Pathophysiology of Alzheimer disease: amyloid, tau and neurodegeneration

At a glance

• Alzheimer disease has two defining lesions: extracellular amyloid plaques (amyloid beta peptide) and intracellular neurofibrillary tangles (hyperphosphorylated tau). Synapse and neuron loss follows, beginning in the medial temporal lobe.
• The amyloid cascade hypothesis holds that amyloid beta accumulation starts a process that drives tau spread, inflammation and neurodegeneration. Amyloid builds up 15 to 20 years before symptoms; tau spread tracks symptoms.
• The cholinergic deficit explains cholinesterase inhibitors; excess glutamatergic signalling explains memantine. Anti-amyloid antibodies target the upstream lesion.