Association Between Choroidal Microvasculature in the Eye and Alzheimer's Disease Risk in Cognitively Healthy Midlife Adults

Objective: To explore associations between measurements of the ocular microvasculature in the choroid (a highly vascularised layer posterior to the retina) and genetic Alzheimer's disease risk. Methods: We measured the choroidal vasculature appearing in optical coherence tomography scans of 69 healthy, mid-life individuals in the PREVENT cohort. The cohort was prospectively split into low, medium, and high-risk groups based on the presence of known risk factors (APOE4 genotype and family history of dementia). We used ordinal logistic regression to test for cross-sectional associations between choroidal measurements and pre-determined risk of future Alzheimer's disease. Results: We observed progressively increased choroidal vasculature between ordinal risk groups, and all choroidal measurements were significantly associated with risk group prediction. APOE4 carriers had significantly thicker choroids and larger vascular tissue compared to non-carriers. Similar trends were observed for those with a family history of dementia. In our sample, a 0.16 mm2 increase in choroidal vascular area was associated with a 2-fold increase in the likelihood of having one or more markers of Alzheimer's disease risk, compared with none. Conclusions: Our results suggest a potential link between the choroidal vasculature and risk of Alzheimer's disease. However, these findings are exploratory and should be replicated in a larger, more diverse sample. ### Competing Interest Statement J.Burke, S. Gibbon, A. Low, C. Hamid, M. Reid‐Schachter, G. Muniz‐Terrera, C. W. Ritchie, B. Dhillon, J. T. O'Brien, S. King, I. J. C. MacCormick and T. J. MacGillivray report no disclosures relevant to the manuscript. Author disclosures are available in the supporting information. ### Funding Statement The PREVENT dementia Programme is funded by the Alzheimer's Society (grant numbers 178, 264 and 329), Alzheimer's Association (grant number TriBEKa-17-519007) and philanthropic donations. This work was supported by the Alzheimer's Drug Discovery Foundation (project no. GDAPB-201808-2016196, "Delivering novel neuro-retinal biomarkers for the early diagnosis of Alzheimer's disease"); NHS Lothian R and D; and British Heart Foundation Centre for Research Excellence Award III (RE/18/5/34216). The funding sources were not involved in designing, conducting, or submitting this work. We would like to acknowledge with special thanks to the PREVENT participants, the participant panel, members of the Scientific Advisory Committee, and funders for their support of the PREVENT dementia programme. J. Burke was supported by the Medical Research Council (grant MR/N013166/1) as part of the Doctoral Training Programme in Precision Medicine at the Usher Institute, University of Edinburgh. S. Gibbon was supported by the UK Biotechnology and Biological Sciences Research Council as part of the EASTBIO Doctoral Training Programme at the University of Edinburgh [grant number: BB/M010996/1]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The PREVENT Dementia programme received multi-site ethical approval from the UK London-Camberwell St Giles National Health Service (NHS) Research Ethics Committee (REC reference: 12/LO/1023, IRAS project ID: 88938), which operates according to the Helsinki Declaration of 1975 (and as revised in 1983). All substantial protocol amendments have been reviewed by the same ethics committees and favourable opinion was granted before implementation at sites. The retinal sub study in Edinburgh was approved by the South East Scotland Research Ethics Committee (15/SS/0146) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The PREVENT dataset is available to access through a data request on the study website (www.preventdementia.co.uk); on the Alzheimer's Disease Data Initiative (ADDI) platform baseline dataset DOI: https://doi.org/10.34688/PREVENTMAIN\_BASELINE\_700V1; Dementia Platforms UK (DPUK); and the Global Alzheimer's Association Network (GAAIN). [https://doi.org/10.34688/PREVENTMAIN\_BASELINE\_700V1][1] [1]: https://doi.org/10.34688/PREVENTMAIN_BASELINE_700V1