Genetic studies of autosomal dominant Alzheimer's disease (AD) revealed that β-amyloid is central to disease pathogenesis. However, amyloid-targeted therapies have generally failed to slow progression in patients with symptomatic disease. This result suggests a transition from an early amyloid-dependent phase to a later amyloid-independent one, during which neurodegeneration occurs and symptoms arise. Microglia, the brain's resident myeloid cells, envelop amyloid and express the majority of genes linked to risk for sporadic late-onset AD. Their activation is associated spatially and temporally with the accumulation of pathological tau. Microglial facilitation of tau pathology may involve apolipoprotein E, the most important genetic risk factor for AD. Once formed, pathological tau spreads between connected neurons, eventually accumulating in the somatic compartment where catastrophic nuclear damage ensues. This emerging understanding of the postamyloid processes leading to neurodegeneration affords the opportunity to develop therapeutics that interrupt this pathological cascade and prevent or delay dementia, even after amyloid deposition.
Keywords: Alzheimer's disease; amyloid; apolipoprotein E; neuroinflammation; tau.