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Pathways to Alzheimer's disease

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Blood tests could revolutionise Alzheimer's diagnosis

While the symptoms of dementia are well-understood, the underlying cause isn’t. PATHAD’s work has shed further light on the pathways of the disease, while developing a biofluid test that could revolutionise diagnosis.

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Alzheimer’s disease (AD) is a neurodegenerative condition causing most dementia cases. There are thought to be both genetic and environmental risk factors. The earliest molecular sign of AD is when amyloid beta – peptides comprising amino acids – clumps together in the tissue of the brain, known as Abeta42. Amyloid beta is produced by neurons in around 20 different forms. When Abeta42 collects in the brain, the concentration of amyloid beta is reduced in the lumbar cerebrospinal fluid (CSF). Measurement of this reduction offers the earliest known biomarker of AD. The PATHAD project, undertaken with the support of the Marie Skłodowska-Curie Actions programme, has refined the measurements of amyloid pathology in brain tissue, while developing tests for the same in blood and CSF. PATHAD also developed several markers of responses to intervention, including: neuronal dysfunction, astrocytic activation and microglial activation. “Blood tests particularly will revolutionise diagnosis of AD. We also know that some tests suggest that anti-amyloid treatments do work. I am very hopeful that soon we will prescribe treatments to patients with early signs of AD and positive blood biomarkers, monitoring effectiveness using the same biomarkers,” says Henrik Zetterberg, the project coordinator.

Investigating AD’s molecular pathways

PATHAD worked with donated post-mortem brain tissue, comparing AD-positive samples with negative ones, or with other neurodegenerative diseases. Sensitive tests were then developed to detect changes in brain biomarkers before also being investigated in blood and CSF. PATHAD relied on mass spectrometry, which functions at extremely sensitive molecular scales, and ‘sandwich immunoassays’, where labelled antibodies are used to capture and detect target molecules. To investigate the tests in blood and CSF, the team used donor samples before and after an AD diagnosis. This allowed them to learn more about when the different biomarkers turn positive and to track the onset of pathologies. Results largely confirmed the so-called ‘amyloid cascade hypothesis’. This states that AD starts with amyloid pathology that leads to a tissue reaction where neurons secrete tau proteins, as well as activating astrocyte and microglia cells. Combined, these prove toxic, progressively depleting brain function. The team also found that the onset of this toxic impact happens earlier than previously supposed, as it seems to immediately affect the synapses and axons of nearby neurons, with tau tangle pathology and neurodegeneration coming later. “We succeeded for a number of biofluid biomarkers. We now have reliable blood tests for amyloid and tau pathology, as well as for neurodegeneration and astrocyte activation,” adds Zetterberg, from the University of Gothenburg, the project host. “As the simplest test, we are now focused on blood biomarkers but will also develop ultrasensitive CSF biomarkers, in case the blood tests prove unworkable.”

Potential to revolutionise neurodegeneration diagnosis

PATHAD’s results could help develop simple, accessible and cheap AD diagnostic tools. This could even take place in primary care settings, although specialist evaluation and advanced neuroimaging, as well as CSF analyses, would still be needed. PATHAD’s data further corroborates a combination of increased production of more amyloid beta forms, alongside their defective clearance, as disease-precipitating factors, supporting both processes as promising targets for treatment. Through a follow-up global consortium funded by the Alzheimer’s Association and Foundation for the National Institutes of Health, the team are now working to introduce these new blood biomarkers into clinical practice. “Given how well the ultrasensitive assays worked, we are also starting similar work for other neurodegenerative biomarkers like the alpha-synuclein and TDP-43 proteins, also useful for other conditions like Parkinson’s,” concludes Zetterberg.

Keywords

PATHAD, Alzheimer’s disease, neuron, neurodegenerative, amyloid beta, cerebrospinal fluid, blood, tau proteins, biomarkers, molecular, disease

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