No single cause has been found to be the underlying factor leading to Alzheimer's Disease. Many factors can contribute to the development of Alzheimer's Disease including, age, genetic inheritance, lifestyle and overall health. These factors can be broken down into two categories, risk factors and genetics.
Alzheimer's Disease is caused by atrophy of the brain, mainly in the cerebral cortex, whose region is essential for cognitive function. Atrophy of neurons in the brain leads to the formation of neurofibrillary plaques and tangles. Plaques and tangles destroy brain cells, causing the disease to dramatically worsen with time, as the severity of Alzheimer's Disease correlates with the number of neurofibrillary tangles.
Neurofibrillary tangles are commonly formed in Alzheimer's patients when there is hyperphosphorylation of the protein Tau, which pairs with other strands of Tau. Tau normally forms as a bridge between microtubules in axons, ensuring the correct connections are made, and that microtubules are stabilised. Therefore, if Tau is missing or mutated, then microtubules lose their organisation and there is an accumulation of filaments. A mutation in Tau is formed by the accumulation of amyloid protein. Abnormal accumulation of amyloid leads to neurofibrillary tangle formation and therefore dementia.
There are many theories in place as to why this atrophy happens, two of which are the cholinergic hypothesis and the amyloid hypothesis.
One theory is that Alzheimer's Disease inhibits the synthesis of the neurotransmitter acetylcholine. Acetylcholine is widely used in the peripheral nervous system and the central nervous system. This hypothesis, however, is not widely accepted as treatments that involve increasing the levels of acetylcholine in the brain have not had great success.
This theory suggests that the amyloid deposits are the underlying cause of Alzheimer's Disease. This comes from evidence that amyloid precursor protein gene (APP) lies on chromosome 21, and that Down's Syndrome patients have an extra copy of chromosome 21, hence an extra copy of the APP gene. Most Down's Syndrome patients exhibit Alzheimer's Disease by the age of 40.
Also, APE04 is a major genetic factor of developing Alzheimer's Disease, this leads to the excessive build up of beta-amyloid in the brain, forming beta-amyloid plaques.