Normal protein function is compromised. This interferes with the function of the damaged brain cells and sets off a toxic cascade, which ultimately results in cell death and later brain atrophy.

According to current theories, amyloid beta (A) builds up abnormally in the brain, either extracellularly as tau and amyloid plaques or intracellularly as neurofibrillary tangles, disrupting neuronal connection and functioning and causing a progressive loss of brain function. Age-related, controlled by brain cholesterol, and linked to other neurodegenerative illnesses, this reduced protein clearance capacity.

Researchers can now observe changes in brain structure and function as well as the growth and spread of aberrant tau and amyloid proteins in the living brain thanks to advancements in brain imaging technology. The protein beta-amyloid is a piece of a bigger protein. When these fragments group together, neurons experience a toxic impact that impairs cell-to-cell communication. Thus, larger deposits known as amyloid plaques continue to develop.

Tau proteins are in charge of carrying nutrients and other necessary elements within neurons as part of their internal support and transport mechanism. Neurofibrillary tangles are made up of tau proteins that have developed abnormal shapes as a result of Alzheimer's disease. The tangles poison cells and interfere with the transport system.

With the exception of 1-2% of cases where deterministic genetic variations have been detected, the cause of the majority of Alzheimer's cases is still largely unknown. The two most popular explanations are the cholinergic hypothesis and the amyloid beta (A) hypothesis, which both seek to explain the fundamental aetiology.

The cholinergic hypothesis, which contends that decreased synthesis of the neurotransmitter acetylcholine is what causes Alzheimer's disease, is the oldest theory and the foundation for the majority of pharmacological therapy. A crucial aspect of Alzheimer's disease progression is the degeneration of cholinergic neurons, which has been observed in the limbic system and cerebral cortex. The extracellular amyloid beta (A) deposits were proposed as the primary cause of the disease in the 1991 amyloid hypothesis. The amyloid precursor protein (APP) gene's position on chromosome 21 and the fact that people with trisomy 21 (Down syndrome), who have an extra gene copy, nearly uniformly show at least the first signs of Alzheimer's disease by the age of 40, provide evidence in favour of this hypothesis.

A significant genetic risk factor for Alzheimer's disease is an isoform of the apolipoprotein known as APOE4, in particular. While apolipoproteins promote the breakdown of beta amyloid, some isoforms (such as APOE4) are less efficient at this process, resulting in an excessive buildup of amyloid in the brain.