Neurodegenerative Biomarkers in Healthy Elderly - with special reference to the preclinical pattern of biological and cognitive markers for Alzheimer’s disease

University dissertation from Clinical Memory Research Unit, Lund University

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by tau and amyloid brain pathology. With the gradual degeneration of neurons, cognitive symptoms will arise and the affected individual will eventually develop AD dementia. The neuropathologic hallmarks of AD have been observed also in cognitively healthy individuals, which has led to the assumption that the disorder has a long preclinical phase. Several biological markers for detecting and predicting AD have been validated over the years, where CSF biomarkers are one of the most recent and accurate markers. The generally perceived notion today is that these biological markers will be altered also in the preclinical phase. An additional aspect is that a review made in this thesis of the control samples in CSF articles, suggests that controls have been selected without efforts to minimize the misclassification of preclinical AD individuals. Therefore the aim of this study was to investigate biological and cognitive markers for AD in a group of cognitively healthy elderly individuals who were used as clinical control subjects in research studies. Setting: The study sample consisted of 62 cognitively healthy elderly individuals from a clinical control group. They were followed for 4.5 years at three occasions and underwent assessments of EEG activity and regional cerebral blood flow (rCBF) as well as repeated assessments of cognitive function and CSF biomarker levels. The CSF biomarkers were Aβ42, total tau (t-tau) and hyperphosphorylated tau (p-tau). The cognitive testing included among others the MMSE, the ADAS-cog, cognitive speed (AQT), and subjective memory impairment. Results: In the sample there were individuals with clinically pathological assessments on each separate biological marker. CSF Aβ42 levels predicted development of subjective memory impairment affecting quality of life at the 3 years follow-up and correlated with delayed word recall and cognitive speed at the 4.5 years follow-up. Additionally, the individuals with decreasing CSF Aβ42 levels during the follow-up performed cognitively worse than those with stable levels at the 4.5 years follow-up. CSF tau levels on the other hand correlated with an increase of the low-frequent theta activity on EEG and showed covariance with rCBF in the right medial frontal lobe and the left fronto-parieto-temporal area. In each case the correlations were stronger for p-tau levels compared to t-tau levels. Increase in theta activity was also correlated with slower cognitive speed. Discussion: In this group of cognitively healthy elderly individuals there were individuals with deteriorated cognitive and biological markers associated with AD. These markers further correlated to one another in specific patterns, where it was the known AD-associated changes of the markers (i.e. low CSF Aβ42, high CSF t-tau and p-tau, decreased EEG rhythm, and decreased rCBF) that were primarily related. The findings could imply that the biomarkers might indicate early neurodegenerative changes of the brain and that these changes could be detectable before extensive cognitive impairment. The findings could also suggest that preclinical AD might be present in this “healthy” study sample. Hence, pathological processes prevailing in AD might bridge the clinically created arbitrary division of normal and non-normal aging of the brain.