PMC:7523471 / 71121-81198 JSONTXT

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and Visual Changes in Alzheimer’s Disease\nAs discussed above, the retina undergoes neuropathological changes similar to the brain in AD patients. This is not surprising given the developmental, physiological, and anatomical similarities between the two tissue types, rendering them vulnerable to AD-related neuronal and functional abnormalities (Byerly and Blackshaw, 2009; London et al., 2013; Jindal, 2015). A host of visual and ocular manifestations were reported in both MCI and AD patients, particularly loss of contrast sensitivity, color discrimination deficits, difficulties with depth and motion perception, circadian rhythm irregularities, and sleep disturbances (Sadun et al., 1987; Katz and Rimmer, 1989; Trick et al., 1989; Cronin-Golomb et al., 1991; Cronin-Golomb, 1995; Lakshminarayanan et al., 1996; Cormack et al., 2000; Rizzo et al., 2000; Pache et al., 2003; Ng et al., 2007; Armstrong, 2009; Salamone et al., 2009; Chang et al., 2014; Nolan et al., 2014; Armstrong and Kergoat, 2015; Salobrar-Garcia et al., 2015; Hart et al., 2016; Javaid et al., 2016; La Morgia et al., 2016; Polo et al., 2017; Cerquera-Jaramillo et al., 2018; Colligris et al., 2018; Risacher et al., 2020). Importantly, retinal changes in AD patients such as RGC degeneration, reduced NFL thickness, and decreased blood circulation were linked to specific visual and ocular disturbances (Hinton et al., 1986; Blanks et al., 1989, 1996a, b; Parisi et al., 2001; Berisha et al., 2007; Paquet et al., 2007; Kesler et al., 2011).\nAlzheimer’s hallmark pathologies Aβ deposits and tauopathy are found in retinal cell types and topographical regions shown to undergo degeneration and physiological abnormalities in both patients and transgenic animal models (Koronyo-Hamaoui et al., 2011; Schön et al., 2012; La Morgia et al., 2016; Koronyo et al., 2017; den Haan et al., 2018; Asanad et al., 2019b; Grimaldi et al., 2019; Habiba et al., 2020; Shi et al., 2020). These findings provide a link between AD-related retinal neuropathology and the visual deficits reported in living patients. For instance, histological examination of retinal tissue shows colocalization of pTau and Aβ pathology in regions associated with RGC loss (Schön et al., 2012; La Morgia et al., 2016; Koronyo et al., 2017; den Haan et al., 2018; Asanad et al., 2019b; Grimaldi et al., 2019; Shi et al., 2020). Specifically, degeneration of RGCs would undoubtedly compromise their essential role in receiving sensory input from photoreceptors via bipolar cells, and in early stages of visual information processing and conveyance to the brain (Demb and Singer, 2015). In support of this, a recent study utilizing OCT and pattern electroretinography (ERG) in AD patients showed a linear relationship between NFL thickness and the bioelectrical integrity of RGCs and their nerve fibers, which are essential for afferent signal transduction (Ngoo et al., 2019).\nIn addition to the above reported changes, irregularities in efferent ocular pathways in conjunction with retinal abnormalities were also associated with altered pupillary light response (PLR) in patients. These alterations include increased latency of pupillary constriction to light, decreased constriction amplitude, faster redilation after light offset, decreased maximum constriction velocity and acceleration (Chougule et al., 2019), and altered pupil dilation response during cognitive tasks (Granholm et al., 2017; Kremen et al., 2019). Therefore, there is growing interest in exploring various aspects of pupillary responses, using specialized pupillometry tools, in pre-clinical and clinically diagnosed AD patients. Further to being governed by both the sympathetic and parasympathetic systems, PLR is also regulated by retinal rods, cones, and mRGCs (Hattar et al., 2003). In line with this, altered PLR in AD patients was associated with retinal mRGC loss (La Morgia et al., 2016), highlighting the consequences of retinal AD pathology for various ocular and visual dysfunctions. Moreover, these intrinsically photosensitive RGCs are also reported to regulate light photoentrainment of circadian rhythms, supported by their tightly regulated communication with photoreceptors and their projections to the central circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) (Lu