|
This review examines key pharmacological strategies
that have been clinically studied for the primary or secondary
prevention of Alzheimer's disease. Much information
(neuropsychological, genetic and imaging) is already available to
characterise an individual's risk for developing Alzheimer's
disease. However, regulatory pathways for obtaining a prevention
indication are less well charted, and such trials tend to involve 3-
to 7-year studies of 1000 - 5000 individuals, depending on baseline
status. Treatments developed for prevention will also need to have
superior safety. For these reasons, > 100 proprietary
pharmacological products are currently being developed for an
Alzheimer's disease treatment, but only a few are being studied for
prevention. Randomised trial data are available for antihypertensive
agents (calcium channel blockers, angiotensin-converting enzyme
inhibitors), pravastatin, simvastatin, conjugated oestrogen,
raloxifene, rofecoxib, CX516 (AMPA agonist) and cholinesterase
inhibitors regarding efficacy for Alzheimer's disease prevention. At
least four large prevention trials of conjugated oestrogen, selenium
and vitamin E, Ginkgo biloba and statins are currently underway.
Strategies using other agents have not yet been evaluated in
Alzheimer's disease prevention clinical trials. These include anti-amyloid
antibodies, active immunisation, selective secretase inhibitors and
modulators, microtubule stabilisers (e.g., paclitaxel), R-flurbiprofen,
xaliproden, ONO-2506, FK962 (somatostatin releaser), SGS 742 (GABA(B)
antagonist), TCH 346 (apoptosis inhibitor), Alzhemedtrade mark,
phophodiesterase inhibitors, rosiglitazone, leuprolide, interferons,
metal-protein attenuating compounds (e.g., PBT2), CX717, rasagaline,
huperzine A, antioxidants and memantine. Studies combining lifestyle
modification and drug therapy have not been conducted. Full
validation of surrogate markers for disease progression (such as
amyloid imaging) should further facilitate drug development.
Reducing the complexity of prevention trials and gaining regulatory
consensus of design is a high priority for the field.
|
