Fight Aging!

Alzheimer's disease is the present poster child for neurodegeneration in late life, the condition that receives the most funding and the greatest attention. It exemplifies the complexity of neurodegeneration, exhibiting multiple interacting forms of pathology, with considerable room for debate over causes and relationships and the relative importance of contributing or associated mechanisms. Is it a condition caused by amyloid-β accumulation, where amyloid later becomes irrelevant as tau pathology takes over? Or is amyloid-β a side-effect of causes of chronic inflammation, where inflammation is the true cause of tau pathology? Or is Alzheimer's something yet more complex, a feedback loop between differing causes, with the relative importance of any given contributing mechanism varying from patient to patient?

In parallel to the search for effective therapies to treat Alzheimer's disease, researchers are also engaged in a search for better, more practical, more cost-effective ways to determine whether or not a patient is in the early stages of the condition. Much of this effort is focused on finding better ways to measure levels of amyloid-β in the brain. Given the present doubts about the role of amyloid-β, it may be that other biomarkers are a better choice, if they can be found. Today's research materials are an example of this sort of investigation, focused on what can be found in blood samples, one of the easier approaches to testing. Another different but analogous line of research is focused on retinal scans, similarly an easier approach to obtaining information on the state of the central nervous system.

New Alzheimer's biomarker may facilitate rapid diagnosis

Discovery of a unique ratio of metabolites from blood samples of early-stage Alzheimer's patients promises to speed diagnosis, allowing earlier treatments to be initiated. "We were delighted to discover that the ratio of two molecules, 2-aminoethyl dihydrogen phosphate and taurine, allows us to reliably discriminate samples of early-stage Alzheimer's patients from controls."

Current attempts to diagnose Alzheimer's disease from blood samples depend on the presence of amyloid fragments, the molecules that cause brain tangles and plaques. "We consider amyloid plaques to be a consequence rather than the cause of Alzheimer's disease. What is exciting about this new discovery is that it does not depend on amyloid and the assay can be performed on analytical equipment that is already present in most large hospitals."

A possible blood plasma biomarker for early-stage Alzheimer's disease

Onset of Alzheimer's disease (AD) symptoms is correlated with accumulations of misfolded proteins and protein fragments, particularly amyloidβ42 (Aβ42) plaques and a dense tauopathy of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau deposits in specific brain regions. There is a latency period between the initiation of AD-type neuropathology in the brain and onset of clinical symptoms. Discovery of new ways of diagnosing AD in the earliest stages, particularly those present during the latency period, could lead to new types of treatment, including reconsideration of previously failed drugs.

Various biomarkers associated with later stages of AD have been suggested including cerebrospinal fluid (CSF) and plasma biomarkers indicative of amyloid deposition, neuronal damage and loss, and the formation of NFTs, notably phosphorylated-tau (P-tau), Aβ42, total-tau (T-tau), as well as neurofilament light protein (NFL), while plasma concentrations of Aβ40 and Aβ42 may not be as useful in diagnosing AD. Biomarkers based on imaging assessing amyloid-beta plaques (PiB-PET scans), tau deposits (tau-PET), brain atrophy (structural MRI), memory-related activity patterns (fMRI), and decreased glucose metabolism (FDG-PET) have also been proposed. Nucleic acid biomarkers for AD have also been proposed.

We have sponsored an FDA-approved Phase IIa clinical trial of L-serine (NCT03062449) for early-stage Alzheimer's disease patients. At the time they receive their initial diagnosis, based on the Clinical Dementia Rating (CDR) score, patients are offered entry into the clinical trial. We hypothesized that a unique metabolic biomarker of early Alzheimer's disease could be identified by examining the physiological amino acids and nitrogen containing compounds within these early disease state blood samples. Using an automated Amino Acid Analyzer along with confirmation from tandem mass-spectroscopy, we examined metabolites displaying clear differences between AD and control blood plasma samples. We found that the concentration of 2-aminoethyl dihydrogen phosphate normalized by taurine concentrations in blood plasma samples reliably identifies early-stage AD patients.