Table 5 Effects of the APOE4 genotype on AD pathological features

Amyloid-β

Increased plaque load and density

-Humans: [160, 339, 340]

-Mice: APP^V717F x humanized APOE4 [66, 341], PDAPP/TRE4 mice [511], E4FAD mice [512]

Increased CAA formation

-Humans: [513, 514]

-Mice: Tg2576 x hAPOE4 KI [344]

Increased Pittsburgh compound B positive amyloid burden

-Humans: [346, 347]

Reduced Aβ₄₂ levels in CSF

-Humans: [346, 348]

Enhanced Aβ fibril formation in vitro

-Aggregation studies [291]

-In vitro studies: [351, 352]

Increased intracellular Aβ generation/Aβ secretion

-Cellular models: [358, 359]

Reduced neprilysin and IDE expression

-Humans: [365, 366]

Reduced cellular clearance of Aβ

-In vitro: [364, 367, 368]

Impaired Aβ removal via BBB

-Humans: [391]

-mice: APP/PS1 mice [435]

-Human and APP knock-in mice: [374]

More severe tau pathology

-Humans: [390]

Tau

Increased tau-induced neurodegeneration

-Mice: P301S/APOE4 knock-in mice [397, 401]

Enhanced tau phosphorylation

-In vitro: [399, 402, 515]

-Mice: E4FAD [516]

Increased cleavage of C-terminal truncated ApoE fragments (linked to increased p-tau and tau tangles-like structures)

-In vitro: [383, 517]

Synapses

Reduced neuronal outgrowth and synaptic density

-In vitro: [447,448,449]

-Mice: APOE4 knock-in [234]

Impaired synaptic plasticity (Long term potentiation)

-In vitro: [452]

-Mice: APOE knock-in [453]

Poor learning and memory

-Mice: APOE4 knock-in [456,457,458]

Autophagy/Endosomes

Decreased/impaired autophagy and mitophagy

-In vitro: [470]

-Mice: APOE4 knock-in [486]

Dysregulated endosomal-lysosomal pathway

-Mice: APOE4 knock-in [518]

Enlarged endosomes

-Humans: [481]

-Mice: APOE4 knock-in [518]

Reduced mRNA levels of autophagy markers

-Humans: [489]