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APOE4 is the greatest genetic risk factor for late-onset Alzheimer's disease (AD), increasing the risk of developing the disease by 3-fold in the 14% of the population that are carriers. Despite 25 years of research, the exact mechanisms underlying how APOE4 contributes to AD pathogenesis remain incompletely defined. APOE in the brain is primarily expressed by astrocytes and microglia, cell types that are now widely appreciated to play key roles in the pathogenesis of AD; thus, a picture is emerging wherein APOE4 disrupts normal glial cell biology, intersecting with changes that occur during normal aging to ultimately cause neurodegeneration and cognitive dysfunction. This review article will summarize how APOE4 alters specific pathways in astrocytes and microglia in the context of AD and the aging brain. APOE itself, as a secreted lipoprotein without enzymatic activity, may prove challenging to directly target therapeutically in the classical sense. Therefore, a deeper understanding of the underlying pathways responsible for APOE4 toxicity is needed so that more tractable pathways and drug targets can be identified to reduce APOE4-mediated disease risk.

Estrogen has well-documented neuroprotective effects in a variety of clinical and experimental disorders of the CNS, including autoimmune inflammation, traumatic injury, stroke, and neurodegenerative diseases. The beneficial effects of estrogens in CNS disorders include mitigation of clinical symptoms, as well as attenuation of histopathological signs of neurodegeneration and inflammation. The cellular mechanisms that underlie these CNS effects of estrogens are uncertain, because a number of different cell types express estrogen receptors in the peripheral immune system and the CNS. Here, we investigated the potential roles of two endogenous CNS cell types in estrogen-mediated neuroprotection. We selectively deleted estrogen receptor-α (ERα) from either neurons or astrocytes using well-characterized Cre-loxP systems for conditional gene knockout in mice, and studied the effects of these conditional gene deletions on ERα ligand-mediated neuroprotective effects in a well-characterized model of adoptive experimental autoimmune encephalomyelitis (EAE). We found that the pronounced and significant neuroprotective effects of systemic treatment with ERα ligand on clinical function, CNS inflammation, and axonal loss during EAE were completely prevented by conditional deletion of ERα from astrocytes, whereas conditional deletion of ERα from neurons had no significant effect. These findings show that signaling through ERα in astrocytes, but not through ERα in neurons, is essential for the beneficial effects of ERα ligand in EAE. Our findings reveal a unique cellular mechanism for estrogen-mediated CNS neuroprotective effects by signaling through astrocytes, and have implications for understanding the pathophysiology of sex hormone effects in diverse CNS disorders.

Trafficking defects in retinal pigmented epithelial (RPE) cells contribute to RPE atrophy, a hallmark of geographic atrophy (GA) in dry age-related macular degeneration (AMD). Dry AMD pathogenesis is multifactorial, including amyloid-β (Aβ) accumulation and oxidative stress—common features of Alzheimer’s disease (AD). The Sigma-2 receptor (S2R) regulates lipid and protein trafficking, and S2R modulators reverse trafficking deficits in neurodegeneration in vitro models. Given overlapping mechanisms contributing to AD and AMD, S2R modulator effects on RPE function were investigated. The S2R modulator CT1812 is in clinical trials for AD, dementia with Lewy bodies, and GA. Leveraging AD trials testing CT1812, unbiased analyses of patient biofluid proteomes revealed that proteins altered by CT1812 associated with GA and macular degeneration disease ontologies and overlapped with proteins altered in dry AMD. Differential expression analysis of RPE transcripts from APP-Swedish/London mutant transgenic mice, a model featuring Aβ accumulation, revealed reversal of autophagy/trafficking transcripts in S2R modulator-treated animals versus vehicle toward healthy control levels. Photoreceptor outer segment (POS) trafficking in human RPE cells showed deficits in response to Aβ 1−42 or hydrogen peroxide compared to vehicle. S2R modulators normalized stressor-induced POS trafficking deficits, resembling healthy control. Taken together, S2R modulation may provide a novel therapeutic strategy for dry AMD.

