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  1. Nick Fox


Dementia is arguably the most urgent public health challenge confronting the developed world. The overarching priority is to find treatments that slow or halt disease progression and to apply those treatments as early as possible so as to have maximum impact on loss of cognitive and neurological function. There is increasing recognition that the neurodegenerative dementias (notably Alzheimer's disease—AD) are characterized by a long prodromal period where molecular pathology gradually accumulates and is followed by a neurodegenerative cascade that leads to neuronal dysfunction and ultimately irreversible damage and loss. Advances in imaging and in cerebrospinal fluid biomarkers mean that we see, measure and track pathological effects at the prodromal stage in vivo. This opens up a window for presymptomatic treatment.

Although the exact sequence, relationships and time course of pathological and biomarker changes in AD are unclear autopsy, imaging and CSF studies suggest that the preclinical phase may extend over many years. Cerebral amyloid deposition may predate clinical decline by more than a decade while hippocampal and brain atrophy rates become abnormal much closer to symptoms.

Recent failures of large phase 3 trials in so called “mild to moderate AD” have led to concerns the most—and potentially the only—effective therapies for neurodegenerative diseases will be those applied at the earliest stages. A ‘self-perpetuating’ aspect to neurodegeneration that is difficult to slow once established, may account, at least in part, for trial failures. Our ability to identify individuals at high risk of a moleculary defined dementia makes earlier intervention possible. Designing such secondary “prevention” trials raises a number of challenges however including how best to identify subjects for inclusion, how to assess how near to symptoms they are and how to assess efficacy. I will discuss issues related to the potential and the difficulties associated with these studies.

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