Does Greater Adult Neurogenesis Allow Some People to Resist Alzheimer's Disease?
Since the discovery that adult mice generate new neurons in the brain, and thus the brain is not wholly reliant upon structures and cells created during development, there has been considerable debate over whether or not this adult neurogenesis exists and is important in humans. This is in part a logistics problem: the human brain is inherently hard to study. It is in part a methodological problem, in that human neurogenesis appears to be different enough from mouse neurogenesis in its details to challenge researchers. Much of the debate of the past fifteen years has focused on whether the tools are working in the way that they are claimed to work, and whether human data actually reflects what those who present it think it reflects. Nonetheless, the present weight of data and scientific consensus support a role for neurogenesis in the maintenance of the aging brain.
So we come to the question of why some people exhibit molecular pathology characteristic of Alzheimer's disease, such as the generation of protein aggregates that can be visualized via imaging approaches, but do not suffer extensive cognitive decline as a result. There is a school of thought that suggests that these individuals have more efficient or greater levels of neurogenesis, capable of compensating for losses. Or that their neurogenic mechanisms are in some way more resistant to the damage of aging. This ties in to the high level concepts of cognitive resilience and cognitive reserve, created by clinicians and researchers seeking to describe the observed differences in the cognitive outcomes of neurodegeneration from individual to individual. Whether differences in neurogenesis are indeed important in this context remains an unanswered question; today's open access paper is an example of ongoing work aimed at developing better tools to obtain better data and thus come to a conclusion.
Not all Alzheimer's leads to dementia
Why do some people experience memory loss and cognitive decline as Alzheimer's builds up in their brain, while others stay mentally sharp? This question lies at the heart of new research into "cognitive resilience", a phenomenon that is gaining attention in neuroscience. "Around 30 percent of older adults who develop Alzheimer's disease never experience its symptoms. We really don't know why. That's a big mystery, and a very important one."
One possible explanation is that resilient brains are better at repairing themselves during Alzheimer's. This idea is linked to a process called adult neurogenesis, which refers to the birth of new neurons in the adult brain. It has been well-established in other animals, but its existence in humans has been debated for years. To study this, researchers used human brain tissue from the Netherlands Brain Bank, which collects and stores donated brain samples for research. They included brains from control donors with no brain pathology, Alzheimer's patients, and individuals with Alzheimer's pathology who remained resilient to developing dementia.
The team found what they were looking for: so-called "immature" neurons. These cells resemble young, not fully developed neurons. While the team had expected to find much more of these cells in the resilient group than in the Alzheimer's patients, the difference was not as big as expected. Instead, the team found that the key difference lies in how the immature neurons behave. "In resilient individuals, these cells seem to activate programs that help them survive and cope with damage. We also see lower signals related to inflammation and cell death."
An attractive approach to treating Alzheimer's disease (AD) could involve harnessing the brain's endogenous regenerative potential to restore function in the degenerating hippocampal network. This strategy presumes the occurrence of adult hippocampal neurogenesis (AHN) in the human brain and the functional integration of newly generated granule cell (GC) neurons into the hippocampal formation. Reconstructing the molecular and cellular signatures of immature hippocampal GC neurons may not only offer novel targets for brain repair and regeneration strategies in the AD human brain but also directly probe the question of whether human AHN contributes to a lifelong buildup of cognitive reserve. This reserve may, in turn, confer resilience to cognitive decline or AD-related dementia later in life.
Despite its therapeutic appeal, identifying and profiling putative neurogenic populations in the adult human brain has not been trivial; beyond reflecting technical roadblocks, this also hints at some potentially unique attributes of these cells. Although single-nucleus RNA sequencing (snRNA-seq)-based studies have identified cells with immature neuronal characteristics in the adult human hippocampus, methodological discrepancies have led to substantial debate in the field. Recently, we examined experimental and computational variables that may confound the results and conclusions of such approaches. Building on these insights, we here establish a refined experimental and computational framework aimed at reliably identifying neurogenic populations in the aged human brain, while minimizing biases inherent to marker-based preselection.
Our findings reveal that immature neuronal signatures persist into adulthood, with some of them potentially arising postnatally. Although these cells present some transcriptional similarities to their fetal counterparts, they also appear to have acquired unique features that may enable them to adapt to the complex adult niche microenvironment. Our findings suggest that the presence of these immature neuronal populations may actively contribute to maintaining homeostasis within the aged human hippocampus and to cognitive resilience in AD.