Cerebrospinal fluid biomarkers can track Alzheimer's disease progression - but also provide clues to disease mechanisms.
Tracking neurodegeneration, particularly before symptoms appear, is a key challenge in dementia research. Alongside brain imaging, there is growing interest in measurement of biochemical markers in cerebrospinal fluid may also provide insight into the cellular changes occurring in the brain.
It is now clear that the origins of Alzheimer's disease go back decades, as neurons accumulate abnormal proteins and die, even before symptoms appear. Measurement of key proteins in cerebrospinal fluid provides a window into these critical changes.
Of great interest, levels of a truncated form of β-amyloid (Aβ42) fall markedly in people destined to develop Alzheimer's disease. Other characteristic changes include an increase in levels of both total tau protein and phosphorylated tau. These markers have recently been incorporated into diagnostic criteria for Alzheimer's disease and the mild cognitive impairment that precedes it.
Furthermore, they may also provide insight into disease mechanisms, as they reflect different aspects of disease. The drop in Aβ42 probably reflects the sequestration of β-amyloid into plaques, total tau assays neuronal death, which leads to the release of intracellular tau, while phospho-tau levels track the formation of fibrillary tangles. Notably, the decline in Aβ42 precedes changes in tau, arguing that it represents an earlier stage in the disease process.
As well as diagnosis, cerebrospinal fluid biomarkers also provide a complementary tool to brain imaging for tracking disease progression. Since changes are apparent years before symptoms appear, they can be used in trials of therapies targeting early, pre-symptomatic phases of disease. Moreover, certain molecular biomarkers will be highly relevant to particular therapeutic strategies - Aβ42, for example, for therapies targeting β-amyloid.
Professor Zetterberg has taken up a position at UCL while maintaining his group in Gothenburg, Sweden - a centre with renowned expertise in biomarker research. As well as these well-characterised biomarkers, he will also be studying the potential of other metabolites - first example, of markers of inflammation or loss of synapses - which may reflect important disease processes. He will also be undertaking proteomic studies to identify new components of cerebrospinal fluid of potential relevance to neurodegeneration.
As well as disease groups, Professor Zetterberg will also be studying members of the 1946 Birth Cohort (see page 28). Such studies will reveal the 'natural history' of biomarker change, and allow comparisons between those who develop Alzheimer's disease and those who do not