Alzheimer's disease

(AD) is a neurodegenerative process resulting in the gradual loss of functional synaptic connections between
neurons leading to decline in memory and other critical cognitive functions. The precise cause of AD is not
known but many believe that the excessive accumulation of a protein fragment known as amyloid is a key
contributor to synaptic and neuronal degeneration. Accumulation of amyloid, and likely other key factors
including those associated with aging and inflammatory mechanisms, promotes a degenerative pattern of
signaling within neurons which in turn leads to accumulation of a toxic form of the tau protein and gradual
deterioration of synapses and neurons.

Current treatment options

AD is the fifth leading cause of death in those over 65 in the us. Among the top ten causes of death, AD is
the only cause that has no treatment options proven to prevent, delay, cure, or even slow its progression.
FDA-approved treatments are limited to amelioration of cognitive symptoms without having significant
effects on underlying degeneration. The first approved class of symptomatic treatments consists of the
acetylcholinesterase inhibitors (donepezil, rivastigmine and galantamine) with the most recent FDA approval
in this class occurring in 2001. A second class of symptomatic treatment was defined by the drug memantine,
an N-methyl-D-aspartate (NMDA) receptor antagonist, approved by the FDA in 2003. These drugs have, at
best, modest effects on cognition, overall function and caregiver ratings and no clearly detectable effects on
progression. The goal of achieving a therapy that slows the underlying progression of neuronal degeneration
to either delay onset or slow progression of the disease has largely focused on efforts to reduce the
accumulation of amyloid either by inhibition of enzymes necessary for its production or by administration of
antibodies targeted against amyloid. Enzyme inhibition has been limited by toxic effects and phase III results
from antibody treatment trials demonstrated little or no significant efficacy. Clearly, additional therapeutic
strategies will be needed.