Background Effective, disease-modifying therapeutics for the treatment of Alzheimer’s disease (AD) remain a large unmet need. Extensive evidence suggests that amyloid beta (Aβ) is central to AD pathophysiology, and Aβ oligomers are among the most toxic forms of Aβ. CT1812 is a novel brain penetrant sigma-2 receptor ligand that interferes with the binding of Aβ oligomers to neurons. Preclinical studies of CT1812 have demonstrated its ability to displace Aβ oligomers from neurons, restore synapses in cell cultures, and improve cognitive measures in mouse models of AD. CT1812 was found to be generally safe and well tolerated in a placebo-controlled phase 1 clinical trial in healthy volunteers and phase 1a/2 clinical trials in patients with mild to moderate dementia due to AD. The unique objective of this study was to incorporate synaptic positron emission tomography (PET) imaging as an outcome measure for CT1812 in AD patients. Methods The present phase 1/2 study was a randomized, double-blind, placebo-controlled, parallel-group trial conducted in 23 participants with mild to moderate dementia due to AD to primarily evaluate the safety of CT1812 and secondarily its pharmacodynamic effects. Participants received either placebo or 100 mg or 300 mg per day of oral CT1812 for 24 weeks. Pharmacodynamic effects were assessed using the exploratory efficacy endpoints synaptic vesicle glycoprotein 2A (SV2A) PET, fluorodeoxyglucose (FDG) PET, volumetric MRI, cognitive clinical measures, as well as cerebrospinal fluid (CSF) biomarkers of AD pathology and synaptic degeneration. Results No treatment differences relative to placebo were observed in the change from baseline at 24 weeks in either SV2A or FDG PET signal, the cognitive clinical rating scales, or in CSF biomarkers. Composite region volumetric MRI revealed a trend towards tissue preservation in participants treated with either dose of CT1812, and nominally significant differences with both doses of CT1812 compared to placebo were found in the pericentral, prefrontal, and hippocampal cortices. CT1812 was safe and well tolerated. Conclusions The safety findings of this 24-week study and the observed changes on volumetric MRI with CT1812 support its further clinical development. Trial registration The clinical trial described in this manuscript is registered at clinicaltrials.gov (NCT03493282).

INTRODUCTION CT1812 (zervimesine) is an orally dosed modulator of the sigma‐2 receptor (S2R) currently in clinical development for the treatment of Alzheimer's disease (AD). CT1812 has been shown in preclinical and early clinical trials to selectively prevent and displace binding of amyloid beta oligomers from their synaptic receptors and has improved cognitive function in animal models of AD. METHODS SEQUEL (NCT04735536) is a completed Phase 2, randomized, placebo‐controlled 4‐week crossover trial in adults with mild‐to‐moderate AD that investigated the effect of CT1812 on safety, synaptic function using quantitative electroencephalography (qEEG), and biomarkers. CT1812 improved established qEEG markers of spontaneous brain activity, suggesting improved neuronal and synaptic function. In the present study, cerebrospinal fluid (CSF)‐based tandem mass tag mass spectrometry (TMT‐MS) was performed on participant samples to investigate proteomic effects and identify potential biomarkers of CT1812. RESULTS Biomarkers found through proteomics analyses to be significantly differentially abundant in CT1812‐ versus placebo‐treated participants supported pathway engagement and proof of mechanism for CT1812. Impacted proteins support a role for CT1812 at synapses, in vesicle trafficking, and in lipoprotein biology. Biomarkers correlated with the previously reported improvements in qEEG‐based functional connectivity (inferred through alpha band Amplitude Envelope Correlations) with CT1812 treatment were also identified and may be potential early surrogate biomarkers of efficacy for CT1812. The processes and functions supported by biomarkers were congruent with those previously revealed in CSF proteomics analyses from phase 1 and 2 AD clinical trials with CT1812. DISCUSSION After 1 month of treatment, the identification of biomarkers supporting pathway engagement, the replication of biomarker findings from prior trials, and the discovery of molecular correlates of improved functional connectivity with CT1812 treatment bolster support for and expound upon the mechanism of action for CT1812 in displacing Aβ oligomers at neuronal synapses, as well as underscores the CT1812 relevance to AD. Highlights Exploratory proteomics identified candidate CSF biomarkers of CT1812 in SEQUEL. Molecular correlates of functional brain connectivity (qEEG) were identified. Proteins impacted by 1 month CT1812 treatment support target engagement. Pharmacodynamic changes found in synapse, immune, vesicle, and lipoprotein biologies. SEQUEL proteomics findings replicated previous trial findings with CT1812.

