Altered ipRGC circuits and function may translate to disrupted sleep and circadian rhythms in Alzheimer’s disease

A new European study reported that disturbances in sleep and circadian rhythms may result from changes in the intrinsically photosensitive retinal ganglion cells (ipRGCs) in patients with Alzheimer’s disease.¹ The investigators led by first author Nicolae Sanda, MD, PhD, reported their results in Communication Biology. He is from Fribourg Cantonal Hospital, Neurology Department, Fribourg, Switzerland, and the Department of Clinical Neurosciences, Geneva University, Geneva, Switzerland.

Sanda and colleagues explained, “One of the earliest symptoms in Alzheimer’s disease is a disruption of sleep and circadian rhythms. Individuals with Alzheimer’s often experience increasingly fragmented sleep and an altered core body temperature rhythm.^2-5 There is now abundant evidence that disruption of the daily rhythms can occur years before the emergence of classical symptoms, such as memory loss in Alzheimer’s disease.^6,7 Excessive daytime sleepiness and sleep behavior disorders are associated with an increased risk of developing AD and dementia suggesting that dysregulation of sleep may be important in the early pathogenesis of neurodegeneration.^8-11

Alzheimer’s disease study methodology

The investigators evaluated the changes in the structure and function of the ipRGCs and ipRGC circuits in postmortem retinal and brain tissue from 13 elderly patients with different stages of Alzheimer’s disease and in normal subjects. Ex vivo electrophysiologic recordings were performed on newly harvested retinas to study the alterations in light perception in patients with Alzheimer’s disease compared to normal individuals.

What did the investigators find in the retinal analyses?

Sanda and colleagues reported that the retinal tissue from the donors with Alzheimer’s disease showed severe loss of ipRGCs. “We found that ipRGC-mediated photoreception was severely altered in Alzheimer’s disease,” they said. However, the rods and cones were normal.

“The remaining ipRGCs exhibited morphologic alterations, hyperexcitability, and were not able to sustain high levels of activation. These changes may be ipRGC subtype-specific and vary across donors with pathological severity. Altered ipRGC circuits and function could contribute to the disruption of sleep and circadian rhythms reported in patients with Alzheimer’s disease. These changes may have been subtype-specific and associated with pathological severity,” the authors reported.

They pointed out that the small size of the study sample may have impacted the results and emphasized that more studies of the ipRGCs are needed to manage symptoms associated with ipRGC-mediated responses to light, develop diagnostic tools, design novel therapeutic strategies and, more generally, to unravel early the pathophysiologic mechanisms leading to neuronal degeneration in Alzheimer’s disease.

Sanda and colleagues concluded, “Despite the limitations, the present study provides a first glimpse of the pathophysiologic mechanisms of neurodegeneration at work in humans. Quantitative studies in larger cohorts and animal models of Alzheimer’s disease will be necessary to confirm these results and mechanistically dissect the processes underlying ipRGC vulnerability to Alzheimer’s disease. This work has the potential to influence both Alzheimer’s disease research and clinical practice by highlighting the retina as a window into brain pathology.”

References
1. Sanda N, Mila D, Kovari E, et al. Functional and morphological alterations of light detection circuits in postmortem retina from donors with different stages of Alzheimer’s-like pathology. Comm Biol. 2026; https://doi.org/10.1038/s42003-026-10465-9
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