Peripheral Retinal and Choroidal Vascular Changes in Down Syndrome: Insights into Early Alzheimer’s Disease Pathology?

Description

Invited speaker and panelist at the DSAD-ADAD conference in Barcelona, Spain:

BACKGROUND: Changes in retinal and choroidal vasculature seen in Alzheimer’s Disease (AD) continuum proposed as a non-invasive, cost-effective CNS proxy for clinical trials. However, these changes are not fully identified in individuals with Down Syndrome (DS), the largest genetically predisposed group for AD.
METHODS: We performed multimodal eye imaging on 24 adults with DS prior to clinical dementia onset and 17 euploid controls. The imaging protocols included ultra-widefield imaging (Optos, California) and optical coherence tomography (Spectralis, Heidelberg). The images were analyzed for central and peripheral retinal vascular changes using the VAMPIRE software and a series of home-built ImageJ plugins.
RESULTS: The mean age was 39 ± 7 years in the DS and 36 ± 9 years in the control group. Females comprised 37.5% of the DS and 52.9% of the control group. Among the DS participants, 47.4% had mild, while 52.6% had moderate intellectual disability. The DS retinas exhibited supernumerary vessels (β=2.53, 95%CI:1.38 to 3.67, P<0.001) that were wider (β=16.9µm, 95%CI:10.8 to 23.0, P<0.001) and thinned more rapidly along their paths (β=-0.66µm/mm, 95%CI:-1.08 to -0.24, P=0.002). There was a more complex central retinal vascular tree (β=0.03, 95%CI:0.01 to 0.04, P<0.001) and a less complex peripheral network (β=-0.03, 95%CI:-0.05 to -0.006, P=0.016), with increased numbers of peripheral microaneurysms and hemorrhages (57.9% vs 11.8%, P=0.004) compared to controls. The choroid, which serves as the primary blood supply to the outer retina, exhibited reduced vascularity in DS (β=-8.97, 95%CI:-12.7 to -5.24, P<0.001).
DISCUSSION: Our findings in the DS cohort suggest that retinal and choroidal vascular involvement may play a role in the early development of AD pathology. Peripheral vascular changes, including microaneurysms and hemorrhages observed in DS, warrant further investigation, particularly regarding their potential link to cerebral microbleeds. We hypothesize that the microvascular abnormalities detected in the far-peripheral retina in our DS cohort may result from blood vessel damage caused by amyloid angiopathy. These changes could potentially serve as biomarkers for patient stratification in future clinical trials.

Period	23 May 2025
Held at	DSAD-ADAD, Spain