The beta-amyloid hypothesis of Alzheimer's Disease (AD) has dominated the t
hinking and research in this area for over a decade and a half. While there
has been a great deal of effort in attempting to prove its centrality in t
his: devastating disease, and while an enormous amount has been learned abo
ut its properties (e.g.. putative toxicity, processing and signaling), A be
ta has not proven to be both necessary and sufficient for the development,
neurotoxicity, and cognitive deficits associated with this disease. Instead
, the few treatments that are available have emerged from aging research an
d are primarily directed toward modification of acetylcholine levels. Clear
ly, it is time to rethink this position and to propose instead that future
approaches should focus upon altering the age-related sensitivity of the ne
uronal environment to insults involving such Factors as inflammation and ox
idative stress. In other words "solve the problems of aging and by extensio
n those of AD will also be reduced." This review is being submitted as a ra
ther Lutherian attempt to "nail an alternative thesis" to the gate of the C
hurch of the Holy Amyloid to open its doors to the idea that aging is the m
ost pervasive element in this disease and A beta is merely one of the plane
ts. (C) 2001 Elsevier Science Inc. All rights reserved.