et al., 1999; Berson et al., 2002; Gooley et al., 2003; Markwell et al., 2010; Chen et al., 2011). Therefore, retinal mRGC loss is suggested to play a key role in the sleep-wake cycle dysfunctions observed in AD patients (La Morgia et al., 2016, 2017). Sleep abnormalities reported in MCI and AD patients include prolonged sleep latency, reduced total sleep duration and rapid eye movement (REM) sleep, sleep fragmentation, frequent awakenings and lower melatonin levels at night, and daytime somnolence (Petit et al., 2004; Ju et al., 2013; Peter-Derex et al., 2015; Feng et al., 2016; La Morgia et al., 2016, 2017; Weissová et al., 2016; Asanad et al., 2019b). Intriguingly, there are reports of sleep disturbances exacerbating or even preceding cognitive impairments (Ju et al., 2014; Bubu et al., 2017; Brzecka et al., 2018). The essential discovery that Aβ accumulates within or in close proximity to mRGCs, which undergo degeneration and dendrite diameter loss, at least in part, can explain impaired sleep patterns and altered pupil dilation in AD patients (La Morgia et al., 2016). These findings also suggest that certain retinal cells are more susceptible to Aβ-induced neurotoxicity and proposes the first retinal damage-based mechanism for functional disturbances commonly seen in AD patients.\nThe spatial distribution of retinal AD pathology may indicate the specific functional deficit. Regionally, both Aβ and pTau pathologies appear to preferentially affect the peripheral superior and inferior retinal quadrants in AD patients (Koronyo-Hamaoui et al., 2011; La Morgia et al., 2016; Koronyo et al., 2017; den Haan et al., 2018). This, along with consistent neuronal loss, degeneration of mRGCs and RGCs, and NFL thinning in these particular peripheral regions, could underlie visual abnormalities such as in contrast sensitivity, motion perception and circadian rhythms described in AD (Trick et al., 1989, 1995; Blanks et al., 1996a; Berisha et al., 2007; Lu et al., 2010; Kesler et al., 2011; Moschos et al., 2012; Ju et al., 2013; Kirbas et al., 2013; Risacher et al., 2013; Kromer et al., 2014; La Morgia et al., 2016). Beyond AD-related manifestations predominantly in the inner layers and peripheral retinal regions, deposits of Aβ were found in close proximity to blood vessels and within vessel walls (Koronyo-Hamaoui et al., 2011; La Morgia et al., 2016; Koronyo et al., 2017; Shi et al., 2020). Furthermore, vascular amyloidosis positively correlated with the degree of vascular PDGFR-β deficiency as well as Aβ40 and Aβ42 alloforms accumulated within degenerating pericytes in MCI and AD retinas (Koronyo et al., 2017; Shi et al., 2020). These findings, together with altered retinal neurovascular coupling and structural vascular abnormalities in clinically diagnosed MCI and AD patients (Berisha et al., 2007; Querques et al., 2019), implicate retinal vascular-associated Aβ in causing or amplifying retinal metabolic dysfunctions and impaired clearance pathways. These changes may lead to functional-visual abnormalities.\nA study in monkeys has recently provided evidence for the involvement of mRGCs in blue color sensitivity (Dacey et al., 2005). AD patients are reported to experience altered color vision with a selective and severity-independent deficiency in blue hue discrimination (Cronin-Golomb et al., 1993; Wijk et al., 1999; Rizzo et al., 2000; Chang et al., 2014; Polo et al., 2017). Interestingly, impaired blue color discrimination also manifests in patients with other neurodegenerative disorders (Paulus et al., 1993; Haug et al., 1995; Birch et al., 1998; Rodnitzky, 1998; Melun et al., 2001; Anssari et al., 2020).\nThe second most common cause of irreversible vision loss is glaucoma, a condition characterized by optic neuropathy, apoptotic RGC degeneration and NFL damage, driven by increased IOP and accumulation of proteinaceous deposits of Aβ and pTau (Cordeiro et al., 2004). Indeed, a higher occurrence of glaucoma was reported in AD patients compared to controls (Bayer et al., 2002; Tamura et al., 2006). Diminished contrast sensitivity, altered motion and depth perception, and oculomotor disturbances in both AD and glaucoma patients are partially attributed to a preferential loss of the functionally relevant magnocellular RGCs (M-cells) and their nerve fibers (Sadun and Bassi, 1990; Fiorentini et al., 1996; La Morgia