Reactive astrogliosis has long been recognized as a ubiquitous feature of CNS pathologies. Although its roles in CNS pathology are only beginning to be defined, genetic tools are enabling molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. It is now clear that reactive astrogliosis is not simply an all-or-nothing phenomenon but, rather, is a finely gradated continuum of molecular, cellular, and functional changes that range from subtle alterations in gene expression to scar formation. These changes can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. Dysfunction of either astrocytes or the process of reactive astrogliosis is emerging as an important potential source of mechanisms that might contribute to, or play primary roles in, a host of CNS disorders via loss of normal or gain of abnormal astrocyte activities. A rapidly growing understanding of the mechanisms underlying astrocyte signaling and reactive astrogliosis has the potential to open doors to identifying many molecules that might serve as novel therapeutic targets for a wide range of neurological disorders. This review considers general principles and examines selected examples regarding the potential of targeting specific molecular aspects of reactive astrogliosis for therapeutic manipulations, including regulation of glutamate, reactive oxygen species, and cytokines.

There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by TMEM97, is expressed in brain and retinal cells, and regulates cell functions via its co-receptor progesterone receptor membrane component 1 (PGRMC1), and through other protein–protein interactions. Studies describing functions of S2R involve the manipulation of expression or pharmacological modulation using exogenous small-molecule ligands. These studies demonstrate that S2R modulates key pathways involved in age-related diseases including autophagy, trafficking, oxidative stress, and amyloid-β and α-synuclein toxicity. Furthermore, S2R modulation can ameliorate functional deficits in cell-based and animal models of disease. This review summarizes the current evidence-based understanding of S2R biology and function, and its potential as a therapeutic target for age-related degenerative diseases of the central nervous system, including Alzheimer’s disease, α-synucleinopathies, and dry age-related macular degeneration.

Background Zervimesine (CT1812) is an experimental oral, small‐molecule drug candidate in development for Alzheimer’s disease and dementia with Lewy bodies (DLB). Zervimesine is designed to protect neurons by preventing the binding of oligomers of pathogenic proteins including β‐amyloid and ɑ‐synuclein. Method The COG1201 ‘SHIMMER’ study is the first study to measure tolerability and clinical effects of zervimesine in adults with DLB. The study enrolled 130 individuals with a clinical diagnosis of DLB and MMSE of 18‐27 who were randomized 1:1:1 to receive once‐daily oral doses of zervimesine (100 or 300 mg) or placebo for 26 weeks. Among clinical assessments tools, SHIMMER employed the Neuropsychiatric Inventory (NPI), Alzheimer's Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL) scale and the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. Result Zervimesine‐treated participants experience strong therapeutic responses across behavioral, functional, cognitive, and movement measures in SHIMMER. At the end of the study period, zervimesine‐treated DLB (n=88) patients progressed 86% slower than placebo‐treated patients (n=42) on the NPI, 52% slower on the ADCS‐ADL and 62% slower on the UPDRS Part III. We intend to present for the first time a detailed characterization of the baseline participant characteristics including demographics, baseline scores on outcome measures, concomitant medications, comorbidities and baseline biomarker levels. Conclusion These data will allow comparison of the SHIMMER population to prior DLB study populations. SHIMMER results support the potential for zervimesine to slow clinical progression in patients with mild‐to‐moderate DLB. The robust therapeutic response observed across neuropsychiatric, cognitive, motor and functional measures is particularly encouraging. An analysis of participant characteristics will help guide recruitment in future clinical studies of zervimesine and its potential use to treat people with DLB. Cognition Therapeutics conducted COG1201 with University of Miami Miller School of Medicine and the Lewy Body Dementia Association under a grant from the National Institute of Aging (R01AG071643).

