve this protein complication or mixed proteinopathies," said Dr. Brix.
"You would identify a patient with amyloid and treat this patient with an anti-amyloid therapy," said Dr. Venkataraman.
An anti-amyloid treatment called aducanumab (an IgG1 monoclonal antibody) is in Phase 3 clinical trials in the US currently. Aducanumab's road to regulatory approval has been rocky with setbacks and pauses, but the FDA granted it a fast-track review in August 2020.
"I expect then as a next step to also see more trials for tau treatments to target the tau pathology," said Dr. Venkataraman, also noting the potential to combine anti-amyloid and anti-tau treatments in individual patients.
The use of biomarker-based diagnostic and prognostic testing in AD could help accelerate research and development of new therapies. The NIA-AA framework for research using the AT(N) classification offers clinical researchers' additional tools for screening subjects for inclusion, based on biomarkers and disease stage.
"Clinical trials have failed due to many reasons, but one, in particular, is because the proper inclusion criteria of patients is difficult to understand," said Dr. Venkataraman. "During trials, sometimes patients are included who are already in the very advanced stages of the disease, making it difficult to reverse what's happening in their brain."
Rolling out testing for blood-based biomarkers, however, would require integrated collaboration between academia, pharma, and in vitro diagnostic manufacturers to standardize protocols for assays to achieve reliability for routine diagnostics or companion diagnostics. Workflows and testing methods would eventually need to be standardized to support complex data analysis across multiple dimensions and scale of testing.
The Alzheimer’s Association created the International Society to Advance Alzheimer's Research and Treatment (ISTAART) to establish consensus on pre-analytical and analytical protocols and develop a repository of clinical reference samples to enable assay harmonization and clinical performance assessment (Hampel, 2018).
According to Dr. Brix, it is crucial for different methods offered by various vendors to be comparable. "We are collaborating now in the field with different vendors and also key opinion leaders to set up standards for sample-handling procedures for blood to set up quality control schemes to be able to identify these biomarkers reliably, regardless of where they came from."
Adopting biomarker-based testing for AD is an essential step in establishing a new pathophysiology-based paradigm for a devastating, irreversible, and fatal disease. It constitutes a critical first step in the foundation for more personalized, tailored therapies for distinct stages of AD progression (Hampel, 2018), giving new hope to the increasing numbers of individuals facing an unrelenting foe.
About the Authors
Dr. Britta Brix (Dept of Neurodegeneration, Lead) is responsible for the department of neurodegeneration at EUROIMMUN (HQ). She and her team strategically drive portfolio development for neurodegeneration and manage scientific affairs, as well as develop the market at an international level. In this role, she has built a strong network within the neurodegenerative community representing EUROIMMUN, for example in the Alzheimer’s Association Global Biomarker Standardization Consortium.During her PhD study, she focused on molecular neurology investigating the interplay between astrocytes, neurons, and endothelial cells under hypoxic conditions in vivo and in vitro. Since Dr. Brix has joined EUROIMMUN, her research focuses on fluid biomarkers in neurodegeneration. Several of her publications on clinical utility of these biomarkers, technical validation, and analytical aspects, as well as sample handling, have been published in high impact journals.
Dr. Iswariya Venkataraman (Scientific Affairs, Lead) is responsible for the scientific affairs team at EUROIMMUN US. In this role, she builds scientific partnerships with healthcare professionals and key decision makers through evidence based and non-promotional scientific activities. She is a member of the ADNI Private Partner Scientific Board, which is an independent, pre-competitive forum for study-related scientific exchange in the field of neurodegeneration.
She holds a Ph. D in the field of neuroscience and during her study she identified novel auto-antigens in autoimmune hyper-excitability disorders. She is also designated as an inventor and holds a patent for identification of a methodology for isolating an autoantibody binding to a polypeptide selected from the super family of proteins called “Soluble NSF Attachment Protein Receptor” (SNARE) in patients with selected autoimmune neurological disorders. She has written several scientific articles regarding biomarkers in neurodegeneration and her work has been published in high impact journal such as Alzheimer’s & Dementia etc.
- Ashton, N. H. (2020). An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders. Nat Rev Neurol, 16, 265–284. Retrieved from https://doi.org/10.1038/s41582-020-0348-0
- Association Association. (2020). Alzheimer's disease facts and figures. https://www.alz.org/alzheimers-dementia/facts-figures#:~:text=More%20than%205%20million%20Americans%20of%20all%20ages%20have%20Alzheimer's,10%25)%20has%20Alzheimer's%20dementia. Retrieved November 18, 2020.
- Blennow K., Hampel H., Weiner M., Zetterberg H. (2010). Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Review Neuro, 10;6(3):131-144
- Hampel, H. O. (2018). Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol, 14, 639–652. Retrieved from https://doi.org/10.1038/s41582-018-0079-7
- Jack, C. R. (2018). NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement Journal, 14(4), 535–562. Retrieved from https://doi.org/10.1016/j.jalz.2018.02.018
- Jack, C. R. (2019). Associations of amyloid, tau, and neurodegeneration biomarker profiles with rates of memory decline among individuals without dementia. JAMA, 321(23), 2316–2325. Retrieved from https://doi:10.1001/jama.2019.7437
- Lucs A., Saltman B., Chung C.H., Steinberg B.M., Schwartz DL. (2012). Opportunities and challenges facing biomarker development for personalized head and neck cancer treatment. Head Neck, 35(2):294-306.
- National Institute on Aging. (2017a). How is Alzheimer's disease diagnosed? https://www.nia.nih.gov/health/how-alzheimers-disease-diagnosed. Reviewed May 22, 2017. Retrieved September 20, 2019.
- National Institue on Aging. (2017b). What happens to the brain in Alzheimer’s disease? https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease. Reviewed May 16, 2017. Retrieved November 18, 2020.
- Nisbet, R.M. (2015). Tau aggregation and its interplay with amyloid-β. Acta neuropathologica, 129(2), 207–220. Retrieved from https://doi.org/10.1007/s00401-014-1371-2
- Small G.W. (2000). Early diagnosis of Alzheimer's disease: update on combining genetic and brain-imaging measures. Dialogues Clin Neurosci, 2(3):241-246.
- Strimbu K., Tavel J.A. (2015). What are biomarkers? Curr Opin HIV AIDS, 5(6):463-466.
- Sutphen C.L., Fagan A.M., Holtzman D.M. (2014). Progress update: fluid and imaging biomarkers in Alzheimer's disease. Biol Psychiatry, 75(7):520-526.