Evaluation of the role of biomarkers in Alzheimer’s disease and age-related cognitive decline

Abstract

An ageing population will lead to an increase in age-related cognitive decline and dementia syndromes such as Alzheimer’s disease (AD), which can seriously limit an individual’s independence and quality of life. Identifying biomarkers associated with cognitive impairment in both ageing and AD are needed as they will improve our understanding of underlying pathophysiology and may eventually improve prognoses via the identification of at-risk individuals and the development of novel therapeutics.

Several pathological changes in the brain which are typically seen in AD can be detected in the cerebrospinal fluid (CSF) and plasma of middle- and late-life adults without dementia. Previous work has identified associations between CSF markers and cognitive functions, although a synthesis of the large number of studies is needed.

Furthermore CSF marker levels may also differ with AD risk factors, however evidence is mixed. Increasingly, research has shifted to focus on blood-based biomarkers which provide the benefit of being less invasive and more accessible. Several plasma biomarkers have been associated with cognitive functions in ageing, although few studies use appropriate cognitive tests, and even fewer have examined these proteins in the brain. There remains no gold-standard biomarkers associated with cognitive functions in either AD or age-related cognitive decline, therefore additional approaches are needed to fully understand their relationship. The aims of the current thesis are to: investigate CSF biomarkers associated with cognition in dementia and ageing; assess the relationship between CSF biomarkers and AD risk factors; examine whether plasma biomarkers are associated with age-related cognitive decline; and lastly, to examine the level of proteins (which have previously been investigated as biomarkers) in post-mortem brain tissue.

Cerebrospinal fluid biomarkers associated with cognition have been investigated across a range of dementia syndromes and age-related cognitive decline. While much of the work has focused on tau and amyloid-beta (Aβ), there is burgeoning research around markers such as neurogranin and neurofilament-light. Due to a wide range of markers investigated across several dementia syndromes and ageing, the roles of each marker are less clear. Therefore, a systematic review was conducted examining the association between CSF synaptic/axonal markers, and cognitive functions across dementia syndromes and typical ageing. Sixty-seven studies were included in the review in Chapter 3. Despite substantial heterogeneity in the field, there was evidence for an association between CSF neurofilament-light and cognition in AD, frontotemporal dementia, and typical cognitive ageing. Cerebrospinal fluid neurogranin tended to be associated with cognition in those with CSF tau and CSF Aβ profiles indicative of AD.

Chapter 4 focuses on the interaction between Apolipoprotein E (APOE) and sex on CSF tau levels in a middle-life cohort without dementia. Females account for an estimated 60% of those diagnosed with AD and the APOE4 allele is widely recognised to be the strongest genetic risk factor for late-onset AD. However, evidence for the interaction between these two risk factors is mixed. In this chapter, a significant interaction between APOE, sex, and CSF AD biomarkers was found, suggesting that tau accumulation may be independent of Ab in females, but not males. This has potential implications for the implementation of CSF AD biomarkers in clinical practice and pharmacological interventions which target cortical Ab.

Chapter 5 focuses on the relationship between plasma biomarkers and cognitive functions in typical ageing. Previous studies have focused on this relationship, however, few use appropriate cognitive tests for a sample without dementia. In this chapter, the association between cognitive ability and plasma phosphor-tau 181 (ptau181), Ab, neurofilament-light (NfL), and glial fibrillary acidic protein (GFAP) were investigated in the Lothian Birth Cohort 1936. A significant relationship was observed between baseline p-tau181, NfL, GFAP and cognitive decline up to ~ 10-years later.

Further, increasing levels of p-tau181 over time were associated with steeper cognitive decline. The results of this chapter suggest that plasma p-tau181, NfL, and GFAP may be useful biomarkers of age-related cognitive decline.

In Chapter 6, several of the aforementioned markers that were previously investigated in the CSF and plasma are examined in post-mortem brain tissue. While previous work has focused on these markers in the CSF and plasma, few studies have investigated them in post-mortem tissue and how levels differ between AD and typically ageing participants. Relative differences in neurogranin, p-tau181, p-tau231, total tau, and SNAP-25 were examined by western blot in AD cases, healthy ageing cases, and mid-life cases. The results of this chapter provide evidence of a reduction of neurogranin and SNAP-25 at the synapse in AD, as well as an increase of p-tau231.

This suggests that the elevations of CSF neurogranin, SNAP-25, and p-tau231 seen in AD may reflect both the loss of neurogranin/SNAP-25 and the accumulation of ptau231 in synapses.

The final chapter of the thesis summarise the findings of the previous chapters, their limitations, and the impact of this work on the field.