What causes Alzheimer’s Disease (AD) and how does it progress to debilitating neurological symptoms and, eventually, death? This is the paramount question for those within the medical community seeking an effective treatment and potential cure for AD, a disease with no known treatment to delay or stop its progression and no known cure. Currently, three main hypotheses exist with regard to the onset of AD and how it goes about destroying neurons and, with that, one’s memory.
1. The cholinergic hypothesis puts forth that AD is caused by a decrease in acetylcholine, a neurotransmitter associated with, among other things, excitability. Damage to the cholinergic system is thought to play a role in memory loss associated with AD. This hypothesis has lost some ground in recent years, as medications that aim to treat acetylcholine deficiency have shown to be ineffective in many cases.
2. The amyloid hypothesis suggests that deposits of amyloid- beta protein are the main cause of the disease. This hypothesis is compelling, as Apolipoprotein E (APOE), a gene linked to an increased risk for inherited AD, can cause a buildup of amyloid in the brain in those with AD. This buildup forms the characteristic senile plaques associated with AD. Such plaques are dense deposits of both amyloid-beta protein and cellular material located outside and around neurons in particular areas of the brain.
The formation of these plaques in AD takes place when amyloid beta precursor protein (APP), an agent critical to neuron development, survival, and repair, is cut into smaller pieces by enzymes through a process known as proteolysis. This process and its onset is not yet fully understood. A fragment then develops into fibrils of beta-amyloid, which then form plaques outside of the neurons.
The major shortcoming of the amyloid hypothesis is that it does not explain the loss of neurons that occurs with AD. This is, of course, is of utmost importance in treating and finding a cure for the disease. Thus, the third hypothesis–
3. The tau hypothesis states that abnormalities of the tau protein cause AD and its progression to neuron death. In this hypothesis, chemically 
altered hyperphosphorylated tau proteins create tau tangles inside neurons, another trademark characteristic of AD. Such tangles collapse the neuronal transport system, resulting in a lack of communication between neurons and eventually neuron death.
Tau tangles actually accumulate within neurons themselves. The tangles are comprised of aggregates of hyperphosphorylated tau and, as with amyloid plaques, are found in large numbers in specific areas of the brain such as the temporal lobe.
Treatment
Four drugs are currently approved by regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) to treat the symptoms of AD. Three of the four are acetylcholine inhibitors, agents that seek to delay the breakdown of acetylcholine and therefore reduce the rate of destruction of cholinergic neurons, which is a known process in AD. These drugs are based upon the cholinergic hypothesis and have been found to be somewhat effective in mild to moderate stages of AD.
The fourth drug used to treat AD symptoms is Memantine, an NMDA receptor antagonist. Memantine blocks NMDA receptors, reducing overstimulation caused by glutamate, a neurotransmitter that has been shown to cause cell death in neurological diseases such as AD, multiple sclerosis, and Parkinson’s disease. Memantine has been shown to be effective in treating the symptoms of moderate to severe AD.
Current Research and Clinical Trials
Research of more than 400 pharmaceuticals to treat or prevent AD are currently in clinical trials. One focus of current research aims to reduce amyloid beta levels, treatment that prescribes to the amyloid hypothesis. This hypothesis has also led to potential treatments such as a vaccination against amyloid protein. Immunotherapy, which utilizes the immune system’s ability to recognize, attack, and actually break down amyloid deposits may also prove promising. Neuroprotective agents, metal-protein interaction attenuation agents, and a TNF-alpha receptor fusion protein known as etanercept are also demonstrating efficacy as potential agents in the fight against AD. Biomarkers such as p97 may contribute to these treatments by identifying AD before neuronal damage takes place, a critical first step necessary for many potential treatments.
With a better understanding of exactly what roles these agents play in the onset and progression of AD, the potential for effective treatment and a cure may be on the horizon.
