What is the pathophysiology of Alzheimer’s disease?

The underlying cause of Alzheimer’s disease is far from a settled subject, but examining shared brain characteristics of people with the disease may provide insights.

One of the main features of Alzheimer’s disease is the accumulation in the brain of amyloid plaques,^[1] which are made of a peptide called amyloid beta and have been proposed as a major driver of Alzheimer’s disease. This “amyloid hypothesis” has been challenged,^[2] however, notably because drugs targeting the amyloid pathway have not improved cognition in Alzheimer’s disease.^[3]

Another primary feature of Alzheimer’s disease is the presence of neurofibrillary tangles,^[4] which are made up of tau proteins that, like amyloid beta, have misfolded and aggregated in the brain. According to the “tau hypothesis”, these tangles are a cause of or contributor to Alzheimer’s disease. However, because tau proteins serve important functions in the brain, another possibility is that the tangles are simply an indicator of a loss of tau function and are not harmful themselves.

Also common in Alzheimer’s disease is glucose hypometabolism,^[5] a reduction in the brain’s ability to use glucose (a type of sugar) for energy, which is why some researchers call Alzheimer’s “type 3 diabetes”.^[6] This reduction in the brain’s energy production may contribute to the cognitive impairments seen with Alzheimer’s disease and to the development of the disease itself.^[7]

Finally, Alzheimer’s disease is neurodegenerative: it is characterized by the death of neurons (a type of brain cell) and subsequent cerebral atrophy (shrinking of the brain).^[8] This process is believed to be central to the disease process and may be the result, at lea