Some People Resist Alzheimer’s Disease. Does Neurogenesis Hold The Key?

For many decades, it was widely thought that amyloid beta plaques and other types of deposits in the brain were the cause of neurodegenerative diseases like Alzheimer’s. When researchers examined the brains of dementia patients after they had died, they found their brains to be full of this material – aggregates made up of various misfolded proteins. Yet, something didn’t quite add up. When researchers examined the brains of people who were free of neurodegenerative disease upon death, they would sometimes find large amounts of plaque in their brains. A 90 year-old who died in good cognitive health for their age might turn out to have more amyloid in their brain than someone who died with Alzheimer’s disease in their 60s.

It is now generally believed that plaque deposits in the brain are part of a bigger picture when it comes to dementia, but not the fundamental driver. If this plaque is a component of dementia, how is it possible to have plaque in one’s brain without showing symptoms? One idea is that plaque formation occurs as a result of other, more fundamental processes that drive neurodegeneration, such as inflammation and errors in how cells build and handle proteins. The brain has some capacity to offset the damage caused by these processes, so if they occur at low ‘intensity’, someone might accumulate significant amounts of plaque over time without getting dementia. If, on the other hand, those underlying processes occur at a higher rate, then neurodegenerative disease occurs. As a loose analogy, a car that spends most of its time on main roads will eventually accumulate dirt and dust, but the functional components of the car will still be in considerably better shape than a car that drives on uneven dirt roads.

Cognitive Reserve

Another idea that feeds into this is the concept of cognitive reserve. Cognitive reserve describes the ability of the brain to ‘absorb’ damage without suffering a significant loss of cognitive function. This could be because some people have better cognitive function to start with, so they can afford to lose more of it without suffering a level of cognitive impairment that impacts their daily life. However, scientists have long wondered whether the brain might also be able to repair some of the fundamental damage driving dementia, including by regenerating lost brain cells. Until relatively recently, scientists believed the brain to have essentially no regenerative capacity, but we now know that this probably isn’t true. Research suggests that even in the brains of older adults, there remains some ability to grow new neurons (neurogenesis). This is an important revelation, because it means that there may be a way to boost the regenerative capacity of the brain in order to delay, or perhaps even reverse, neurodegenerative disease.

The Study

That finally brings us to today’s study. Researchers set out not only to improve the methods for detecting neurogenesis within the adult human brain, but also to investigate whether any differences could be observed between brains that might explain why some people can develop Alzheimer’s-like pathology without getting dementia.

Researchers started by investigating human brain tissue from the hippocampus, a brain region involved in learning and memory that is severely affected in Alzheimer’s disease. They gathered hippocampal tissue from 24 deceased human donors. 12 tissue samples were from people with moderate to severe Alzheimer’s, while 6 were control tissue samples from people with no cognitive decline and no Alzheimer’s pathology in their brains. The remaining 6 samples, dubbed the resilient group, were from people who had no cognitive decline, but whose brains were found to have Alzheimer’s pathology when examined post-mortem.

Quality Over Quantity

Researchers then analysed cells from the dentate gyrus, a region of the hippocampus in which adult neurogenesis occurs. They used RNA sequencing (essentially measuring which genes are expressed and to what extent) to identify immature neurons (neurons that were not yet fully developed, indicating neurogenesis). The researchers suspected that they might find significantly more immature neurons in the brains of those in the resilient group, explaining their ability to resist Alzheimer’s pathology. However, this was not the case – instead, what set the resilient group apart was the ‘quality’ of their immature neurons. When looking at gene expression in these neurons, researchers identified patterns of gene expression consistent with anti-inflammatory signals, neurotrophic signals (neuron growth), and neuroprotective effects. On the other hand, normal gene expression and cellular interactions were disrupted in immature neurons from Alzheimer’s samples.

Another Piece of the Puzzle

These findings could potentially help explain why some people do not suffer cognitive decline despite having the pathology of Alzheimer’s disease. Even as Alzheimer’s eats away at brain function, this could be somewhat counteracted by the generation of new neurons and by the beneficial signals that they release, helping to preserve tissue function.

It’s important to remember that correlation isn’t causation – while differences in immature neurons could help explain why some people resist Alzheimer’s pathology, it is also possible that they simply have a milder form of the disease that does not harm neurogenesis as much. While adult neurogenesis is now known to exist, there is still some debate over whether it really occurs at sufficient levels to have any impact on brain function, let alone in Alzheimer’s disease. Let’s hope that the answer is yes, and that there are ways of targeting neurogenesis to confer this resilience on other people. There are some ways in which neurogenesis might be supported, such as via BDNF (brain-derived neurotrophic factor), a protein whose production is increased by exercise that researchers have delivered to animals via gene therapy with some success.