Article Text

Original research
APOE genotypes modify the obesity paradox in dementia
  1. Mitsuru Shinohara1,2,3,
  2. Ghupurjan Gheni1,
  3. Junichi Hitomi1,
  4. Guojun Bu2,
  5. Naoyuki Sato1,3
  1. 1 Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
  2. 2 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA
  3. 3 Department of Aging Neurobiology, Osaka University, Suita, Osaka, Japan
  1. Correspondence to Naoyuki Sato; nsato{at}; Dr Mitsuru Shinohara; shinohara{at}


Background While obesity in midlife is a risk factor for dementia, several studies suggested that obesity also protected against dementia, hence so-called obesity paradox. The current study aims to address the relationship between apolipoprotein E (APOE) genotype and obesity in dementia.

Methods Clinical and neuropathological records of the National Alzheimer’s Coordinating Center (NACC) in the USA, which longitudinally followed approximately 20 000 subjects with different cognitive statues, APOE genotype and obesity states, were reviewed.

Results Obesity was associated with cognitive decline in early elderly cognitively normal individuals without APOE4, especially those with APOE2. Neuropathological analyses adjusted for dementia status showed that APOE2 carriers tended to have more microinfarcts and haemorrhages due to obesity. On the other hand, obesity was associated with a lower frequency of dementia and less cognitive impairment in individuals with mild cognitive impairment or dementia. Such trends were particularly strong in APOE4 carriers. Obesity was associated with fewer Alzheimer’s pathologies in individuals with dementia.

Conclusions Obesity may accelerate cognitive decline in middle to early elderly cognitive normal individuals without APOE4 likely by provoking vascular impairments. On the other hand, obesity may ease cognitive impairment in both individuals with dementia and individuals at the predementia stage, especially those with APOE4, through protecting against Alzheimer’s pathologies. These results support that APOE genotype modifies the obesity paradox in dementia.

  • dementia

Data availability statement

Data are available in a public, open access repository. The raw data are available from NACC ( on request. The details of analysis (statistical models, used variables, etc) are available from the corresponding authors on request.

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Data availability statement

Data are available in a public, open access repository. The raw data are available from NACC ( on request. The details of analysis (statistical models, used variables, etc) are available from the corresponding authors on request.

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  • Contributors MS and NS contributed to the concept and study design. MS, GG, JH, GB and NS contributed to data acquisition and analysis. MS and NS contributed to drafting the manuscript and figures. All authors edited and reviewed the final manuscript. MS and NS accept full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish.

  • Funding This work was supported in part by the Research Funding for Longevity Sciences from National Center for Geriatrics and Gerontology (28-45, 19-3 and 21-12 to NS); Grants-in-Aid from Japan Promotion of Science (17H04154 and 21H02844 to NS; 21H03391 to MS); a Takeda Science Foundation Research Encouragement Grant (to NS and MS); a research grant from Mitsui Sumitomo Insurance Welfare Foundation (to NS); a NACC Junior Investigator Award (to MS) and National Institutes of Health (NIH) grants R37AG027924, RF1AG057181, RF1AG046205 (to GB). The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADRCs: P30 AG062429 (PI James Brewer, MD, PhD), P30 AG066468 (PI Oscar Lopez, MD), P30 AG062421 (PI Bradley Hyman, MD, PhD), P30 AG066509 (PI Thomas Grabowski, MD), P30 AG066514 (PI Mary Sano, PhD), P30 AG066530 (PI Helena Chui, MD), P30 AG066507 (PI Marilyn Albert, PhD), P30 AG066444 (PI John Morris, MD), P30 AG066518 (PI Jeffrey Kaye, MD), P30 AG066512 (PI Thomas Wisniewski, MD), P30 AG066462 (PI Scott Small, MD), P30 AG072979 (PI David Wolk, MD), P30 AG072972 (PI Charles DeCarli, MD), P30 AG072976 (PI Andrew Saykin, PsyD), P30 AG072975 (PI David Bennett, MD), P30 AG072978 (PI Neil Kowall, MD), P30 AG072977 (PI Robert Vassar, PhD), P30 AG066519 (PI Frank LaFerla, PhD), P30 AG062677 (PI Ronald Petersen, MD, PhD), P30 AG079280 (PI Eric Reiman, MD), P30 AG062422 (PI Gil Rabinovici, MD), P30 AG066511 (PI Allan Levey, MD, PhD), P30 AG072946 (PI Linda Van Eldik, PhD), P30 AG062715 (PI Sanjay Asthana, MD, FRCP), P30 AG072973 (PI Russell Swerdlow, MD), P30 AG066506 (PI Todd Golde, MD, PhD), P30 AG066508 (PI Stephen Strittmatter, MD, PhD), P30 AG066515 (PI Victor Henderson, MD, MS), P30 AG072947 (PI Suzanne Craft, PhD), P30 AG072931 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053 (PI Justin Miller, PhD), P20 AG068077 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD).

  • Competing interests GB is currently an employee of SciNeuro Pharmaceuticals. All other authors declare that they have no conflicts of interest with the content of this article.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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