et al., 2017). Moreover, impaired contrast sensitivity in MCI patients was shown to significantly correlate with the cerebral burden of amyloid and tau pathology (Risacher et al., 2020). Given the higher concentration of rods in the peripheral retina and their importance in motion and depth perception, low-contrast sensitivity, and peripheral vision, it is not surprising that these visual functions may be adversely influenced by the increased levels of Aβ deposits and pTau in the periphery (Gilmore et al., 1994; Risacher et al., 2013). Cumulative evidence of vision loss and ocular impairments accompanied by progressive retinal changes in AD and other neurodegenerative disorders, including glaucoma, multiple sclerosis (MS), PD, and Huntington’s disease (HD), robustly support the involvement of specific retinal pathologies in functional and visual manifestations of these conditions (Fisher et al., 2006; Gupta et al., 2008; Archibald et al., 2009; Green et al., 2010; London et al., 2013; Kersten et al., 2015; Andrade et al., 2016; Weil et al., 2016; La Morgia et al., 2017).\nDespite many recent advancements, the field of AD retinopathy is still in its infancy and more studies focusing on mechanistic and causative factors are necessary to determine the connection between specific retinal pathologies, neuronal-type impairments and visual-functional deficits."}

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and Visual Changes in Alzheimer’s Disease\nAs discussed above, the retina undergoes neuropathological changes similar to the brain in AD patients. This is not surprising given the developmental, physiological, and anatomical similarities between the two tissue types, rendering them vulnerable to AD-related neuronal and functional abnormalities (Byerly and Blackshaw, 2009; London et al., 2013; Jindal, 2015). A host of visual and ocular manifestations were reported in both MCI and AD patients, particularly loss of contrast sensitivity, color discrimination deficits, difficulties with depth and motion perception, circadian rhythm irregularities, and sleep disturbances (Sadun et al., 1987; Katz and Rimmer, 1989; Trick et al., 1989; Cronin-Golomb et al., 1991; Cronin-Golomb, 1995; Lakshminarayanan et al., 1996; Cormack et al., 2000; Rizzo et al., 2000; Pache et al., 2003; Ng et al., 2007; Armstrong, 2009; Salamone et al., 2009; Chang et al., 2014; Nolan et al., 2014; Armstrong and Kergoat, 2015; Salobrar-Garcia et al., 2015; Hart et al., 2016; Javaid et al., 2016; La Morgia et al., 2016; Polo et al., 2017; Cerquera-Jaramillo et al., 2018; Colligris et al., 2018; Risacher et al., 2020). Importantly, retinal changes in AD patients such as RGC degeneration, reduced NFL thickness, and decreased blood circulation were linked to specific visual and ocular disturbances (Hinton et al., 1986; Blanks et al., 1989, 1996a, b; Parisi et al., 2001; Berisha et al., 2007; Paquet et al., 2007; Kesler et al., 2011).\nAlzheimer’s hallmark pathologies Aβ deposits and tauopathy are found in retinal cell types and topographical regions shown to undergo degeneration and physiological abnormalities in both patients and transgenic animal models (Koronyo-Hamaoui et al., 2011; Schön et al., 2012; La Morgia et al., 2016; Koronyo et al., 2017; den Haan et al., 2018; Asanad et al., 2019b; Grimaldi et al., 2019; Habiba et al., 2020; Shi et al., 2020). These findings provide a link between AD-related retinal neuropathology and the visual deficits reported in living patients. For instance, histological examination of retinal tissue shows colocalization of pTau and Aβ pathology in regions associated with RGC loss (Schön et al., 2012; La Morgia et al., 2016; Koronyo et al., 2017; den Haan et al., 2018; Asanad et al., 2019b; Grimaldi et al., 2019; Shi et al., 2020). Specifically, degeneration of RGCs would undoubtedly compromise their essential role in receiving sensory input from photoreceptors via bipolar cells, and in early stages of visual information processing and conveyance to the brain (Demb and Singer, 2015). In support of this, a recent study utilizing OCT and pattern electroretinography (ERG) in AD patients showed a linear relationship between NFL thickness and the bioelectrical integrity of RGCs and their nerve fibers, which are essential for afferent signal transduction (Ngoo et al., 2019).