Study: OCT Detects Retinal Changes in Familial Alzheimer Disease Mutation

Investigators show how retinal biomarkers as imaged using optical coherence tomography is associated with early-onset familial Alzheimer disease.

Optical coherence tomography (OCT) detected significant thinning of the inner nuclear layer and outer plexiform layer of the retina in patients with early-onset familial Alzheimer disease compared with a control group — even before onset of cognitive decline, according to a study published in JAMA Ophthalmology.

Research demonstrates that OCT can detect pathologic retinal changes in non-inherited forms of Alzheimer disease. In the cross-sectional imaging study conducted between 2015-2020, researchers set out to see if OCT can also detect retinal alterations in the cognitively unaffected carriers of one mutation, presenilin 1 (PSEN1 [OMIM 104311]) E280A.

“Individuals with autosomal dominant mutations for Alzheimer disease are valuable in determining biomarkers present prior to the onset of cognitive decline, improving the ability to diagnose Alzheimer disease as early as possible,” noted the investigators. “[OCT] has surfaced as a potential noninvasive technique capable of analyzing central nervous system tissues for biomarkers of Alzheimer disease.”

Researchers looked at 10 carriers of the PSEN1 E280A mutation (7 women; mean [SD] age, 36.3 [8.1] years) who were cognitively unimpaired and 10 healthy noncarrier family members (7 women; mean [SD] age, 36.4 [8.2] years) from a Colombian family. Analysis was part of a prospective observational study on early-onset Alzheimer disease at Massachusetts Eye and Ear and Massachusetts General Hospital, both of Harvard Medical School, Boston, Massachusetts, and the Group of Neuroscience of Antioquia, University of Antioquia, Antioquia, Colombia.

They performed mixed-effects multiple linear regression, comparing the thickness values of the whole retina and individual retina layers of mutation carriers and noncarriers. They used simple linear-effects and mixed-effects multiple linear regression models to assess if age was an effect modifier for the mutation of β levels and retinal thickness. Fundus photographs were used for additional comparisons.

When compared with noncarrier controls, researchers found that PSEN1 mutation carriers with unaffected cognitive abilities had a generalized decrease in their whole retina’s thickness and its individual layers. In fact, the inner nuclear layer (outer superior quadrant, β = –3.06; P =.007; outer inferior quadrant, β = –2.60; P =.02), outer plexiform layer (outer superior quadrant, β = –3.44; P =.03), and outer nuclear layer (central quadrant, β = –8.61; P = .03; inner nasal quadrant, β = –8.39; P =.04; inner temporal quadrant, β = –9.39; P =.02) had the greatest amount of statistically significant thinning. 

“Age was a significant effect modifier for the association between PSEN1 mutation and amyloid β levels in cortical regions (β = 0.03; P =.001) but not for the association between PSEN1 mutation and retinal thickness,” the investigators reported. “No statistical difference was detected in any of the vascular parameters studied.”

Results could assist clinicians, they noted: “These findings suggest that OCT can detect functional and morphologic changes in the retina of carriers of familial Alzheimer disease who are cognitively unimpaired several years before clinical onset, suggesting that OCT findings and retinal vascular parameters may be biomarkers prior to the onset of cognitive decline.”

But more cohort studies with larger sample sizes will be needed to confirm if OCT could “be used as an early biomarker to identify cognitively normal individuals at higher risk” for Alzheimer disease, investigators reported.

The study’s authors noted a few limitations. They include the fact that it was conducted in 1 family with early-onset disease. Additionally, their findings likely can’t be extrapolated to late-onset and other Alzheimer disease mutations. And, the small sample size, while challenging to expand in those with rarer early-onset familial Alzheimer disease, still limits its statistical power. 


Armstrong GW, Kim LA, Vingopoulos F, et al. Retinal imaging findings in carriers with psen1-associated early-onset familial alzheimer disease before onset of cognitive symptoms. JAMA Ophthalmology. Published online November 12, 2020. doi:10.1001/jamaophthalmol.2020.4909