Early visual alterations in individuals at-risk of Alzheimer's disease: a multidisciplinary approach

Abstract

Background: The earliest pathological features of Alzheimer's disease (AD) appear decades before the clinical symptoms. The pathology affects the brain and the eye, leading to retinal structural changes and functional visual alterations. Healthy individuals at high risk of developing AD present alterations in these ophthalmological measures, as well as in resting-state electrophysiological activity. However, it is unknown whether the ophthalmological alterations are related to the visual-related electrophysiological activity. Elucidating this relationship is paramount to understand the mechanisms underlying the early deterioration of the system and an important step in assessing the suitability of these measures as early biomarkers of disease.

Methods: In total, 144 healthy subjects: 105 with family history of AD and 39 without, underwent ophthalmologic analysis, magnetoencephalography recording, and genotyping. A subdivision was made to compare groups with less demographic and more risk differences: 28 high-risk subjects (relatives/APOEɛ4 +) and 16 low-risk (non-relatives/APOEɛ4 -). Differences in visual acuity, contrast sensitivity, and macular thickness were evaluated. Correlations between each variable and visual-related electrophysiological measures (M100 latency and time-frequency power) were calculated for each group.

Results: High-risk groups showed increased visual acuity. Visual acuity was also related to a lower M100 latency and a greater power time-frequency cluster in the high-risk group. Low-risk groups did not show this relationship. High-risk groups presented trends towards a greater contrast sensitivity that did not remain significant after correction for multiple comparisons. The highest-risk group showed trends towards the thinning of the inner plexiform and inner nuclear layers that did not remain significant after correction. The correlation between contrast sensitivity and macular thickness, and the electrophysiological measures were not significant after correction. The difference between the high- and low- risk groups correlations was no significant.

Conclusions: To our knowledge, this paper is the first of its kind, assessing the relationship between ophthalmological and electrophysiological measures in healthy subjects at distinct levels of risk of AD. The results are novel and unexpected, showing an increase in visual acuity among high-risk subjects, who also exhibit a relationship between this measure and visual-related electrophysiological activity. These results have not been previously explored and could constitute a useful object of research as biomarkers for early detection and the evaluation of potential interventions' effectiveness.

Keywords: Alzheimer’s disease; At risk for AD; Magnetoencephalography; Optical coherence tomography; Visual function.

Fig. 1

Flow diagram of study participants. The participants without family history of AD (FH −) and non-carriers of ApoE ɛ4 (ApoE ɛ4 −) in green and the participants with family history of AD (FH +) and carriers of ApoE ɛ4 (ApoE ɛ4 +) in red

Fig. 2

M100 latency. A Grand-averaged power at the calcarine fissure. B Grand-averaged power in the brain at 100 ms

Fig. 3

Visual response related time–frequency analysis. A Grand-averaged TF representation in the sensor space. B Grand-averaged TF representation in the sensors inside the A rectangles. C Grand-averaged TF representation in the source space (calcarine cortex). Rectangles in A indicate the sensors in which the activity is best perceived. Rectangles in B and C indicate the TF range in which the activity is more prevalent, which is later used for the analysis

Fig. 4

Cluster-based permutation test for the relationships of TF activity with visual function. Blue colors indicate negative correlations, while yellow colors indicate positive correlations. The time–frequency-sensor triplets pertaining to the significant cluster are shown in solid colors. A Correlation between visual acuity and TF in the FH + group (sensors); B correlation between visual acuity and TF in the FH + _40-60ɛ4+ group (sensors); C correlation between visual acuity and TF in the FH + group (calcarine); D correlation between visual acuity and TF in the FH + _40-60ɛ4+ group (calcarine)

Fig. 5

Colorimetric differences in the retinal thickness in each layer between the groups. FH + _40-60ɛ4+ vs FH − _40-60ɛ4− in the macular OCT rings. In red, thickening; in blue, thinning. (RNFL: retinal nerve fiber layer; GCL: ganglion cell layer; IPL: inner plexiform layer; INL: inner nuclear layer; OPL: outer plexiform layer; ONL: outer nuclear layer; RPE: retinal pigment epithelium). * p < 0.05. Wilcoxon rank sum test with continuity correction. The significance is lost after correction for multiple comparisons