Biomarkers for Dementia

Major neurocognitive disorders, also known as dementia, affect more than 55 million people worldwide, over 60% of whom live in low-and middle-income countries. Every year, there are nearly 10 million new cases. Dementia is not a specific disease but rather a general term for the loss of cognitive functioning including the impaired ability to remember, think, or make decisions, which interferes with a person’s ability to do everyday activities.  Dementia results from a variety of diseases and injuries that affect the brain. Alzheimer’s disease is the most common form of dementia and may contribute to 60–70% of cases. Dementia can range in severity, from the early, mildest stage to the most severe stage where the person is completely dependent on others for basic activities. Although dementia mostly affects older adults, it is not a normal part of ageing.

The diagnosis of dementia has evolved from a purely clinical process to become a more complex exercise that integrates neuropsychological and biomarker evidence. Diagnosis of dementia usually begins with a thorough history of a person’s medical and family history, followed by cognitive and neurological tests. Brain scans, including CT, MRI and PET scans looking for tau and amyloid plaques may be conducted and, in some cases, genetic tests may be done in situations such as when a person has an early age of onset with a strong family history of Alzheimer’s or frontotemporal dementia. There has been a major push to identify biomarkers – biological indicators circulating in the body – that are able to accurately diagnose dementia-associated diseases.

Currently validated biomarkers for dementia, including Alzheimer’s disease, are beta-amyloid (Aβ42 or the ratio of Aβ42/Aβ40), total tau (t-tau), and phosphorylated tau (p-tau) proteins, and neurofilament light (NfL), which are measured in cerebrospinal fluid (CSF). The combination of CSF biomarkers and neuroimaging have shown high diagnostic accuracy however, as these are not readily accessible, expensive, highly invasive and require specialized facilities, multiple investigations have been conducted to identify biomarkers in peripheral fluid to detect early pathological changes that occur in the brain. Peripheral biomarkers can be different molecules such as proteins, peptides, nucleic acids, microRNAs, lipids, and metabolites which can be detected in plasma, serum, exosomes or cellular components. The investigation and development of peripheral biomarkers for dementia, specifically blood-based biomarkers, has been the focus of intense investigation in recent years.

The Future of Biomarkers for Dementia

The recent development of blood-based biomarkers has marked a turning point for diagnosing dementia, making it possible to measure NfL, Aβ42/Aβ40, and P-tau (either phosphorylated at threonine 181 or 217) in plasma. Numerous clinical trials are underway to evaluate their utility for the clinical management of dementia. In particular, plasma P-tau181 and P-tau217, have shown especially high diagnostic performance for discriminating Alzheimer’s disease dementia from other neurodegenerative diseases. Plasma P-tau has also recently been shown to be suitable for individualized prediction of cognitive decline in individuals with mild cognitive impairment. However, in the clinical workup of patients with cognitive complaints, it is unlikely that plasma P-tau (or any other biomarker) will achieve the highest potential predictive accuracy alone due to the multifactorial and high heterogenous clinical presentation of dementia-associated disorders.

The last two years have marked important milestones in the quest for novel biomarkers for dementia-associated diseases. A study published in December 2022 has identified brain-derived (BD) tau as a biomarker that can distinguish Alzheimer’s disease from other neurodegenerative diseases. The study presents the development and validation of an ultrasensitive immunoassay, using a monoclonal antibody that selectively binds to CNS tau isoforms in plasma. Clinical performance in five independent cohorts shows that plasma BD-tau is specific to the neuropathological diagnosis of Alzheimer’s disease and is unaffected by mixed pathologies.

More recently, a new study published in February 2023, has identified placental growth factor (PIGF) as a single diagnostic biomarker for vascular cognitive impairment which can measure the degree of vascular injury. Patients with higher levels of PlGF – a key molecule involved in the formation of new blood vessels, or angiogenesis – were more likely to have cognitive impairment or evidence of brain injury. This marks years of research into PIGF after researchers identified signalling pathways involved in angiogenesis as potential biomarkers, theorizing that the body may respond to damaged small blood vessels in the brain with intensified efforts to grow more. Chronic injury to cerebral arterioles, capillaries and venules, ultimately results in a cascade of blood-brain barrier leakage, cortical and sub-cortical microinfarction, and delayed neurodegeneration. The presence of PIGF shows a strong association with vascular cognitive impairment and is also being proposed as a biomarker of treatment response.

Blog written by Caroline Beltran PhD, Scientific Consultant at Synexa

Synexa: Biomarkers and Drug Development

Synexa Life Sciences has provided state-of-the-art biomarker and bioanalytical services to biopharma customers for over 20 years. We provide and validate biomarker assays that can be used with lipids to develop therapeutic targets for those involved in central nervous system drug development. Using assays such as MSD or ELISA, Synexa has been able to measure many of the abovementioned proteins.

Contact us for more information on how biomarkers are used in Dementia drug development or to learn more about our services.

References:

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  • Gonzalez-Ortiz et al., 2023. Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration, Brain, Volume 146, Issue 3, March 2023, Pages 1152–1165.
  • Hinman., et al., 2023. Placental Growth Factor is a Sensitive Biomarker for Vascular Cognitive Impairment. Alzheimer’s & Dementia. Alzheimer’s Dement, 2023; 1-9.
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