Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms

Abstract

IMPORTANCE 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. Optical coherence tomography (OCT) has surfaced as a potential noninvasive technique capable of analyzing central nervous system tissues for biomarkers of Alzheimer disease.OBJECTIVE To evaluate whether OCT can detect early retinal alterations in carriers of the presenilin 1 (PSEN1 [OMIM 104311]) E280A mutation who are cognitively unimpaired. DESIGN, SETTING, AND PARTICIPANTSA cross-sectional imaging study conducted from July 13, 2015, to September 16, 2020, included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired and 10 healthy noncarrier family members, all leveraged from a homogenous Colombian kindred. Statistical analysis was conducted from September 9, 2017, to September 16, 2020.MAIN OUTCOMES AND MEASURES Mixed-effects multiple linear regression was performed to compare the thickness values of the whole retina and individual retinal layers on OCT scans between mutation carriers and noncarriers. Simple linear-effects and mixed-effects multiple linear regression models were used to assess whether age was an effect modifier for PSEN1 mutation of amyloid β levels and retinal thickness, respectively. Fundus photographs were used to compare the number of arterial and venous branch points, arterial and venous tortuosity, and fractal dimension. RESULTSThis study included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired (7 women [70%]; mean [SD] age, 36.3 [8.1] years) and 10 healthy noncarrier family members (7 women [70%]; mean [SD] age, 36.4 [8.2] years). Compared with noncarrier controls, PSEN1 mutation carriers who were cognitively unimpaired had a generalized decrease in thickness of the whole retina as well as individual layers detected on OCT scans, with 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) showing 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. No statistical difference was detected in any of the vascular parameters studied.CONCLUSIONS AND RELEVANCE 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.

Retinal pathological features and proteome signatures of Alzheimer’s disease

“…Hence, Aβ 42 may be an early pathological marker in AD retinas, comparable to brain amyloid pathology, and may be used to facilitate early diagnosis. Interestingly, given that we identified similar retinal changes in persons with familial AD due to PSEN1 mutations, our data support similarities between downstream retinal manifestations in autosomal dominant and sporadic AD, despite the fact that the initiating pathogenic events are distinct [3,104].…”

Retinotopic degeneration of the retina and optic tracts in autosomal dominant Alzheimer's disease

“…When we removed these four subjects from the data set, the findings and significance of the results were similar. To address the limited number of family‐matched controls within our consecutively recruited cohort, we compared retinal thickness and sublayer thickness between our cohort and a recently published cohort of Latinx subjects at risk for ADAD ( PSEN1 E280A mutation) and unaffected family members 23 . These groups serve as good controls because of similarity in mean age, ethnicity, and familial relationship to subjects with ADAD‐causing mutations.…”

“…For example, comparisons of cerebrospinal fluid Aβ42, Aβ40, tau, and phosphorylated tau between carriers of pathogenic variants of ADAD and subjects with LOAD demonstrate similar biomarker profiles and rates of cognitive decline 22 . Retinal imaging of asymptomatic ADAD subjects also demonstrates thinning that is similar to RNFL and GCIPL thinning in mild cognitive impairment (MCI) and LOAD 23,24 . Therefore, ADAD is a valuable model for studying AD biomarkers particularly because subjects with ADAD are young and lack confounding comorbid disease observed in LOAD.…”

The Progress of Label-Free Optical Imaging in Alzheimer’s Disease Screening and Diagnosis

“…In an attempt to assess the early diagnosis potential of OCT, Armstrong et al (2021) spent 5 years recruiting ten carriers with PSEN1 gene mutation, which is the critical causative gene mutation of familiar early onset AD. Compared with the noncarrier group, the PSEN1 mutation carriers showed a significant decrease in the retinal thickness of outer superior quadrant, outer nasal quadrant, outer temporal quadrant, inner superior quadrant, inner inferior quadrant, inner temporal quadrant, and some other individual retinal layers.…”