\nIn addition to the above reported changes, irregularities in efferent ocular pathways in conjunction with retinal abnormalities were also associated with altered pupillary light response (PLR) in patients. These alterations include increased latency of pupillary constriction to light, decreased constriction amplitude, faster redilation after light offset, decreased maximum constriction velocity and acceleration (Chougule et al., 2019), and altered pupil dilation response during cognitive tasks (Granholm et al., 2017; Kremen et al., 2019). Therefore, there is growing interest in exploring various aspects of pupillary responses, using specialized pupillometry tools, in pre-clinical and clinically diagnosed AD patients. Further to being governed by both the sympathetic and parasympathetic systems, PLR is also regulated by retinal rods, cones, and mRGCs (Hattar et al., 2003). In line with this, altered PLR in AD patients was associated with retinal mRGC loss (La Morgia et al., 2016), highlighting the consequences of retinal AD pathology for various ocular and visual dysfunctions. Moreover, these intrinsically photosensitive RGCs are also reported to regulate light photoentrainment of circadian rhythms, supported by their tightly regulated communication with photoreceptors and their projections to the central circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) (Lu et al., 1999; Berson et al., 2002; Gooley et al., 2003; Markwell et al., 2010; Chen et al., 2011). Therefore, retinal mRGC loss is suggested to play a key role in the sleep-wake cycle dysfunctions observed in AD patients (La Morgia et al., 2016, 2017). Sleep abnormalities reported in MCI and AD patients include prolonged sleep latency, reduced total sleep duration and rapid eye movement (REM) sleep, sleep fragmentation, frequent awakenings and lower melatonin levels at night, and daytime somnolence (Petit et al., 2004; Ju et al., 2013; Peter-Derex et al., 2015; Feng et al., 2016; La Morgia et al., 2016, 2017; Weissová et al., 2016; Asanad et al., 2019b). Intriguingly, there are reports of sleep disturbances exacerbating or even preceding cognitive impairments (Ju et al., 2014; Bubu et al., 2017; Brzecka et al., 2018). The essential discovery that Aβ accumulates within or in close proximity to mRGCs, which undergo degeneration and dendrite diameter loss, at least in part, can explain impaired sleep patterns and altered pupil dilation in AD patients (La Morgia et al., 2016). These findings also suggest that certain retinal cells are more susceptible to Aβ-induced neurotoxicity and proposes the first retinal damage-based mechanism for functional disturbances commonly seen in AD patients.\nThe spatial distribution of retinal AD pathology may indicate the specific functional deficit. Regionally, both Aβ and pTau pathologies appear to preferentially affect the peripheral superior and inferior retinal quadrants in AD patients (Koronyo-Hamaoui et al., 2011; La Morgia et al., 2016; Koronyo et al., 2017; den Haan et al., 2018). This, along with consistent neuronal loss, degeneration of mRGCs and RGCs, and NFL thinning in these particular peripheral regions, could underlie visual abnormalities such as in contrast sensitivity, motion perception and circadian rhythms described in AD (Trick et al., 1989, 1995; Blanks et al., 1996a; Berisha et al., 2007; Lu et al., 2010; Kesler et al., 2011; Moschos et al., 2012; Ju et al., 2013; Kirbas et al., 2013; Risacher et al., 2013; Kromer et al., 2014; La Morgia et al., 2016). Beyond AD-related manifestations predominantly in the inner layers and peripheral retinal regions, deposits of Aβ were found in close proximity to blood vessels and within vessel walls (Koronyo-Hamaoui et al., 2011; La Morgia et al., 2016; Koronyo et al., 2017; Shi et al., 2020). Furthermore, vascular amyloidosis positively correlated with the degree of vascular PDGFR-β deficiency as well as Aβ40 and Aβ42 alloforms accumulated within degenerating pericytes in MCI and AD retinas (Koronyo et al., 2017; Shi et al., 2020). These findings, together with altered retinal neurovascular coupling and structural vascular abnormalities in clinically diagnosed MCI and AD patients (Berisha et al., 2007; Querques et al., 2019), implicate retinal vascular-associated Aβ in causing or amplifying retinal metabolic dysfunctions and impaired clearance pathways. These changes may lead to functional-visual abnormalities.