Alzheimer’s disease as a multilevel pathological network: mechanisms, heterogeneity, and therapeutic translation

Amyloid-β (Aβ) plaques and Alzheimer-type tau pathology are the neuropathological hallmarks of Alzheimer’s disease, but their burden does not fully explain variation in vulnerability, symptoms or progression. This structured narrative review presents a multilevel conceptual framework for comparing how protein pathology relates to synaptic and network dysfunction, cellular maintenance, glial responses and systemic conditions. Its contribution is a set of relationship-specific appraisal rules: a driver, mediator, amplifier or modifier role must be supported for a defined outcome, biological setting and stage, with human associations distinguished from experimental causal tests. Roles remain unassigned when evidence cannot discriminate among causal contributions, responses and compensation. Threshold, topography and tempo organize heterogeneity without defining validated subtypes. Measurements must match the biological process and intended use; biomarker change cannot by itself establish clinical benefit. Therapeutic reasoning considers stage, co-pathology, safety, delivery conditions and patient priorities. Four provisional predictions concern post-onset complement inhibition in a tauopathy model, frailty-related modification of pathology–clinical coupling, the predictive value of complementary measurements and incremental clinical benefit from a conditional combination strategy. Each specifies the comparison and findings that would weaken the proposed relationship or use. The framework is an evidence map rather than a quantitative network or validated treatment algorithm. Its narrative evidence base and uneven human causal support limit generalization; prospective evaluation is required to establish added explanatory, predictive or clinical value.