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Alzheimer's disease (AD) is a devastating condition affecting over 600,000 people in the United Kingdom alone. The progress being made in the understanding of AD and related disorders at a molecular level is not being matched by progress in clinical assessment. Diagnosis is performed by clinical interview with supplementary investigations to exclude rare treatable causes of confusion. As specific treatments are generated for prevention or modification of AD, the limitations in diagnosing the disease will become more clinically relevant and might substantially delay effective assessment and utilisation of treatments. Progress in clinical trials of putative disease modification therapies would be much enhanced if these could be directed towards those suffering from early dementia. As there is evidence that the cognitive decline of AD and other disorders is preceded by neuropathological deterioration, which starts many years earlier, then it is probable that disease modification therapies would effectively be secondary preventative strategies. However, whilst differential diagnosis of established dementia is difficult, the reliable detection of a neurodegenerative process before the onset of a full dementia syndrome is not currently possible. There are no independent markers of the prodromal phase of dementia (even when cognition is demonstrably compromised) and it is difficult to predict which individuals with subjective memory impairment will progress to full dementia. Measurement of change is also highly problematical. Thus, in AD and related disorders all three areas of assessment—differential diagnosis, early diagnosis and measurement of change—are mostly limited at present to clinical assessment and do not use biomarkers. The Alzheimer's Association and the National Institute of Ageing recognised the urgent need for an independent marker of disease status, and a consensus group hosted by them laid down the criteria for a successful biomarker. Ideally it would be ‘reliable, reproducible, non-invasive, simple to perform and inexpensive’ whilst having a sensitivity and specificity of more than 80%. No such marker is yet available. AD and fronto-temporal dementia (FTD) are part of the
group of disorders known as the tauopathies characterised by aggregates
of highly phosphorylated tau protein. Various tau kinases have been identified
of which glycogen synthase kinase-3 (GSK-3) and CDK5 appear to be the best
candidates. However, although both have been shown to phosphorylate tau
in vitro, in neurons and in transgenic models there is only modest evidence
that either is altered in vivo. GSK-3 has been shown to co-localise with
neurofibrillary tangles, and p25, the precursor of CDK5, has been shown
to be present to excess in post mortem AD brain. However, such post-mortem
studies pose the question as to whether these observations are a cause
or an effect of neurodegeneration; an important issue carrying direct therapeutic
implications.
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