Dr Vemuri emphasized, however, that the findings for people who do not carry the gene should not discourage people from exercising and from taking part in activities that stimulate the mind, such as reading books and magazines, playing games, and using computers. “There is substantial evidence that these activities help to delay the onset of memory and thinking problems,” he said. “What we don’t know is how this process works.”

The researchers noted that there are several possible explanations for why highly educated carriers of the APOE4 gene who continue to stimulate their minds in middle age have lower levels of amyloid plaques than those who do not.

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One explanation is that higher levels of education and higher levels of midlife mental stimulation do somehow prevent amyloid deposition, and this effect is observable in APOE4 carriers because they are accumulating amyloid at an earlier age and faster rate than non-APOE4 carriers. “With greater power, we might see the same protective association in APOE4 non-carriers,” the authors wrote. “The problem is that there is not a good biological explanation of how these features could forestall amyloid deposition.”

Another possible explanation is reverse causality — that it is not low mental stimulation that leads to increased amyloid buildup, but increased amyloid buildup that leads to decreased mental stimulation. It is possible that “among all educated APOE4 carriers, those with the highest amyloid levels in middle age are most likely to experience subtle cognitive symptoms at that time and consequently avoid strenuous intellectual activity, thus placing them in the low cognitive activity group,” the authors wrote.

While the reverse causality explanation is a possibility, “our findings show [that] further study is needed, and suggest that differing education levels in other recent studies may explain the conflicting results seen in the research literature,” Dr Vemuri said.


Vemuri P, Lesnick TG, Przybelski SA, et al. Effect of intellectual enrichment on AD biomarker trajectories: Longitudinal imaging study. Neurology. 2016; doi:10.1212/WNL.0000000000002490.