Pathophysiological Mechanisms and Diagnostic Markers in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD), the most common cause of dementia, is a growing concern. As the life expectancy increases across the globe, the number of affected people is estimated to reach 100 million by 2050. Efforts to develop effective treatments for humans have mostly been based on the assumption that a faulty homeostasis of beta amyloid (Aβ) is the triggering or the driving factor behind this condition. So far these efforts have failed, making a better understanding of other pathophysiological mechanisms behind this disease necessary in order to find new therapeutic approaches. The aim for this thesis was to explore such mechanisms. Besides changes typical of AD, these patients often show signs of vascular disease. In order to explore how white matter changes (WMLs) affects the course of disease, we analyzed CSF levels of phosphorylated tau (P-tau) and assessed WMLs on brain scans in healthy controls and patients with mild cognitive impairment. We found that a pathological level of P-tau and WMLs in the parietal lobes independently increased the risk of developing AD dementia, but that the risk was considerably higher for patients that had both. Next, we analyzed the CSF/plasma ratio of albumin, as a proxy for blood-brain barrier integrity, and found it to be increased in AD and other common dementias. This ratio was not associated with the APOE genotype, as had previously been suggested, or markers of Aβ load. Instead, we found it to be associated with diabetes mellitus and markers of microvascular damage in the brain. We then moved on from vascular factors to other mechanisms suggested in AD.The insulin-like growth factor (IGF) related system is implicated in regulating life-span and in growth-promotion and neuroprotection in the human nervous system. There are reports of changes to the IGF-related system in cognitive disorders. When we analyzed components of this system in healthy controls and patients with AD we found differences in CSF and blood plasma levels of IGF-II and some of its associated binding proteins, possibly reflecting an activated general response to neuronal damage. Lastly, we analyzed CSF biomarkers of synaptic degeneration (neurogranin) and microglial activation (YKL-40) in healthy controls, patients with mild cognitive impairment and patients with common dementias. We found the former to be selectively increased in AD dementia, whereas the latter was increased in both AD and frontotemporal dementia. However, these biomarkers did not improve the diagnostic accuracy of either prodromal AD or AD dementia when compared to established CSF biomarkers of AD. Nevertheless, we think they are useful, since they reflect other processes in AD than Aβ deposition and axonal damage. We hope that the results from this thesis has provided new insights into the pathophysiological mechanisms in AD and that they might suggest novel routes for exploring this complex condition.
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