Find all causes of Alzheimer's disease and a cure

In an effort to understand how the pathology of Alzheimer’s disease spreads through the brain, scientists meticulously mapped the genetic activity of 1.3 million cells across six regions of the brain.

Their findings identify subtypes of neurons in the entorhinal cortex and hippocampus that are particularly susceptible to Alzheimer’s disease—a discovery that helps explain why these regions consistently develop Alzheimer’s pathology earlier than do other regions. This project also identified specific cellular pathways, including the Reelin pathway, as possible influencers in the progression of the disease. The research also revealed the protective role of astrocytes in fostering cognitive resilience against Alzheimer’s. By mapping cellular changes associated with disease progression across the brain, the project yielded new insights into how this causal chain could someday be interrupted therapeutically.

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Globally, Alzheimer’s disease is the number one cause of dementia, yet the mechanisms that advance its pathology across the brain are not fully understood. To shed light on what happens to individual cells in a human brain affected by Alzheimer’s disease, a team of scientists created a single-cell transcriptomic atlas of six different regions of the aging human brain.

Transcriptomics is the study of how cells use DNA. While every cell in the human body contains the same DNA, each cell type—whether in the brain, liver, or skin—uses this genetic code differently. Cells copy sections of DNA into RNA and then use that RNA code to build the proteins they need to perform their functions. Scientists can learn valuable information about a cell’s identity and activity by examining the RNA transcripts each cell creates. Transcriptomics, in a sense, creates a unique fingerprint for each cell.

Drs. Li-Huei Tsai and Manolis Kellis, the study’s co-senior authors, used this approach to profile over a million cells from brain tissue samples of individuals diagnosed with Alzheimer’s and those without the disease. The result is a detailed atlas that organizes changes in cellular activity by brain region, cell type, and cognitive performance throughout the individual’s life.

Their findings pinpoint specific neurons in the entorhinal cortex and hippocampus as particularly susceptible to Alzheimer’s disease, aligning with existing knowledge of these regions as early sites of Alzheimer’s disease pathology. “What is new in this study,” Dr. Tsai explains, “is we were able to pinpoint the signature of the cells in the entorhinal cortex and hippocampus that are most vulnerable.” This research takes the understanding of Alzheimer’s from a broad regional perspective to the level of individual affected cells.

One of the study’s significant discoveries was that these vulnerable neurons either heavily expressed the protein Reelin or were directly influenced by Reelin signaling. Reelin has recently gained attention for its potential neuroprotective properties, especially following a 2023 study of a Colombian man with a rare genetic mutation typically linked to early-onset Alzheimer’s. Despite having amyloid plaques and tau tangles in his brain at death, the man never exhibited cognitive symptoms. His protection stemmed from a mutation in the Reelin gene, which made the protein more potent in its ability to protect the brain.

In their study, Drs. Tsai and Kellis linked the loss of neurons and neural circuits that produced or relied on Reelin to poorer cognitive performance throughout individuals’ lifetimes. “Somehow, Reelin-positive neurons are more vulnerable than other cells in the entorhinal cortex to death,” Dr. Tsai notes. “Once these cells start to reduce in number, the protective force of Reelin is reduced.”

The study also uncovered that some individuals showed cognitive resilience. Despite the presence of Alzheimer’s pathology in their brains, these individuals performed better than expected on cognitive tests during their lifetimes. Researchers attributed their resilience to astrocytes, a type of brain cell that plays a crucial role in supporting neurons. Astrocytes are involved in everything from reducing toxic neurotransmitter levels to maintaining the brain’s protective blood-brain barrier. In resilient brains, astrocytes became more active in anti-inflammatory processes and increased their metabolism of choline, a critical precursor in several pathways essential for brain health.

The development of this single-cell transcriptomic atlas marks a significant advance in our understanding of Alzheimer’s disease at the cellular level. By pinpointing the neurons most at risk and uncovering a protective role of astrocytes, this research highlights new targets for study for therapeutic potential. As the scientific community continues to search for viable Alzheimer’s therapies, this atlas—available online*—could prove to be an invaluable resource for guiding future research.

In the brain, accumulation of abnormal tau is one component of the destructive pathology leading to Alzheimer’s disease. Throughout our lifetime, microglia are the resident innate immune cells of the brain removing debris and unwanted particles. With age and increased cell damage, microglia can shift from protective to destructive. A new study reveals that mice with brain shrinkage due to abnormal tau, similar to that in Alzheimer’s, have more destructive T cells in their brains, attracted by the microglia. Understanding the role of T cells in neurodegeneration may lead to new areas of therapeutic strategies.

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In Alzheimer’s, amyloid beta begins to build up in plaque bundles in the brain, years before cognitive symptoms emerge. The increased levels of amyloid are followed by an accumulation of aberrant tau and neurodegeneration, which more closely correlate with cognitive decline. Despite high levels of amyloid plaques, mouse models with amyloid do not develop brain atrophy. In contrast, with age, mouse models with tau develop neurodegeneration similar to that in AD patients— and this damage is exacerbated by APOE4, the strongest genetic risk factor for sporadic AD. In this study, an increase in T cells in the brains of the tau mice was observed, and these T cells were recruited by the microglia to enter the brain. Together, the two cell types promoted neurodegeneration.

When the brain sustains damage, microglia activate and can shift from a housekeeping to a disease-associated state. The study found that with greater brain atrophy in the mice with tau, there was more microglial activation and the cells entered an overactive state. Researchers also observed significantly higher levels of T cells in the mice with tau, as compared with mice with amyloid plaques, where the microglia also were overactivated but there were no T cells. The higher levels of T cells in the tau mice aligned with more severe brain atrophy and neurodegeneration. This also was observed in postmortem AD human brains. Areas with a lot of tau pathology displayed increased levels of T cells, while areas with amyloid buildup alone did not.

Further research in mice showed that, in the brain, the two types of immune cells work together to create inflammatory conditions that drive neurodegeneration. Microglia release molecules that attract and activate T cells. T cells drive microglia to become inflammatory, which can cause further neurodegeneration.

Removing microglia from the brain or T cells from the periphery in the tau mice profoundly reduced neurodegeneration. Without microglia, T cells did not infiltrate the brain, suggesting that microglia play a crucial role in facilitating T cells to cross into the brain. Depleting T cells from the periphery also was neuroprotective and improved the ability of mice to perform on behavioral and cognitive tests. Together, these findings add to the emerging body of scientific evidence suggesting that the brain’s innate immune system and the body’s peripheral immunity cross talk with each other in health and disease.

In summary, the research sheds new light on the complex role and interplay of immune cells in Alzheimer’s disease, and for the first time demonstrates a role for peripheral T cells in neurodegeneration. The study offers new avenues for future therapeutic investigation into targeting T cells for the treatment of AD.