Beyond amyloid: the next generation of Alzheimer's disease therapeutics.
The precise pathological events that cause cognitive deficits in Alzheimer's disease remain to be determined. The most widely held view is that accumulation of amyloid beta peptide initiates the disease process; however, with more than eighteen amyloid-based therapeutic candidates currently in clinical trials, the targeting of amyloid alone may not be sufficient to improve functional deficits over the course of the disease. Alternative targets, such as the tau protein and apolipoprotein E, have thus been increasingly investigated, and in the future, therapeutic strategies will likely address events that are upstream of a more broadly construed pathological cascade that includes but is not limited to the generation and accumulation of amyloid beta. Consideration of such events provides the basis for an "indirect amyloid hypothesis," for which data are beginning to emerge. Although it is clinically defined by simple post-mortem criteria, Alzheimer's disease likely has a complex etiology, and effective treatments for this disease will become ever more urgent as the world's population ages.
Seabrook
Guy R
GR
Department of Alzheimer's Research, Merck Research Laboratories, West Point, PA 19486, USA. guy_seabrook@merck.com
Ray
William J
WJ
Shearman
Mark
M
Hutton
Michael
M
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015195:Drug Design; D006801:Humans; D018377:Neurotransmitter Agents / Q000494:pharmacology / Q000627:therapeutic use*; D012307:Risk Factors
D016229:Amyloid beta-Peptides; D018377:Neurotransmitter Agents