Morphological and functional alteration of light perception circuits in AD patients

Disruption of sleep and circadian rhythms is one of the earliest symptoms of Alzheimer’s disease (AD). Circadian entrainment and the modulation of alertness are non-visual responses to light driven by intrinsically photosensitive retinal ganglion cells (ipRGCs). However, little is known about ipRGCs in the context of AD. To explore structural and functional changes of ipRGCs and ipRGC circuits, we analyzed the retinas and brains of 13 elderly patients (9 males, 4 females, aged 69-103) ranging from normal to neuropathologically defined AD.

We performed extracellular electrophysiological recordings on freshly harvested retinas using multi-electrode arrays. While rod and cone responses were moderately affected, we found a decreased density of ipRGCs in donors with advanced AD pathology, which was confirmed by immunostaining. The remaining ipRGCs displayed morphological alterations as well as abnormal responses to light, including hyperexcitability. These changes appeared to be subtype-specific and correlated with the advancement of the disease.

Altered ipRGCs circuits and function could contribute to the disruption of sleep and circadian rhythms reported in AD patients. The measurement of ipRGC-dependent responses to light could constitute a promising tool to predict or monitor pathological changes in the brain.