Exercise, APOE genotype, and the evolution of the human lifespan

Trends Neurosci. 2014 May;37(5):247-55. doi: 10.1016/j.tins.2014.03.001. Epub 2014 Mar 30.


Humans have exceptionally long lifespans compared with other mammals. However, our longevity evolved when our ancestors had two copies of the apolipoprotein E (APOE) ɛ4 allele, a genotype that leads to a high risk of Alzheimer's disease (AD), cardiovascular disease, and increased mortality. How did human aging evolve within this genetic constraint? Drawing from neuroscience, anthropology, and brain-imaging research, we propose the hypothesis that the evolution of increased physical activity approximately 2 million years ago served to reduce the amyloid plaque and vascular burden of APOE ɛ4, relaxing genetic constraints on aging. This multidisciplinary approach links human evolution with health and provides a complementary perspective on aging and neurodegenerative disease that may help identify key mechanisms and targets for intervention.

Keywords: Alzheimer's disease; aerobic fitness; aging; apolipoprotein; dementia; vitamin D.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Aging / genetics*
  • Aging / physiology*
  • Alzheimer Disease / genetics
  • Apolipoproteins E / genetics*
  • Biological Evolution*
  • Exercise / physiology*
  • Genotype
  • Humans
  • Neurodegenerative Diseases / genetics


  • Apolipoproteins E