Recent studies, backed by the National Institutes of Health (NIH) and utilizing advanced brain mapping techniques, indicate that Alzheimer’s disease could cause brain damage in two separate stages. Scientists have noted that the initial phase occurs gradually and without noticeable symptoms—occurring prior to any memory issues—and primarily affects a select few vulnerable cell types. On the other hand, the later phase results in more widespread damage, aligning with the onset of symptoms and the swift buildup of plaque, tangles, and other indicators typical of Alzheimer’s.
“One significant hurdle in diagnosing and treating Alzheimer’s stems from the fact that much of the brain damage occurs long before symptoms manifest. Being able to identify these early changes allows us to observe what transpires in an individual’s brain during the earliest stages of the illness,” explained Richard J. Hodes, M.D., director of NIH’s National Institute on Aging. “These findings fundamentally change our understanding of how Alzheimer’s affects the brain and will inform the creation of new treatments for this severe condition.”
Researchers examined the brains of 84 individuals, and their findings, published in Nature Neuroscience, indicate that damage to a specific type of cell known as an inhibitory neuron in the early stage could set off the neural circuit issues associated with the disease. The study also corroborated earlier research on how Alzheimer’s impacts the brain while uncovering numerous new alterations that may occur throughout the illness.
In this research, scientists employed sophisticated genetic analysis methods to investigate cells within the middle temporal gyrus, a brain region responsible for language, memory, and vision. This area has previously shown vulnerability to various changes commonly associated with Alzheimer’s. Additionally, it is a well-mapped region for control donors. By juxtaposing data from control donors with that from Alzheimer’s patients, scientists constructed a genetic and cellular timeline illustrating the disease’s progression.
Historically, research has indicated that Alzheimer’s damage progresses through several stages characterized by increasing cell death, inflammation, and the buildup of proteins in the form of plaques and tangles. However, this study proposes a two-phase model for the disease’s impact on the brain, with many traditional changes occurring rapidly during the second phase, which coincides with the emergence of memory problems and other symptoms.
The study reveals that the earliest brain changes unfold gradually and “quietly” in the initial phase before symptoms arise. These changes include the slow formation of plaques, activation of the brain’s immune responses, damage to the protective insulation around neurons, and the loss of certain cells known as somatostatin (SST) inhibitory neurons.
This latter discovery surprised the researchers, as it has typically been believed that Alzheimer’s primarily harms excitatory neurons, which convey activating signals. Conversely, inhibitory neurons provide calming signals to other cells. The authors of the paper proposed that the decline of SST inhibitory neurons might initiate the neural circuitry alterations that characterize the disease.
In a separate study funded by the NIH, researchers at MIT found that a gene named REELIN might contribute to some neurons’ susceptibility to Alzheimer’s. They also discovered that star-shaped brain cells known as astrocytes could either resist or offer resilience against the disease’s damaging effects.
The researchers examined brains included in the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD), aimed at developing a comprehensive map of brain damage associated with the illness. The project was spearheaded by Mariano I. Gabitto, Ph.D., and Kyle J. Travaglini, Ph.D., from the Allen Institute in Seattle. They utilized cutting-edge tools arising from the NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative—specifically the Cell Census Network (BICCN)—to analyze over 3.4 million brain cells from donors at various stages of Alzheimer’s. Tissue samples were sourced from the Adult Changes in Thought study and the University of Washington Alzheimer’s Disease Research Center.
“This research underscores how powerful new technologies developed through the NIH’s BRAIN Initiative are transforming our understanding of diseases like Alzheimer’s. With these advanced tools, scientists have been able to detect the earliest cellular changes in the brain, painting a more comprehensive picture of the disease’s progression,” stated John Ngai, Ph.D., director of The BRAIN Initiative®. “The insights gained from this study may aid scientists and drug developers globally in crafting diagnostics and treatments tailored to specific stages of Alzheimer’s and other dementias.”
This investigation was supported by NIH grants: U19AG060909, P30AG066509, U19AG066567, U01AG006781. Additional funding was provided by the Nancy and Buster Alvord Endowment. The Rush University Alzheimer’s Disease Center in Chicago contributed donor metadata from the Religious Orders Memory/Memory and Aging Project.
Researchers can access data from the SEA-AD study by visiting the study’s website: https://portal.brain-map.org/explore/seattle-alzheimers-disease
