Afferent and Efferent Visual Markers of Alzheimer's Disease: A Review and Update in Early Stage Disease

Abstract

Vision, which requires extensive neural involvement, is often impaired in Alzheimer's disease (AD). Over the last few decades, accumulating evidence has shown that various visual functions and structures are compromised in Alzheimer's dementia and when measured can detect those with dementia from those with normal aging. These visual changes involve both the afferent and efferent parts of the visual system, which correspond to the sensory and eye movement aspects of vision, respectively. There are fewer, but a growing number of studies, that focus on the detection of predementia stages. Visual biomarkers that detect these stages are paramount in the development of successful disease-modifying therapies by identifying appropriate research participants and in identifying those who would receive future therapies. This review provides a summary and update on common afferent and efferent visual markers of AD with a focus on mild cognitive impairment (MCI) and preclinical disease detection. We further propose future directions in this area. Given the ease of performing visual tests, the accessibility of the eye, and advances in ocular technology, visual measures have the potential to be effective, practical, and non-invasive biomarkers of AD.

Keywords: Alzheimer’s disease; afferent visual system; efferent visual system; mild cognitive impairment; optical coherence tomography; pupillometry; saccadic eye movement; visual biomarkers.

Figure 1

(A) Afferent visual system; visual information is initially captured by light-sensitive photoreceptors in the retina and transmitted through the optic nerve and then optic tract, which directly synapses on the lateral geniculate nucleus (LGN) of the thalamus. From the LGN, the optic radiations carry information to the primary visual cortex in the occipital lobe for initial visual processing and then multiple extra-striate cortices for higher-level processing (not pictured here). (B) Efferent visual system; To initiate a saccade, excitatory signals from cortical regions such as the frontal, parietal, and supplementary eye fields (FEF, PEF, SEF) are sent to the superior colliculus (SC) in the brainstem, which then projects to the saccade burst generator in the reticular formation. The FEF initiates voluntary and memory-guided saccades, the PEF initiates reflexive saccades, and the SEF initiates saccades that correlate with body movement. In the indirect pathway, the substantia nigra pars reticulata (SNPR) in the basal ganglia sends inhibitory signals to the SC to inhibit a saccade. To override the indirect pathway, the FEF is activated before the saccade generation, which inhibits the SNPR through the caudate nucleus (CN). The dorsolateral prefrontal cortex (DLPFC) helps modulate anti-saccades by inhibiting reflexive saccades and generating subsequent voluntary saccades away from a presented stimulus. Excitatory signals are shown in green and inhibitory signals in red.