\nA study in monkeys has recently provided evidence for the involvement of mRGCs in blue color sensitivity (Dacey et al., 2005). AD patients are reported to experience altered color vision with a selective and severity-independent deficiency in blue hue discrimination (Cronin-Golomb et al., 1993; Wijk et al., 1999; Rizzo et al., 2000; Chang et al., 2014; Polo et al., 2017). Interestingly, impaired blue color discrimination also manifests in patients with other neurodegenerative disorders (Paulus et al., 1993; Haug et al., 1995; Birch et al., 1998; Rodnitzky, 1998; Melun et al., 2001; Anssari et al., 2020).\nThe second most common cause of irreversible vision loss is glaucoma, a condition characterized by optic neuropathy, apoptotic RGC degeneration and NFL damage, driven by increased IOP and accumulation of proteinaceous deposits of Aβ and pTau (Cordeiro et al., 2004). Indeed, a higher occurrence of glaucoma was reported in AD patients compared to controls (Bayer et al., 2002; Tamura et al., 2006). Diminished contrast sensitivity, altered motion and depth perception, and oculomotor disturbances in both AD and glaucoma patients are partially attributed to a preferential loss of the functionally relevant magnocellular RGCs (M-cells) and their nerve fibers (Sadun and Bassi, 1990; Fiorentini et al., 1996; La Morgia et al., 2017). Moreover, impaired contrast sensitivity in MCI patients was shown to significantly correlate with the cerebral burden of amyloid and tau pathology (Risacher et al., 2020). Given the higher concentration of rods in the peripheral retina and their importance in motion and depth perception, low-contrast sensitivity, and peripheral vision, it is not surprising that these visual functions may be adversely influenced by the increased levels of Aβ deposits and pTau in the periphery (Gilmore et al., 1994; Risacher et al., 2013). Cumulative evidence of vision loss and ocular impairments accompanied by progressive retinal changes in AD and other neurodegenerative disorders, including glaucoma, multiple sclerosis (MS), PD, and Huntington’s disease (HD), robustly support the involvement of specific retinal pathologies in functional and visual manifestations of these conditions (Fisher et al., 2006; Gupta et al., 2008; Archibald et al., 2009; Green et al., 2010; London et al., 2013; Kersten et al., 2015; Andrade et al., 2016; Weil et al., 2016; La Morgia et al., 2017).\nDespite many recent advancements, the field of AD retinopathy is still in its infancy and more studies focusing on mechanistic and causative factors are necessary to determine the connection between specific retinal pathologies, neuronal-type impairments and visual-functional deficits."}

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span":{"begin":9719,"end":9723},"obj":"26233693"},{"id":"33041751-26853218-816849","span":{"begin":9741,"end":9745},"obj":"26853218"},{"id":"33041751-27412389-816850","span":{"begin":9760,"end":9764},"obj":"27412389"},{"id":"33041751-28522986-816851","span":{"begin":9784,"end":9788},"obj":"28522986"}],"text":"Functional and Visual Changes in Alzheimer’s Disease\nAs discussed above, the retina undergoes neuropathological changes similar to the brain in AD patients. This is not surprising given the developmental, physiological, and anatomical similarities between the two tissue types, rendering them vulnerable to AD-related neuronal and functional abnormalities (Byerly and Blackshaw, 2009; London et al., 2013; Jindal, 2015). A host of visual and ocular manifestations were reported in both MCI and AD patients, particularly loss of contrast sensitivity, color discrimination deficits, difficulties with depth and motion perception, circadian rhythm irregularities, and sleep disturbances (Sadun et al., 1987; Katz and Rimmer, 1989; Trick et al., 1989; Cronin-Golomb et al., 1991; Cronin-Golomb, 1995; Lakshminarayanan et al., 1996; Cormack et al., 2000; Rizzo et al., 2000; Pache et al., 2003; Ng et al., 2007; Armstrong, 2009; Salamone et al., 2009; Chang et al., 2014; Nolan et al., 2014; Armstrong and Kergoat, 2015; Salobrar-Garcia et al., 2015; Hart et al., 2016; Javaid et al., 2016; La Morgia et al., 2016; Polo et al., 2017; Cerquera-Jaramillo et al., 2018; Colligris et al., 2018; Risacher et al., 2020). Importantly, retinal changes in AD patients such as RGC degeneration, reduced NFL thickness, and decreased blood circulation were linked to specific visual and ocular disturbances (Hinton et al., 1986; Blanks et al., 1989, 1996a, b; Parisi et al., 2001; Berisha et al., 2007; Paquet et al., 2007; Kesler et al., 2011).