Date of Award
Doctor of Philosophy
School of Medical and Health Sciences
Alzheimer’s disease (AD) is the most common form of dementia in the elderly whose main neuropathological features are the presence of extracellular senile plaques in the brain and the intracellular accumulation of hyperphosphorylated tau filaments. However, a relatively cheap and non-invasive method for the diagnosis of AD remains elusive. Recent studies have indicated that cerebral biochemical changes take place decades before the clinical onset of the disease, but current methodologies, brain scan (PET amyloid imaging) and cerebrospinal fluid (CSF) analysis, are unsuited for community-wide screening. Brain scanning methods non-invasively assess amyloid load but are extremely expensive and cannot be used for clinical routine analyses. Conversely, CSF analysis measuring specific AD-related biomarkers (Aβ and tau) are invasive and require trained personnel. While these methodologies are considered the best options for identifying individuals at risk for AD, neither technique is suitable for community-wide screening. These problems could be solved by developing an AD-related blood-based biomarker panel that could reflect the amount of amyloid deposition in the brain, identifying individuals at risk for AD, thereby bypassing the need for current methodologies. This blood analysis would be a cheap and non-invasive community screen, and thus suitable for use in clinical pathology laboratories.
In this thesis, I am presenting my work on specific blood-based AD-related biomarkers. The first part of the thesis is focused on High Density Lipoprotein (HDL) subclasses and its protein cargo. Previous studies have indicated that small HDL subclass is linked to anti-inflammatory and anti-oxidative features, while many of the molecules associated to HDL, have been related to AD. My initial analysis has indicated that protective small HDL subclass is reduced in AD and positively correlate with cognitive functions. Furthermore, I have also isolated HDL particles and shown that HDL composition is changed in AD, with a significant increase of cholesterol/ApoA-I and ApoD/ApoA-I ratios and reduced ApoA-II/ApoA-I ratio.
Additionally, cholesterol/ApoA-I ratio is also positively associated to increased ventricular volume, while ApoA-II/ApoA-I and ApoJ/ApoA-I ratios are positively associated with grey matter volume, hippocampal volume and are negatively associated with ventricular volume. Taken together, these data indicate that plasma HDL composition is related to brain volumetric data and has the potential to be used as part of a broader AD-related biomarker panel.
In the second part of this thesis, in collaboration with colleagues, I have evaluated the levels of specific AD-related biomarkers (Aβ1-42, Aβ1-40, t-tau, p-tau181, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NFL)) in two different cohorts. Our results have indicated that Aβ1-42/Aβ1-40 ratio, p-tau181 and GFAP levels are reliable biomarkers for identifying individuals with ongoing brain amyloidosis and could also be used in a broader AD-related biomarker panel.
While additional studies are necessary, these early data indicate that the development of a specific biomarker panel for AD is achievable. This discovery would allow for the detection of individuals at risk for AD before the clinical onset of the disease, thereby allowing for early medical intervention(s).
Pedrini, S. (2023). An overview of blood-based biomarkers in AD. https://ro.ecu.edu.au/theses/2623