Strategies for disease modification in Alzheimer's disease

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Abstract
Alzheimer's disease (AD) accounts for most cases of dementia that are diagnosed after the age of 60. Acetylcholinesterase inhibitors and NMDA (N-methyl-D-aspartate) antagonists provide some relief from the symptoms of AD, but no treatment with a strong disease-modifying effect is currently available. This review discusses the current status of research into disease-modifying approaches, with particular reference to anti-amyloid strategies. The two main disease mechanism-based approaches are based on the involvement of two proteins — amyloid-β (Aβ) and tau — in AD pathology. Aβ is the main constituent of senile plaques — one of the key pathological characteristics of AD. Tau is the main component of neurofibrillary tangles, the other hallmark lesion of AD. It would seem attractive to identify brain-penetrable small molecule drugs that interfere with Aβ–Aβ peptide interactions, and, over the past decade, several different assay formats for the identification of nucleation and deposition inhibitors have been described. However, only a few aggregation inhibitors have moved into clinical testing. Anti-amyloid immunotherapy for AD has received considerable attention following reports that amyloid pathology was reduced in an amyloid precursor protein (APP) transgenic mouse model on vaccination with aggregated amyloid-β42 (Aβ42). Clinical trials were terminated after four early reports of meningoencephalitis, but a post-mortem study in one patient showed evidence of plaque reduction. The most direct approach in anti-amyloid therapy is reduction of Aβ42 production. Aβ is generated from APP by the sequential action of β-secretase and γ-secretase. A third protease, α-secretase, can preclude Aβ production by cleaving the peptide in two. This outline points to three strategies to reduce Aβ: inhibition of β-secretase, inhibition of γ-secretase and stimulation of α-secretase. Two key treatment approaches for AD have been driven by retrospective epidemiology: non-steroidal anti-inflammatory drugs and cholesterol-lowering agents. In both cases, the exact target in the disease cascade remains to be elucidated. In the near future, molecules representing several of the strategies outlined in this review will enter clinical trials, so we should find out in the next few years whether the promise of disease modification by any of these strategies is fulfilled. If successful, anti-amyloid drugs would be the first to address the pathogenic mechanism of a CNS disease, and they could become the standard of care in AD.