{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T03:22:15Z","timestamp":1791861735755,"version":"4.3.4"},"reference-count":75,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,12,18]],"date-time":"2015-12-18T00:00:00Z","timestamp":1450396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild\u2010moderate AD patients, and in a subgroup of 16 we evaluated rest\u2013activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross\u2010sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid \u03b2 (A\u03b2) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age\u2010matched controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrated an age\u2010related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (<jats:italic>p<\/jats:italic>\u2009=\u20090.038), more evident in the superior quadrant (<jats:italic>p<\/jats:italic>\u2009=\u20090.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (<jats:italic>p<\/jats:italic>\u2009=\u20090.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (<jats:italic>p<\/jats:italic>\u2009=\u20090.003) across all ages and abnormal mRGC dendritic morphology and size (<jats:italic>p<\/jats:italic>\u2009=\u20090.003). In flat\u2010mounted AD retinas, A\u03b2 accumulation was remarkably evident inside and around mRGCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>We show variable degrees of rest\u2013activity circadian dysfunction in AD patients. We also demonstrate age\u2010related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with A\u03b2 deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD. 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