Alzheimer’s triggers may originate outside the brain

Although Alzheimer’s disease is the most common form of dementia, many aspects of its origins remain unclear. Researchers at Washington University School of Medicine have now found evidence that certain immune cells linked to the disease may be activated by other immune cells outside the brain.

The researchers believe the finding could open the door to new treatments that interrupt this process.

“This means we shouldn’t look at Alzheimer’s only inside the brain, but outside it as well,” said lead author Hao Hu, a postdoctoral researcher at Washington University. “We need to view the disease more holistically. It affects the brain, but the whole body is actually involved.”

When the Immune System Turns Against the Brain

The brains of people with Alzheimer’s become filled with abnormal forms of two proteins, beta-amyloid and tau. For years, many researchers have considered beta-amyloid a major driver of brain damage. However, this view has become increasingly complex as newer anti-amyloid treatments have shown only modest benefits in slowing disease progression.

Previous research by the team pointed to another possible driver of Alzheimer’s symptoms: the accumulation of immune cells known as T cells in the brain.

While the buildup of amyloid and tau proteins may remain an important early feature of the disease, high levels of T cells, potentially working alongside another type of immune cell called microglia, may contribute directly to the resulting damage.

In an earlier mouse study, the researchers removed or blocked the activity of T cells, which appeared to reduce inflammation and further neurological damage.

T cells are normally activated by another type of immune cell known as dendritic cells. The researchers were particularly interested in a subtype called conventional dendritic cells. However, relatively few of these cells are found in the brain, and previous findings suggested that those present there were unlikely to be responsible for the T-cell-related damage observed in Alzheimer’s.

The team therefore looked beyond the brain for a possible source.

In the new study, the researchers genetically eliminated dendritic cells from lymph nodes outside the brain and other sites in the body. This appeared to prevent the excessive accumulation of T cells in the brain.

More importantly, the intervention reduced the expected brain damage in the mice while preserving normal cognition. Notably, these improvements occurred even though levels of abnormal tau protein in the brain did not decrease.

The findings are currently limited to mice, and further research will be needed to determine whether dendritic cells and T cells play a similar role in Alzheimer’s disease in humans.

Several questions also remain unanswered, including what initially prompts dendritic cells to direct T cells toward the brain. The researchers suspect that the accumulation of abnormal tau protein may be one of the key triggers.

If the findings are confirmed in future studies, they could point to new strategies for treating Alzheimer’s disease.

The team plans to investigate whether removing dendritic cells later in life can still reduce brain damage in mice. This approach could more closely mimic potential treatments for older people at risk of Alzheimer’s. The researchers also plan to explore whether targeting only specific lymph nodes could provide benefits while minimizing potential side effects.