Beta Amyloid and Tau
One of the hallmarks of Alzheimer's disease are whitish deposits of a pathologically modified and misfolded protein, amyloid. These insoluble plaques were originally believed to be the major culprits of neurodegeneration, but today many researchers believe that their formation might be a protective mechanism and that soluble forms of amyloid are much more neurotoxic.
The pharmaceutical industry has expended huge amounts of planning, money, and time to design and test drugs that are in some way directed against beta-amyloid or its precursor protein. Despite these intense efforts that have carried on for many years, small molecule secretase inhibitors that were supposed to abrogate erroneous processing of the amyloid precursor protein and monoclonal antibodies that are directed against Abeta itself have without exception failed in late.stage clinical trials.
In the face all of these failures, the voices that doubt the exclusive validity of the so-called amyloid cascade hypothesis of Alzheimer's disease are growing louder, basically stating that the drug development community should start asking different questions. To cite one of these assessments:
"Pursuit of a linear, reductionistic amyloidocentric approach to AD research, which some have compared to a religious faith, has resulted in other, equally plausible but as yet unvalidated AD hypotheses being underfunded leading to a disastrous roadblock in the search for urgently needed AD therapeutics." (Biochem Pharmacol. 2013; 85(3):289-305 - see the abstract)
While amyloid plaques form in the space between the brain cells, tangles of hyperphosphorylated and misfolded tau protein precipitate inside the neurons, disrupting vital transport processes. These neurofibrillary tangles are even more immediately neurotoxic than beta-amyloid, and even less accessible for drugs -- which is one good reason why they have received comparatively little attention by the pharmaceutical industry. Some interesting candidates exist, including therapeutic vaccines, but they are in very early stages of development.