A long-standing question has been whether the detrimental effects of apoE4 in AD pathogenesis reflect a loss of normal function or a gain of toxic effects1,55. Studies in animals suggest both possibilities1,55, and it has been difficult to address this question in humans. Our hiPSC-derived neuron model of apoE deficiency and the complementary experiments of reintroducing apoE4 into the apoE-null human neurons strongly argue for a gain of toxic effects of apoE4 in AD pathogenesis, at least for its effects on tau phosphorylation, Aβ production, and GABAergic neuron degeneration. This conclusion is in line with the report of an apoE-deficient patient that detailed neurocognitive studies failed to demonstrate any defects30. This information has critical implications for developing drugs targeting apoE4: reducing apoE4 expression might be an attractive strategy.