Background Zervimesine (CT1812) is an experimental oral, small‐molecule drug candidate in development for Alzheimer’s disease (AD) and dementia with Lewy bodies. Zervimesine is designed to protect neuronal synapses by preventing the binding of amyloid beta (Aβ) oligomers. Method The Phase 2 COG0201 ‘SHINE’ clinical trial measured tolerability and clinical effects of zervimesine in adults with amyloid‐positive mild‐to‐moderate AD (MMSE 18 to 26). The study enrolled 153 individuals at 30 U.S. and international sites. Participants were randomized 1:1:1 to receive placebo or one of two doses (100 or 300mg) of oral zervimesine daily for 26 weeks. Patients were assessed using a traditional battery of symptomatic assessments (ADAS‐Cog, MMSE, ADSC‐ADL and CGIC). A pre‐specified analysis evaluated treatment effect relative to placebo based on median plasma p‐tau217 value. Result In the full mITT population in SHINE, zervimesine‐treated participants (n=101) declined 39% less on ADAS‐Cog 11 and 70% less on MMSE relative to placebo (n=49). Participants with plasma p‐tau217 levels below the median of 1.0 pg/mL had an even more robust response. Zervimesine‐treated patients with sub‐median levels of plasma p‐tau217 (n=45) experienced 95% less cognitive decline on ADAS‐Cog 11 and 108% less decline on MMSE vs placebo (n=24). We will present for the first time at AAIC the distribution of plasma p‐tau217 by MMSE severity in SHINE and demonstrate that this enhanced response was similar for patients with MMSE 22‐26 and MMSE 18‐21, encompassing the full range of baseline severity in this study. Conclusion Results from the SHINE study provide compelling evidence that zervimesine has the potential to slow cognitive decline in patients with AD. Participants with lower disease burden, as measured by plasma p‐tau217 experienced a more pronounced treatment effect. Importantly, this benefit was observed in people across the mild‐to‐moderate MMSE spectrum. While preliminary, these results suggest that having a lower disease burden as measured by plasma p‐tau217 may provide a therapeutic window to still treat patients in the moderate MMSE range. SHINE was supported by a grant from the National Institute of Aging (R01AG058660).

Zervimesine (CT1812) is an experimental oral, small-molecule drug candidate in development for Alzheimer's disease and dementia with Lewy bodies (DLB). Zervimesine is designed to protect neurons by preventing the binding of oligomers of pathogenic proteins including β-amyloid and ɑ-synuclein. The COG1201 'SHIMMER' study is the first study to measure tolerability and clinical effects of zervimesine in adults with DLB. The study enrolled 130 individuals with a clinical diagnosis of DLB and MMSE of 18-27 who were randomized 1:1:1 to receive once-daily oral doses of zervimesine (100 or 300 mg) or placebo for 26 weeks. Among clinical assessments tools, SHIMMER employed the Neuropsychiatric Inventory (NPI), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale and the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. Zervimesine-treated participants experience strong therapeutic responses across behavioral, functional, cognitive, and movement measures in SHIMMER. At the end of the study period, zervimesine-treated DLB (n=88) patients progressed 86% slower than placebo-treated patients (n=42) on the NPI, 52% slower on the ADCS-ADL and 62% slower on the UPDRS Part III. We intend to present for the first time a detailed characterization of the baseline participant characteristics including demographics, baseline scores on outcome measures, concomitant medications, comorbidities and baseline biomarker levels. These data will allow comparison of the SHIMMER population to prior DLB study populations. SHIMMER results support the potential for zervimesine to slow clinical progression in patients with mild-to-moderate DLB. The robust therapeutic response observed across neuropsychiatric, cognitive, motor and functional measures is particularly encouraging. An analysis of participant characteristics will help guide recruitment in future clinical studies of zervimesine and its potential use to treat people with DLB. Cognition Therapeutics conducted COG1201 with University of Miami Miller School of Medicine and the Lewy Body Dementia Association under a grant from the National Institute of Aging (R01AG071643).