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April 13, 2020

Longevity Gene KLOTHO and Alzheimer Disease—A Better Fate for Individuals Who Carry APOE ε4

Author Affiliations
  • 1Weill Institute of Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco
  • 2Associate Editor, JAMA Neurology, Chicago, Illinois
  • 3Memory and Aging Center, University of California, San Francisco, San Francisco
  • 4Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco
JAMA Neurol. 2020;77(7):798-800. doi:10.1001/jamaneurol.2020.0112

The apolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for Alzheimer disease (AD), the most common neurodegenerative condition. Unfortunately, APOE4 is not rare. Approximately 23% of the US population carries an allele. One copy increases risk of developing AD by 3-fold; 2 copies increases it by more than 12-fold. The APOE4 allele shortens the time to disease onset and reduces survival1,2 in both sporadic and familial AD. Beyond AD, APOE4 increases the likelihood of cognitive decline in patients with other neurologic disorders,3 elderly people who are clinically normal,4 and even patients with head trauma as putatively mild as heading a ball in soccer.5 Neuroanatomic differences with APOE4 have been detected in AD-relevant brain regions in adolescence6 and as early as infanthood.7 Remarkably—despite the lifelong influences of APOE4—not all who carry the allele are fated for AD.

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