\nAlzheimer’s hallmark pathologies Aβ deposits and tauopathy are found in retinal cell types and topographical regions shown to undergo degeneration and physiological abnormalities in both patients and transgenic animal models (Koronyo-Hamaoui et al., 2011; Schön et al., 2012; La Morgia et al., 2016; Koronyo et al., 2017; den Haan et al., 2018; Asanad et al., 2019b; Grimaldi et al., 2019; Habiba et al., 2020; Shi et al., 2020). These findings provide a link between AD-related retinal neuropathology and the visual deficits reported in living patients. For instance, histological examination of retinal tissue shows colocalization of pTau and Aβ pathology in regions associated with RGC loss (Schön et al., 2012; La Morgia et al., 2016; Koronyo et al., 2017; den Haan et al., 2018; Asanad et al., 2019b; Grimaldi et al., 2019; Shi et al., 2020). Specifically, degeneration of RGCs would undoubtedly compromise their essential role in receiving sensory input from photoreceptors via bipolar cells, and in early stages of visual information processing and conveyance to the brain (Demb and Singer, 2015). In support of this, a recent study utilizing OCT and pattern electroretinography (ERG) in AD patients showed a linear relationship between NFL thickness and the bioelectrical integrity of RGCs and their nerve fibers, which are essential for afferent signal transduction (Ngoo et al., 2019).\nIn addition to the above reported changes, irregularities in efferent ocular pathways in conjunction with retinal abnormalities were also associated with altered pupillary light response (PLR) in patients. These alterations include increased latency of pupillary constriction to light, decreased constriction amplitude, faster redilation after light offset, decreased maximum constriction velocity and acceleration (Chougule et al., 2019), and altered pupil dilation response during cognitive tasks (Granholm et al., 2017; Kremen et al., 2019). Therefore, there is growing interest in exploring various aspects of pupillary responses, using specialized pupillometry tools, in pre-clinical and clinically diagnosed AD patients. Further to being governed by both the sympathetic and parasympathetic systems, PLR is also regulated by retinal rods, cones, and mRGCs (Hattar et al., 2003). In line with this, altered PLR in AD patients was associated with retinal mRGC loss (La Morgia et al., 2016), highlighting the consequences of retinal AD pathology for various ocular and visual dysfunctions. Moreover, these intrinsically photosensitive RGCs are also reported to regulate light photoentrainment of circadian rhythms, supported by their tightly regulated communication with photoreceptors and their projections to the central circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) (Lu et al., 1999; Berson et al., 2002; Gooley et al., 2003; Markwell et al., 2010; Chen et al., 2011). Therefore, retinal mRGC loss is suggested to play a key role in the sleep-wake cycle dysfunctions observed in AD patients (La Morgia et al., 2016, 2017). Sleep abnormalities reported in MCI and AD patients include prolonged sleep latency, reduced total sleep duration and rapid eye movement (REM) sleep, sleep fragmentation, frequent awakenings and lower melatonin levels at night, and daytime somnolence (Petit et al., 2004; Ju et al., 2013; Peter-Derex et al., 2015; Feng et al., 2016; La Morgia et al., 2016, 2017; Weissová et al., 2016; Asanad et al., 2019b). Intriguingly, there are reports of sleep disturbances exacerbating or even preceding cognitive impairments (Ju et al., 2014; Bubu et al., 2017; Brzecka et al., 2018). The essential discovery that Aβ accumulates within or in close proximity to mRGCs, which undergo degeneration and dendrite diameter loss, at least in part, can explain impaired sleep patterns and altered pupil dilation in AD patients (La Morgia et al., 2016). These findings also suggest that certain retinal cells are more susceptible to Aβ-induced neurotoxicity and proposes the first retinal damage-based mechanism for functional disturbances commonly seen in AD patients.