Alzheimer's disease is caused by progressive damage to brain cells and subsequent loss of the chemicals that they produce, known as neurotransmitters. One of these neurotransmitters is acetylcholine, decreases of which play a role in some of the problems seen in people with Alzheimer's disease, including difficulties with memory and attention.
Acetylcholine and Cholinergic Neurons
Acetylcholine is found in cells called cholinergic neurons. These neurons are located in a number of areas in the brain and spinal cord, and are involved in a variety of functions, including cognitive processing and motor function. When a cholinergic neuron releases acetylcholine, it latches onto a neighboring neuron at locations called receptors, which are the mechanisms needed to pass signals along from cell to cell.
Alzheimer's and Cholinergic Neurons
The cholinergic neurons most affected in Alzheimer's disease are those located in an area called the nucleus basalis of Meynert (NbM), found in a structure called the basal forebrain. The NbM houses neurons connected to other parts of the brain called the cortex and amygdala, which are areas involved in learning, memory, attention and emotional regulation.
There is a long history of discoveries regarding how acetylcholine is involved in Alzheimer's disease, reviewed by Magdolna Pakaski and Janos Kalman in the November 2008 edition of "Neurochemistry International" and by Reinhard Schliebs and Thomas Arendt in the November 2006 edition of the "Journal of Neural Transmission." It was shown about 50 years ago that drugs that block acetylcholine release can block memory functions, and later shown that one of the enzymes needed to form acetylcholine---called choline acetyltransferase, or ChAT---drops to significantly lower levels in people with Alzheimer's disease, corresponding to the degree of symptoms. A significant reduction in the number of cholinergic neurons in the basal forebrain of Alzheimer's sufferers was found in the 1980s, and in more recent times has come the revelation of decreases and/or disruption to acetylcholine receptors.
Causes of Cholinergic Neuron Loss
Although in Alzheimer's disease brains there is the appearance of plaques containing the substance fibrillary beta-amyloid, there is no direct connection between the number and location of plaques and cholinergic neuron loss. Loss has instead been more closely linked to a soluble form of beta-amyloid that can disrupt the production and release of acetylcholine, and interfere with the actions of a chemical called nerve growth factor that is involved in maintaining the structure and function of cholinergic neurons. There are also indications that damage can be due to the immune system reaction to the initial production of fibrillary beta-amyloid, before plaque formation, that involves the release of harmful chemicals.
Acetylcholinesterase inhibitors stop the release of the enzyme acetylcholinesterase that breaks down acetylcholine when it is released. They do not stop the destruction of cholinergic cells; so although they may temporarily boost the performance of someone with Alzheimer's disease, their main advantage is that they may slow the progression of decline by keeping acetylcholine levels as high as possible despite cell damage and destruction.