As they approach a state that makes it much more likely that they will develop Alzheimer’s disease, people produce too much of a chemical protein involved in brain function.
In the process, the brain shrinks, according to research published Monday in the journal Nature Neuroscience.
Alzheimer’s is caused by the loss of protein in the brain, which is concentrated in the synapses – the spaces between neurons where signals are exchanged – and where a particular gene – ADAPT1 – is most active. The gene produces what is known as APOE4, an enzyme that turns on APOE1, a protein known to help build up neurons.
Each generation of humans generates a smaller amount of APOE4, so the only way to repair this damage to brain function is to boost APOE1. Increased production of APOE1 is also the pathogenic factor thought to cause Alzheimer’s.
Researchers at the Karolinska Institute in Sweden investigated the cognitive performance of high-risk individuals within Sweden, Iceland and Norway between the ages of 50 and 70, seeing how much and what types of brain functions they performed.
“We showed that amyloid plaques accumulate less rapidly in people with higher levels of APOE1 but that to recover from the effects of APP, your production of APOE1 must be substantial,” said Magnus Björklund, associate professor in Neuroscience at Karolinska and one of the authors of the study.
Levels of the enzyme in the brain were tested before people began to develop Alzheimer’s, at age 57, and after at 69. Prior to diagnosis, levels of APOE1 were even, which meant no change in cognitive functions.
But at age 69, for every 1 percent increase in levels of APOE1, the cognitive test scores increased by 12 percent.
“We were surprised by the magnitude of the effect,” Björklund said. “One of the obvious aspects of this is that to restore function in the Alzheimer’s disease model, you really need to be able to reverse the negative changes in the Alzheimer’s disease process. It is not uncommon to see trials trying to establish an antidote for the disease itself.”
A cocktail of drugs that could reverse the symptoms of Alzheimer’s, while in decline in many people and currently not approved for use in the United States, have shown small benefits to individuals with mild memory loss.
“To reverse these negative changes in the brain, there has to be an end to the negative signal production at the protein level,” Björklund said. “The first molecules to be targeted for restoring normal signaling could be drugs that reduce secretion of the messenger molecules that cause the protein damage, such as gene therapy in humans.”
The researchers think that individual molecules may have a more comprehensive impact. For example, drugs that activate APOE1 may be beneficial to those who are younger than 70, but others may work better to help an older person with mild memory problems.
The researchers said that the association of APOE4 and dementia is not new, and that previous research, while more in depth, failed to yield the same effect.
“Our new result may relate to another risk factor for early Alzheimer’s, brain aging,” Björklund said. “Previous studies have found a connection between age of onset of Alzheimer’s and risk of the disease, especially with age 70.”
More research is needed to discover whether increasing APOE levels would have any long-term effects, as well as to establish whether any drugs that currently work to alleviate symptoms might be better for preventing cognitive impairment.
But even in the most severe case of Alzheimer’s dementia, a person might be in a better position to learn the signs and symptoms of cognitive impairment as opposed to full-blown Alzheimer’s.
“There are not a lot of symptoms in mild Alzheimer’s disease compared to dementia,” Björklund said. “But because of the earlier onset of Alzheimer’s disease, there is little delay in the onset of the pathology. For adults age 50-59, the average age for onset of the Alzheimer’s pathology is eight years less than in adults 60-69. However, the average age of onset of Alzheimer’s in 60-69 is 10 years shorter than in adults 50-59. So our findings might point to a slight advantage in diagnosing Alzheimer’s disease at an earlier age.”