Early-onset axonal pathology and β-amyloidosis in human brains with hematological malignances and cardiovascular...

β-Amyloid (Aβ) and tau pathologies are hallmark lesions of Alzheimer's disease (AD) and they develop in human brain following differential spatiotemporal trajectories. Accordingly, young/adult-onset tau-independent β-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 implication, 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 Aβ formation. Aβ 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 pathology. 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, Aβ 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 associated with β-amyloid processor protein and β-secretase 1 upregulation, but not with intra-axonal amyloid tracer staining. The current findings suggest that hematological malignances and cardiovascular diseases are risk conditions for early-onset cerebral axonal pathology and β-amyloidosis, potentially attributable to vascular injury.