Latest updates on the advancements and breakthroughs of the BRAIN Initiative in Alzheimer’s research. Brain mapping tools developed through the BRAIN Initiative Cell Census Network have enabled researchers to study how aging affects the brain as a whole.
Alzheimer’s disease is a neurodegenerative condition characterized by memory loss, cognitive decline, metabolic issues, and behavioral impairments. The risk increases with age. These symptoms can strip away the independence of aging individuals, making it impossible for them to perform routine tasks without help. Given the significant impact of Alzheimer’s disease and the limitations of existing knowledge on both healthy aging and the onset of Alzheimer’s symptoms, research is urgently needed to understand the precise molecular mechanisms that lead certain cells to become susceptible to the onset and progression of Alzheimer’s disease. Advancements in brain mapping tools provided by the BRAIN Initiative Cell Census Network have made it possible to leverage research findings from two scientific teams to identify the initial cellular alterations in the brain associated with healthy aging and Alzheimer’s disease, providing a more comprehensive understanding of the disease’s progression.
The two research teams driving these breakthroughs are from the Allen Institute for Brain Science. One team is supported in part by the National Institute of Aging (NIA) and the National Institute of Mental Health through the Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®. The other team is part of the Seattle’s Alzheimer’s Disease Brain Cell Atlas (SEA-AD) consortium and is supported by the NIA.
Healthy age-related cell susceptibility
Since the primary risk factor of Alzheimer’s disease is age itself, the team led by Kelly Jin, Ph.D., Bosiljka Tasic, Ph.D., and Hongkui Zeng, Ph.D. located and characterized more than 1.2 million brain cells from young and aging mice to determine which brain cells may be most affected by healthy aging. They found that aging decreased the activity of genes associated with the development of neurons that control learning, memory, and scent recognition. Additionally, they found that aging leads to increased activity of genes associated with the development of blood vessel cells, immune cells, and inflammatory cells of the brain. The largest changes in genetic activity associated with age occurred in two places: 1) the hypothalamus, a small part of the brain that controls essential functions like hunger, thirst, body temperature, and hormone release; and 2) the third ventricle, a narrow cavity in the brain that produces, secretes, and circulates cerebrospinal fluid, which cushions the brain and removes waste. As noted in the NIA press release, given the involvement of the hypothalamus in body metabolism, these structural findings align with other studies suggesting that intermittent fasting can increase lifespan.
These findings, published in Nature, provide new insights into how healthy aging affects the brain and may guide the development of new treatments for age-related brain disorders like Alzheimer’s disease. For more details visit the NIA press release.
Alzheimer’s disease-related cell susceptibility
A separate study published in Nature Neuroscience has challenged the traditional understanding of Alzheimer’s progression. The study, led by Mariano I. Gabitto, Ph.D., and Kyle J. Travaglini, Ph.D., used advanced genetic analysis tools developed as part of the BRAIN Initiative Cell Census Network to map genetic and cellular changes associated with Alzheimer’s disease.
To create a timeline of disease progression, scientists studied brain tissue samples from 84 human donors covering the full spectrum of Alzheimer’s disease pathologies and mapped out the changes in genes and cells as the disease advanced. They uncovered that Alzheimer’s disease may damage the brain in two distinct phases. The early phase is subtle, impacting only a few vulnerable cell types before the development of memory problems. The late phase is more damaging, occurs at the same time as the appearance of symptoms, and is accompanied by the rapid buildup of plaques and tangles. Additionally, the team found that Alzheimer’s related pathology primarily affects a class of inhibitory neurons, which reduce signals to other cells, that might initiate the neural circuitry changes related to the disease. This finding contrasts with the traditional belief that Alzheimer’s related pathology primarily affects excitatory neurons, which send activating signals to other cells, in the early stages of the disease.
These novel insights into cell types that are initially affected by Alzheimer’s disease may guide the development of tailored treatments for Alzheimer’s disease. To learn more, check out the National Institute of Aging press release.
References:
Jin, K. et al. Brain-wide cell-type specific transcriptomic signatures of healthy aging in mice. Nature. 2025 January 1 doi: https://doi.org/10.1038/s41586-024-08350-8
Gabitto, M. I.; Travaglini, K. J.; et al. Integrated multimodal cell atlas of Alzheimer’s disease. Nature Neuroscience. 2024 October 15 doi: 10.1038/s41593-024-01774-5