Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis

Abstract

Alzheimer's disease is characterized by abnormal elevation of Abeta peptide and abnormal hyperphosphorylation of the tau protein. The "amyloid hypothesis," which is based on molecular defects observed in autosomal-dominant early-onset Alzheimer's disease (EOAD), suggests a serial model of causality, whereby elevation of Abeta drives other disease features including tau hyperphosphorylation. Here, we review recent evidence from drug trials, genetic studies, and experimental work in animal models that suggests that an alternative model might exist in late-onset AD (LOAD), the complex and more common form of the disease. Specifically, we hypothesize a "dual pathway" model of causality, whereby Abeta and tau can be linked by separate mechanisms driven by a common upstream driver. This model may account for the results of recent drug trials and, if confirmed, may guide future drug development.

Figure 1. Two Hypothesized Models Linking Core Features of Alzheimer’s Disease

The amyloid hypothesis assumes a serial model of causality, whereby abnormal elevations in Aβ drive tau hyperphosphorylation and other downstream manifestations of the disease. According to the dual pathway hypothesis, Aβ elevations and tau hyperphosphorylation can be linked by separate mechanisms driven by a common upstream molecular defect.

Figure 2. Anatomical Progression of Alzheimer’s Disease

In the typical progression of Alzheimer’s disease, primary motor and sensory cortex are affected in the last stage of the disease, Braak stage VI. During the last stage of disease, the primary visual cortex is characterized by tau hyperphosphorylation (as shown using anti-phospho-tau antibodies), neurofibrillary tangles, and amyloid plaques (adapted from Braak et al., 2006 with kind permission of Springer Science/Business Media).

Figure 3. Molecular Defects that Support a Dual Pathway Hypothesis in Late-Onset Disease

Examples of dual pathways linking elevations of Aβ peptide and tau hyperphosphorylation through common upstream molecular defects implicated in late-onset Alzheimer’s disease.