APOE and Alzheimer disease: In the same vein, we and others observed an increase in synapse numbers with apolipoprotein E4 (ApoE4) similar to that detected here with Aβ released from APP, which is also puzzling in suggesting that ApoE4, the most important genetic risk factor for sporadic AD, predisposes to AD but enhances instead of suppressing synapse formation (44, 56, 57).