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Cognitive decline and diabetes: a systematic review of the neuropathological correlates accounting for cognition at death
  1. Gina Hadley1,2,
  2. Jiali Zhang3,
  3. Eva Harris-Skillman2,
  4. Zoi Alexopoulou3,
  5. Gabriele C DeLuca2,4,
  6. Sarah T Pendlebury1,4,5
  1. 1 Departments of General (internal) Medicine and Geratology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  2. 2 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
  3. 3 St Anne's College, University of Oxford, Oxford, UK
  4. 4 NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK
  5. 5 Wolfson Centre for Prevention of Stroke and Dementia, Wolfson Building, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
  1. Correspondence to Professor Sarah T Pendlebury, Wolfson Centre for Prevention of Stroke and Dementia, Oxford University, Oxford OX3 9DU, UK; sarah.pendlebury{at}


Given conflicting findings in epidemiologic studies, we determined the relative contributions of different neuropathologies to the excess risk of cognitive decline in diabetes mellitus (DM) through a systematic review of the literature. Included studies compared subjects with and without DM and reported neuropathological outcomes accounting for cognition at death. Data on Alzheimer’s disease (AD) pathology, cerebrovascular disease and non-vascular, non-AD pathology were extracted from each study. Eleven studies (n=6 prospective cohorts, n=5 retrospective post-mortem series, total n=6330) met inclusion criteria. All 11 studies quantified AD changes and 10/11 measured cerebrovascular disease: macroscopic lesions (n=9), microinfarcts (n=8), cerebral amyloid angiopathy (CAA, n=7), lacunes (n=6), white matter disease (n=5), haemorrhages (n=4), microbleeds (n=1), hippocampal microvasculature (n=1). Other pathology was infrequently examined. No study reported increased AD pathology in DM, three studies showed a decrease (n=872) and four (n= 4018) showed no difference, after adjustment for cognition at death. No study reported reduced cerebrovascular pathology in DM. Three studies (n=2345) reported an increase in large infarcts, lacunes and microinfarcts. One study found lower cognitive scores in DM compared to non-DM subjects despite similar cerebrovascular and AD-pathology load suggesting contributions from other neuropathological processes. In conclusion, lack of an association between DM and AD-related neuropathology was consistent across studies, irrespective of methodology. In contrast to AD, DM was associated with increased large and small vessel disease. Data on other pathologies such as non-AD neurodegeneration, and blood-brain-barrier breakdown were lacking. Further studies evaluating relative contributions of different neuropathologies to the excess risk of DM are needed.

  • diabetes
  • cognition
  • Alzheimer's disease
  • vascular dementia
  • neuropathology

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  • Contributors GH searched the literature, examined available studies, extracted the data and led the review process. JZ reviewed available studies, extracted the data, analysed the results and cowrote the paper. EH-S extracted the data and analysed the results. ZA participated in the literature search, contributed to and reviewed the paper. GH and STP wrote the paper. GCD reviewed and made critical revisions of the paper. STP and GCD conceived the original idea for this study.

  • Funding GCD and STP are supported by the National Institutes of Health Research Biomedical Research Centre (BRC), Oxford.

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.