\nThe spatial distribution of retinal AD pathology may indicate the specific functional deficit. Regionally, both Aβ and pTau pathologies appear to preferentially affect the peripheral superior and inferior retinal quadrants in AD patients (Koronyo-Hamaoui et al., 2011; La Morgia et al., 2016; Koronyo et al., 2017; den Haan et al., 2018). This, along with consistent neuronal loss, degeneration of mRGCs and RGCs, and NFL thinning in these particular peripheral regions, could underlie visual abnormalities such as in contrast sensitivity, motion perception and circadian rhythms described in AD (Trick et al., 1989, 1995; Blanks et al., 1996a; Berisha et al., 2007; Lu et al., 2010; Kesler et al., 2011; Moschos et al., 2012; Ju et al., 2013; Kirbas et al., 2013; Risacher et al., 2013; Kromer et al., 2014; La Morgia et al., 2016). Beyond AD-related manifestations predominantly in the inner layers and peripheral retinal regions, deposits of Aβ were found in close proximity to blood vessels and within vessel walls (Koronyo-Hamaoui et al., 2011; La Morgia et al., 2016; Koronyo et al., 2017; Shi et al., 2020). Furthermore, vascular amyloidosis positively correlated with the degree of vascular PDGFR-β deficiency as well as Aβ40 and Aβ42 alloforms accumulated within degenerating pericytes in MCI and AD retinas (Koronyo et al., 2017; Shi et al., 2020). These findings, together with altered retinal neurovascular coupling and structural vascular abnormalities in clinically diagnosed MCI and AD patients (Berisha et al., 2007; Querques et al., 2019), implicate retinal vascular-associated Aβ in causing or amplifying retinal metabolic dysfunctions and impaired clearance pathways. These changes may lead to functional-visual abnormalities.\nA study in monkeys has recently provided evidence for the involvement of mRGCs in blue color sensitivity (Dacey et al., 2005). AD patients are reported to experience altered color vision with a selective and severity-independent deficiency in blue hue discrimination (Cronin-Golomb et al., 1993; Wijk et al., 1999; Rizzo et al., 2000; Chang et al., 2014; Polo et al., 2017). Interestingly, impaired blue color discrimination also manifests in patients with other neurodegenerative disorders (Paulus et al., 1993; Haug et al., 1995; Birch et al., 1998; Rodnitzky, 1998; Melun et al., 2001; Anssari et al., 2020).\nThe second most common cause of irreversible vision loss is glaucoma, a condition characterized by optic neuropathy, apoptotic RGC degeneration and NFL damage, driven by increased IOP and accumulation of proteinaceous deposits of Aβ and pTau (Cordeiro et al., 2004). Indeed, a higher occurrence of glaucoma was reported in AD patients compared to controls (Bayer et al., 2002; Tamura et al., 2006). Diminished contrast sensitivity, altered motion and depth perception, and oculomotor disturbances in both AD and glaucoma patients are partially attributed to a preferential loss of the functionally relevant magnocellular RGCs (M-cells) and their nerve fibers (Sadun and Bassi, 1990; Fiorentini et al., 1996; La Morgia et al., 2017). Moreover, impaired contrast sensitivity in MCI patients was shown to significantly correlate with the cerebral burden of amyloid and tau pathology (Risacher et al., 2020). Given the higher concentration of rods in the peripheral retina and their importance in motion and depth perception, low-contrast sensitivity, and peripheral vision, it is not surprising that these visual functions may be adversely influenced by the increased levels of Aβ deposits and pTau in the periphery (Gilmore et al., 1994; Risacher et al., 2013). Cumulative evidence of vision loss and ocular impairments accompanied by progressive retinal changes in AD and other neurodegenerative disorders, including glaucoma, multiple sclerosis (MS), PD, and Huntington’s disease (HD), robustly support the involvement of specific retinal pathologies in functional and visual manifestations of these conditions (Fisher et al., 2006; Gupta et al., 2008; Archibald et al., 2009; Green et al., 2010; London et al., 2013; Kersten et al., 2015; Andrade et al., 2016; Weil et al., 2016; La Morgia et al., 2017).\nDespite many recent advancements, the field of AD retinopathy is still in its infancy and more studies focusing on mechanistic and causative factors are necessary to determine the connection between specific retinal pathologies, neuronal-type impairments and visual-functional deficits."}