We don’t know.
There have been a number of theories around, the most popular being the amyloid cascade hypothesis.
Alzheimer’s disease is named after Dr Alois Alzheimer, a German neurologist and psychiatrist.
In 1901 he became involved in the care of a 51 year old woman called Auguste Deter at the Frankfurt asylum. She had loss of short-term memory and over the next few years continued to deteriorate with progressive difficulty with speech and other behavioural symptoms including wandering, agitation, paranoia, and incontinence.
Relatively little dementia was seen in those days, mostly because people didn’t live that long!
Also at that time senility and dementia were perceived to be part of normal ageing. Auguste would have had what today would have been determined as “early onset dementia”. Alzheimer’s disease typically is diagnosed in people over the age of 65.
After her death in 1906, Dr Alzheimer performed an autopsy on her brain, using silver staining techniques to show the neurons. He noted that her brain showed considerable atrophy and loss of neurons. He also noted some unusual formations, which he called senile plaques and neurofibrillary tangles. He thought that these could be linked as being either the cause or result of her condition.
We now know that these senile plaques are formed of an aggregation of a protein called beta amyloid. Beta amyloid is a normal substance found in neurons. They have been thought only to become an issue when in excess it aggregates around neurons preventing normal electrical transmission of impulses and leading to neuronal death.
The neurofibrillar tangles are made of a different protein called tau, which forms inside the neurons and also leads to the death of surrounding neurons.
Over the last thirty years or so, much research has been focussed on targeting the amyloid cascade hypothesis. Multiple studies have endeavoured to discover ways of controlling beta amyloid and how to get rid of it. Yet the clinical outcomes have not been always as expected. Clearing the amyloid doesn’t always lead to improved cognition.
Karl Herrup chair of the Department of Cell Biology and neuroscience at Reutgers University has now proposed a new hypothesis recently published in the Journal of Neuroscience.
He hopes this will stimulate further discussion and lead to new experimental and diagnostic advances.
Herrup starts with our age. Age is considered the major risk to developing Alzheimer’s. As we get older our speed of processing and cognitive functions start to slow down, but this in itself does not herald the risk of developing Alzheimer’s.
The amyloid cascade theory has failed to explain the paradox of why some people will at autopsy show extensive brain changes with multiple clumps of amyloid and tangles and yet clinically show no evidence of the disease prior to their death. Others with marked clinical changes of dementia have after death been found to have no such amyloid deposits in their brain.
David Snowdon in his book “Ageing With Grace”, wrote about the nun, Sister Bernadette who clinically appeared in charge of all her faculties and performed well mentally in all of her memory tests each year, right up until her death from a heart attack. When her brain was examined post mortem, it appeared as the brain of a person with extensive Alzheimer’s disease. Yet outwardly she had shown no sign.
More evidence has been showing that inflammation has a significant role in the development of Alzheimer’s and that vascular and Alzheimer’s dementia may be more closely interlinked than originally thought.
In this new hypothesis Herrup believes three steps need to occur to take a person from normal functioning to clinical manifestation of Alzheimer’s.
1. An initial brain injury, probably vascular.
2. A chronic neuro-inflammatory response unique to Alzheimer’s.
3. A discontinuous cellular change of state involving most, if not all the cell types of the brain that only moves one way. Here the physiology of the neurons and other cells in the brain are altered.
Herrup states, “The initiating injury may trigger a protective response in the brain cells. But the real problem is that the response itself doesn’t know when to quit, continuing even after the injury itself subsides. The real damage is done by the persistence of the response and not by the injury itself”
“Because this theory implies that the beta amyloid aggregation is not central to the biology of Alzheimer’s, this means that it is perfectly possible to have amyloid plaques and no Alzheimer’s, and no amyloid plaques and have Alzheimer’s”
It may be that we will now see a new direction being taken in further research and study to continue to unravel the story of what actually causes Alzheimer’s.
With the expected “epidemic” of Alzheimer’s likely to occur over the next few decades as the baby boomers age, this further exploration of new ideas will hopefully take us one step closer not only to understanding this terrible disease but one step closer to finding an effective treatment.
K. Herrup. Reimagining Alzheimer’s Disease–An Age-Based Hypothesis. Journal of Neuroscience, 2010; 30 (50): 16755 DOI: 10.1523/JNEUROSCI.4521-10.2010