Autosomal dominant Alzheimer's disease (ADAD) is a rare form of Alzheimer's disease (AD) in which the biology of the disease can be explored during the presymptomatic phase of the illness. The retina is an outgrowth of the central nervous system and therefore provides the opportunity for direct observation of neural tissue and its vasculature during life. Retinal thinning measured in vivo has been previously described in persons carrying ADAD mutations through fundoscopy but its pathologic correlates have not been reported. We describe retinal lesions detected using fundoscopy in vivo in a patient homozygous for the A431E mutation in PSEN1 and its pathological correlates. Retinal lesions seen with fundoscopy during life corresponded to intraretinal and prelaminar optic nerve head amyloid β42-protein that were surrounded by perivascular anti-11A50-B10-Aβ40 and gliosis. We then performed a cross-sectional, observational study of forty-one Latinos in three cohorts consisting of (1) persons with ADAD causing mutations, (2) at 50% risk for, but testing negative for ADAD mutations, and (3) elderly subjects not at-risk for ADAD. Clinical exam demonstrated novel, yellow, intraretinal lesions in Cohort 1 in absence of drusen. Fifty-six percent of Cohort 1 subjects had >10 retinal lesions compared to 0% and 25% for Cohorts 2 and 3, respectively (P < 0.04). There has been some controversy as to the detectability of Aβ in the retina of persons with AD during life and our findings verify the presence of intraretinal, prelaminar, and perivascular amyloidosis detectable during life in a subset of AD patients

AHK is a consultant and recipient of research funding/materials from Carl Zeiss Meditec and consultant to Regenxbio, Aspen Biosciences and Alcon. JMR is a DMC member of Renew Group Private Limited and a consultant for InnoSense. YK and MKH are co-founding members and minor shareholders of NeuroVision Imaging Inc. The other authors report no competing interests.

AHK and JMR are supported by R01EY030564, U01AG051218, UH3NS100614, and R01AG062007. MKH and YK are supported by the National Institutes of Health (NIH)/National Institute on Aging (NIA) grants: R01AG056478, R01AG075998, and R01AG055865, as well as supported by The Hertz Innovation Fund, and the Gordon, Jona Goldrich, and Haim Saban Private Foundations.

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:

IRB of Johns Hopkins Medicine gave ethical approval for this work

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).

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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

Data from this manuscript are available for review based on written requests for non-commercial use, with appropriate IRB approval and legitimate research goals. Since retinal images are considered inherently identifiable and there are very few subjects with or at risk for ADAD some images may not be sharable to protect subject privacy.