Research shows non-invasive novel biomarkers can predict Alzheimer's risk

Since the National Institute on Aging and Alzheimer's Association published its 2011 guidelines detailing distinct diagnostic recommendations for preclinical, mild cognitive impairment and dementia stages, research geared towards Alzheimer's disease (AD) research has progressed.

As a neurodegenerative syndrome, diagnosis originally depended on the clinical picture, MRIs and cognitive testing. However, more recently, this exceptionally complex disease continuum has primarily come to be defined by its biological manifestations.

Characterizing the disease by its biology allows for more consistent characterization and facilitates a better understanding of the disease and its mechanisms ¹. Additionally, it also offers better accuracy in clinical trials ¹.

With the transition towards precision and personalized medicine, in the area of AD, biomarkers are critical. Biomarkers associated with the specific states and stages of the disease at an individual level are necessary to provide the best patient management options. They are also needed as clinical trial endpoints to help develop an understanding of this complex disease.

Due to the rigorous search for useful AD biomarkers and general central nervous system diseases, the race towards confirming new biomarkers in these indications is a fast-moving and stimulating task.

This article discusses current, non-invasive biomarkers and investigational biomarkers for the research and diagnosis of Alzheimer's disease, as well as clinical trial partner proficiencies that may be useful along the path of development.

Currently established Alzheimer's disease biomarkers for early diagnosis and clinical trials

It is recognized that biological signs of AD appear 15 to 20 years prior to the first clinical symptoms, as levels of amyloid-β (Aβ) and tau peptides build up in the brain. These aggregates set off intracellular signaling that results in apoptosis.

The central cerebrospinal fluid (CSF) biomarkers of neuronal degeneration include:

• Beta-amyloid 42 protein (Aβ42)
• Phosphorylated tau protein (p-tau)
• Total tau protein (t-tau)

CSF levels of these three biomarkers can precisely stage the disease. Imaging studies are also utilized for the diagnosis of AD: MRI has the capacity to detect Beta-amyloid aggregation and cortical atrophy. Specific positron emission tomography (PET) imaging with radiotracers facilitates visualization of both tau-protein tangles and β-amyloid plaques in vivo ².

In short, the current blended approach utilized in the differential diagnosis and confirmation of AD and during clinical trial evaluations may include:

• Biomarkers in CSF
• Clinical tests
• Cognitive tests
• Imaging

Although imaging and CSF biomarker studies like this have the capacity to catch AD in the presymptomatic phase – 15 to 20 years before the onset of symptoms – they are extremely invasive, expensive and unable to be used as screening tests. When patients do eventually present symptoms, they are already cognitively impaired.

While effective therapies are not yet available, there is evidence to suggest that incorporating of early lifestyle interventions can prevent the onset of dementia in predisposed individuals ^3-4.

For clinical trial and screening qualification, viable early screening tests are an absolute necessity.

Developing blood-based biomarkers for early diagnosis of Alzheimer's disease

As of yet, no standard clinical diagnostic techniques are available for the diagnosis of AD from blood samples. Yet, a significant number of continuing studies and recent publications are focused on promising blood biomarkers for this goal.

• P-tau 181: An ultrasensitive blood immunoassay showed that plasma p-tau 181 levels were linked with the degree of tau and β-amyloid pathologies and differentiated AD from other neurodegenerative disorders ⁵. Numerous other studies awaiting publication agree.
• β-amyloid 42/40: An immunoprecipitation and liquid chromatography-mass spectrometry assay displayed that plasma Aβ42/ Aβ40, especially when combined with age and apolipoprotein E (APOE ε4) status (see below), diagnosed brain amyloidosis accurately (confirmed by PET), even in individuals that were cognitively normal ⁶.
• Aβ42 and t-tau: An immunomagnetic reduction assay in a small study of patients with mild cognitive impairment indicated that elevated plasma Aβ42 and t-tau levels are related to later cognitive decline ⁷.
• Neurofilament light chain (NfL): Concentrations of plasma NfL were seen to link with degree of neurodegeneration in Aβ+ subjects, as demonstrated by decreased fluorodeoxyglucose uptake in PET imaging ⁸.

Assays with the sensitivity to detect these biomarkers at extremely low concentrations in the blood are expected to aid the clinical diagnosis of prodromal Alzheimer's disease through a simple blood test.

A research lab with a history of pioneering and early-stage implementation of non-invasive biomarker techniques is likely to offer drug developers the essential services for effective transition from bench to market.

Experts with both extensive and practical, collaborative research experience; Standard and complicated testing methods, and teams specifically committed to validating and translating new biomarkers from bench to market are all vital for the successful biomarker and companion diagnostic development to assist in clinical trials.

Image Credit: Cerba Research

Genetics presents additional biomarkers for AD diagnosis and research

Acquiring as much knowledge about a disease can produce additional predictive biomarkers and reveal therapeutic opportunities by distinguishing disease causes, mechanisms and characteristic progression.

Although AD is largely sporadic, recent genomic studies across vast cohorts have detected a number of genetic associations for the disease. Biomarker changes in these heritable forms of AD are typically similar to those for intermittent AD ⁹.

For instance, an autosomal dominant, early-onset form of AD contains a genetic mutation that influences signaling at the neuronal level. Particularly, affected genes code for presynaptic vesicle protein synaptotagmin and presenilin, an accelerator when converting amyloid protein precursor (APP) to amyloid β-protein ¹⁰.

