Most of the drug trials in Alzheimer disease dementia are targeted at the removal of amyloid-β, showing large decreases in amyloid-β on PET scans, but only modest to no effects on cognitive impairment and clinical outcomes.48 We found that over one-fourth of the effect of APOE ε4 on cognition is mediated by cerebrovascular factors, suggesting that the ε4 allele exerts its effect on late-life cognitive impairment not solely through the accumulation of β-amyloid plaques. This evidence concerns the gene APOE and Alzheimer disease.