Bone marrow in Alzheimer’s disease shows an immune-cell defect

Bone marrow in Alzheimer’s disease is not an obvious place to look for trouble. The disease affects the brain, so research naturally focuses on neurons, amyloid plaques and immune cells within the nervous system. A new study broadens that picture: abnormalities can be detected in the system that produces some immune cells before they even enter the bloodstream.

The cells at the center of the story are monocytes, components of the innate immune system that develop in the bone marrow. After entering tissues, monocytes can differentiate into macrophages, cells that engulf damaged material and help regulate inflammatory responses.

Earlier work in mouse models of Alzheimer’s disease suggested that macrophages arriving from the blood can help the brain cope with disease pathology. That raised a basic question. If these cells can be beneficial, why are more of them not naturally recruited to the affected brain?

The researchers looked upstream — at the place where these cells are made.

The defect appears before the cells reach the blood

The team examined hematopoiesis in 5×FAD mice, a widely used genetic model of amyloid pathology. Changes were already apparent among stem and progenitor cells in the bone marrow.

Normally, hematopoietic stem cells maintain the cellular supply from which different blood-cell lineages are continually produced. In 5×FAD mice, this process was altered, including the production of myeloid cells, the lineage that gives rise to monocytes.

The researchers traced this disruption to excessive type I interferon signaling. Interferons are immune signaling molecules best known for their role in antiviral defense. But persistent or inappropriate activation of the same pathway can reshape immune function.

In the 5×FAD bone marrow, the interferon response was associated with impaired monocyte development. The abnormality therefore appeared before these cells left the bone marrow and before they had an opportunity to enter the diseased brain.

This was more than the detection of another inflammatory marker in neurodegeneration. It pointed to an alteration in the production process of immune cells that could otherwise contribute to the brain’s response to pathology.

Turning off the signal

A critical set of experiments tested whether interferon signaling was actually part of the causal pathway in this mouse model.

The researchers blocked type I interferon signaling with neutralizing antibodies. In a separate approach, they reconstituted 5×FAD mice with bone marrow lacking IFNAR1, a receptor required for cells to respond normally to type I interferons.

Both interventions shifted the system. Myelopoiesis recovered, monocyte phenotypes became more normal, and more monocyte-derived macrophages reached the brain. These changes were accompanied by an improvement in disease pathology.

That intervention matters. In the mouse model, the researchers did not merely observe that abnormal bone marrow function and brain pathology occurred together. Manipulating the peripheral interferon pathway changed downstream events, supporting a mechanistic connection between altered blood-cell production and disease progression.

The human evidence has a different weight

The study also included samples from people with Alzheimer’s disease. Their circulating monocytes showed a related abnormal phenotype, providing evidence that the mouse findings have a human counterpart.

But the experimental rescue belongs to the mouse part of the study. The researchers did not demonstrate that blocking type I interferon treats Alzheimer’s disease in people, and the study was not a clinical trial of an interferon-targeting therapy.

The 5×FAD model also develops aggressive amyloid pathology because of engineered genetic changes. It captures important aspects of Alzheimer-like amyloidosis but cannot reproduce the full biology of the much more common sporadic human disease.

The broader finding is therefore not a new Alzheimer’s treatment. It is a change in where the biology of the disease may need to be examined. Immune dysfunction associated with Alzheimer’s can be detected outside the brain, at the stage when bone marrow is generating cells that may later be called upon to support the brain.

In this view, the brain and bone marrow are not independent compartments. They can become different points along the same disease-related immune pathway.