The awareness of this makes these proteins biomarker candidates for general AD.

An additional example of a genetic biomarker for AD, the various APOE polymorphs ε2, ε3, and ε4 are related to differing concentrations of CSF Aβ42. The APOE genotype influences a patient's risk factor for developing AD.

Patients with the ε4 allele demonstrate earlier declines in CSF Aβ42 concentrations, analogous to earlier amyloid deposition. The enhanced risk is greatest in homozygous ε4 carriers but is also raised in carriers of heterozygous ε4 ¹¹.

Genetics-driven biomarker discovery for AD is still a work in process, with a recent genome-wide meta-analysis verifying 20 known high-risk loci while determining five new ones, clearing a path for future investigations ¹².

Involved pathways were affiliated with immunity, lipid metabolism, tau binding proteins and APP metabolism, reflecting the complex nature of Alzheimer's disease.

Multiomics approach to biomarker discovery

No individual biomarker is inclined to serves as the signature for a disease as complex as AD. Complete characterization of the disease may necessitate incorporation, not only of genomics factors but also proteomics factors, lipidomics, transcriptomics factors and metabolomics factors, all working together.

A team with a high degree of skill and an expert technical platform are necessary for the integration of all the individual components of metabolic survey research into a full and clinically relevant profile.

CNS biomarkers for other diseases

Differential diagnosis among neurodegenerative diseases can be a challenge when cognitive and clinical tests are deemed to be inconclusive.

Special biomarkers can also assist such cases as well. For example, in the lack of biomarkers for AD, an increase in special biomarker studies of CSF protein 40-3-3 can indicate accelerated progressive dementias from cerebral injury or prion diseases, such as Creutzfeldt-Jacob (CJD).

To validate a diagnosis of CJD, cerebrospinal fluid real-time quaking-induced conversion is an extremely sensitive and special test for the presence of protease-resistant prion protein ¹³.

Future diagnostic profiling, research tools and therapeutic developments

Through a mixture of metabolomics, genomics and proteomics, biomarker profiles of patients prone to developing AD can be generated. Simultaneously, clinical research diagnostics can be advanced to better explain the dysfunctional pathways leading to AD brain pathology in combination with corresponding therapeutic targets.

Eventually, gene therapies – potentially RNA interference techniques – may be designed to limit the level of amyloid precursor protein gene expression in these patients to delay or prevent the onset of Down's symptoms.

Non-invasive biomarkers for Alzheimer's disease will help with prevention soon and therapies later

As the global population is ever-aging, reducing the incidence of Alzheimer's disease is currently a research priority. In the near future, innovative, non-invasive AD biomarkers may be available for prevention screening and to support clinical research.

It is possible to incorporate quantification of plasma tau, β-amyloid, and neurofilament concentrations into this blood-based biomarker testing method.

Developing effective biomarkers that facilitate the development of precision medicine and personalized medicine requires genuine expertise across a spectrum of specialties from proteomics, to genetics, to metabolomics. It also demands experienced assistance in biomarker validation and planning.

Biomarker studies and multiomics profiling will offer a better understanding of Alzheimer's disease, help establish new therapeutic agents and enable the implementation of preventive interventions well before the onset of this devastating and widespread disease.

References

1. Jack CR Jr et al, NIA-AA Research framework: Toward a biological definition of Alzheimer's disease, Alzheimer's Dement 14(4):535-62, 2018
2. La Joie R et al, Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tauPET, Sci Transl Med 12(524): eaau5,732, 2020
3. Sabia S et al, Association of ideal cardiovascular health at age 50 with incidence of dementia: 25- year follow-up of Whitehall II cohort study, BMJ 366: ppl4,414, 2019
4. Lefèvre-Arbogast S et al, Nutrition and Metabolic Profiles in the Natural History of Dementia: Recent Insights from Systems Biology and Life Course Epidemiology, Curr Nutr Rep 8(3): pp256-69, 2019
5. Karikari TK et al, Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts, Lancet Neurol 19(5): pp422-33, 2020
6. Schindler SE et al, High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis, Neurology 93(17): e1,647-e59, 2019
7. Chen T et al, Plasma Aβ42 and Total Tau Predict Cognitive Decline in Amnestic Mild Cognitive Impairment, Nature Sci Rep 9(1): p13,984, 2019
8. Benedet AL et al, Plasma neurofilament light associates with Alzheimer's disease metabolic decline in amyloid-positive individuals, Alzheimer's Dement (Amst) 11: pp679-89, 2019
9. Lista S et al, Biomarkers in sporadic and familial Alzheimer's disease, J Alzheimer's Dis 47(2): pp291-317, 2015
10. Öhrfelt A et al, The presynaptic vesicle protein synaptotagmin is a novel biomarker for Alzheimer's disease, Alzheimer's Res Ther 8(1): p41, 2016
11. Lautner R et al, Preclinical effects of APOE ε4 on cerebrospinal fluid Aβ42 concentrations, Alz Res Ther 9: p87, 2017
12. Kunkle BW et al, Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing, Nat Genet 51(3): pp414-30, 2019
13. Fiorini M et al, High diagnostic accuracy of RT-QuIC assay in a prospective study of patients with suspected sCJD, Int J Mol Sci 21(3): p880, 2020
14. Ballard C et al, Dementia in Down's syndrome, Lancet Neurol 15(6): pp622-36, 2016

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