Early-onset β-amyloidosis in human brains with hematological malignances and cardiovascular diseases: Revisiting injury/stress induced axonal pathology

Abstract

{beta}-Amyloid (A{beta}) and tau pathologies are hallmarks of Alzheimers disease (AD) and they develop in human brain following differential spatiotemporal trajectories. As such, young/adult-onset tau-independent {beta}-amyloidosis is rare. We encountered four such cases among 397 banked brains, with the donors died of hematological malignances (blood cancers) or cardiovascular diseases. To explore the pathological implications, we examined 17 brains (10-87 year-old, y) from blood cancer patients and three (52-82 y) with cardiovascular diseases, focusing on vascular injury, axonal pathology and A{beta} formation. A{beta} plaques occurred in two adult brains (31 y, 63 y) with blood cancers and two (52 y, 65 y) with cardiovascular diseases in the absence of tau. In the blood cancer brains, 17/17 had vascular injuries seen in hematoxylin-eosin stained sections, 13/17 had iron leakage, and 13/17 had axonal pathology. Malignant cell infiltration was found in 5/14 brains with myeloid, lymphocytic and lymphoma malignances, with light chain infiltration in 3/3 brains with multiple myeloma. In the cardiovascular disease brains, A{beta} deposition primarily as diffuse plaques occurred in the cerebral cortex, with vascular and axonal pathologies in the white matter, striatum and internal capsule. Using a multi-labeling approach, the injury/stress induced axonal pathology was found to concur with {beta}-amyloid processor protein elevation and enhanced {beta}-secretase 1 processing but not intraneuronal A{beta} accumulation. The current findings suggest that hematological malignances and cardiovascular diseases are risk conditions for early-onset cerebral {beta}-amyloidosis, potentially attributable to vascular injury.