Fig. 2.

The neuropathology of Alzheimer disease. The major pathological hallmarks of AD include parenchymal amyloid deposition (brown) and intraneuronal tau hyperphosphorylation and subsequent aggregation (1 – yellow). Tau aggregation leads to the formation of neurofilament tangles that are closely associated with neurodegeneration in AD. These pathological hallmarks lead to loss of synapses and synaptic plasticity, which result in cognitive impairment. In addition, amyloid plaques and tau tangles induce a strong response in the tissue resident immune cells, namely microglia (2 – green). Genome-wide association studies position microglia at the epicenter of AD pathogenesis, as several risk factor genes are enriched in microglia and affect their ability to respond to amyloid deposition. In addition, elevated levels of oligomeric amyloid early in the disease process induce potent capillary constriction by promoting pericyte contraction (3 – gray) that results in a significant reduction of cerebral blood flow, which is the first clinically detectable symptom of AD. Finally, accumulation of amyloid is linked to pronounced astrocyte reactivity (4 – blue), leading to astrocytic end feet retraction and their inability to maintain synaptic homeostasis and vascular health.