The lack of effect of genetically predicted IGF1 and IGFBP3 on AD risk contrasts many of the conventional case–control studies that reported that disease risk was raised in those with lower circulating measures of IGF peptides.7,8,11,12,31,32 Given that measured circulating IGFs are highly responsive to concurrent influences of lifestyle factors that could be affected by disease status, such as recent physical activity, these studies may be particularly prone to bias from reverse causation. This evidence concerns the gene IGFBP3 and Alzheimer disease.