Lecanemab in Early Alzheimer’s Disease

Dyck, Christopher H. van; Swanson, Chad J.; Aisen, Paul S.; Bateman, Randall J.; Chen, Christopher; Gee, Michelle; Kanekiyo, Michio; Li, David; Reyderman, Larisa; Cohen, Sharon; Froelich, Lutz; Katayama, Sadao; Sabbagh, Marwan; Vellas, Bruno; Watson, David; Dhadda, Shobha; Irizarry, Michael C.; Kramer, Lynn D.; Iwatsubo, Takeshi

doi:10.1056/nejmoa2212948

Cited by 1,538 publications

(1,502 citation statements)

References 25 publications

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“…Aducanumab (Aduhelm ® ) was approved by the FDA in 2021 and has been reported to be able to reduce Aβ aggregation and improve cognition 68 . More recently, results from a double-blind phase 3 clinical trial using another monoclonal antibody, Lecanemab, demonstrated that this drug that targets soluble Aβ soluble protofibrils could reduce cognitive decline in the early stages of AD 69 . This evidence suggested that targeting to reduce Aβ accumulation could delay or reverse neuronal damage and dementia and thus could be a potential AD treatment.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Characterization of Cerebral Hemodynamics in the TgF344-AD Rat Model of Alzheimer’s Disease

Fang

Tang

Zhang

et al. 2022

Preprint

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Alzheimer's Disease (AD) is a global healthcare crisis. The TgF344-AD rat is an AD model exhibiting age-dependent AD pathological hallmarks. We confirmed that AD rats developed cognitive deficits at 6 months without alteration of any other major biophysical parameters. We longitudinally characterized cerebral hemodynamics in AD rats at 3, 4, 6, and 14 months. The myogenic responses of the cerebral arteries and arterioles were impaired at 4 months of age in the AD rats. Consistent with the ex vivo results, the AD rat exhibited poor autoregulation of surface and deep cortical cerebral blood flow two months preceding cognitive decline. The dysfunction of cerebral hemodynamics in AD is exacerbated with age associated with reduced cerebral perfusion. Further, abolished cell contractility contributes to cerebral hemodynamics imbalance in AD. This may be attributed to enhanced ROS production, reduced mitochondrial respiration and ATP production, and disrupted actin cytoskeleton in cerebral vascular contractile cells.

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Section: Discussionmentioning

confidence: 99%

Longitudinal Characterization of Cerebral Hemodynamics in the TgF344-AD Rat Model of Alzheimer’s Disease

Fang

Tang

Zhang

et al. 2022

Preprint

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“…These would be exposed in population B fibrils. An unstructured N-terminus is likely recognized by lecanemab, a therapeutic antibody that has recently yielded significant improvements in reducing cognitive decline in a phase three clinical trial, although with significant side effects involving brain edema and hemorrhaging 60 . The observation that population B fibrils are identical to fibrils found in parenchymal amyloid suggests that lecanemab binding to vascular amyloid results in amyloid disaggregation and disruption of the blood vessel walls leading to hemorrhaging.…”

Section: Discussionmentioning

confidence: 99%

An electrostatic cluster guides Aβ40 fibril formation in cerebral amyloid angiopathy

Crooks

Irizarry

et al. 2022

Preprint

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Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar A[beta]; peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to disease progression in Alzheimers disease (AD). We investigate the structure of human-derived A[beta]40 fibrils obtained from patients diagnosed with sporadic or familial Dutch-type (E22Q) CAA. Using cryo-EM, two primary structures are identified containing elements that have not been observed in in vitro A[beta]40 fibril structures. One population has an ordered N-terminal fold comprised of two [beta]-strands stabilized by electrostatic interactions involving D1, E22, D23 and K28. This charged cluster is disrupted in the second population, which exhibits a disordered N-terminus and is favored in fibrils derived from the familial Dutch-type CAA patient. These results illustrate differences between human-derived CAA and AD fibrils, and how familial CAA mutations guide fibril formation.

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“…Current clinical data suggest that the robust plaque removal observed for aducanumab, lecanemab, gantenerumab and donanemab is associated with a reduction in the rate of decline on composite scores of cognition and function for at least three of these mAbs [91][92][93][94]. Despite reaching statistical significance, the observed reductions in clinical decline associated with these therapies are, however, small, raising concerns as to whether treatment effect is clinically meaningful or not [98].…”

Section: Subject Idmentioning

confidence: 99%

“…aducanumab [87], lecanemab [88] and gantenerumab [89]) or specificity for an Aβ species unique to plaques (e.g. donanemab that targets pyroglutamated Aβ [90]) will be less affected by non-aggregated peripheral and central Aβ; indeed, they have been shown to effectively reduce plaques in treated patients [91][92][93][94].…”

Section: Subject Idmentioning

confidence: 99%

Aβ42 oligomer-specific antibody ALZ-201 reduces the neurotoxicity of Alzheimer’s disease brain extracts

Sandberg¹,

Berenjeno‐Correa

Rodriguez

et al. 2022

Alz Res Therapy

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Background In Alzheimer’s disease (AD), amyloid-β 1–42 (Aβ42) neurotoxicity stems mostly from its soluble oligomeric aggregates. Studies of such aggregates have been hampered by the lack of oligomer-specific research tools and their intrinsic instability and heterogeneity. Here, we developed a monoclonal antibody with a unique oligomer-specific binding profile (ALZ-201) using oligomer-stabilising technology. Subsequently, we assessed the etiological relevance of the Aβ targeted by ALZ-201 on physiologically derived, toxic Aβ using extracts from post-mortem brains of AD patients and controls in primary mouse neuron cultures. Methods Mice were immunised with stable oligomers derived from the Aβ42 peptide with A21C/A30C mutations (AβCC), and ALZ-201 was developed using hybridoma technology. Specificity for the oligomeric form of the Aβ42CC antigen and Aβ42 was confirmed using ELISA, and non-reactivity against plaques by immunohistochemistry (IHC). The antibody’s potential for cross-protective activity against pathological Aβ was evaluated in brain tissue samples from 10 individuals confirmed as AD (n=7) and non-AD (n=3) with IHC staining for Aβ and phosphorylated tau (p-Tau) aggregates. Brain extracts were prepared and immunodepleted using the positive control 4G8 antibody, ALZ-201 or an isotype control to ALZ-201. Fractions were biochemically characterised, and toxicity assays were performed in primary mouse neuronal cultures using automated high-content microscopy. Results AD brain extracts proved to be more toxic than controls as demonstrated by neuronal loss and morphological determinants (e.g. synapse density and measures of neurite complexity). Immunodepletion using 4G8 reduced Aβ levels in both AD and control samples compared to ALZ-201 or the isotype control, which showed no significant difference. Importantly, despite the differential effect on the total Aβ content, the neuroprotective effects of 4G8 and ALZ-201 immunodepletion were similar, whereas the isotype control showed no effect. Conclusions ALZ-201 depletes a toxic species in post-mortem AD brain extracts causing a positive physiological and protective impact on the integrity and morphology of mouse neurons. Its unique specificity indicates that a low-abundant, soluble Aβ42 oligomer may account for much of the neurotoxicity in AD. This critical attribute identifies the potential of ALZ-201 as a novel drug candidate for achieving a true, clinical therapeutic effect in AD.

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Lecanemab in Early Alzheimer’s Disease

Cited by 1,538 publications

References 25 publications

Longitudinal Characterization of Cerebral Hemodynamics in the TgF344-AD Rat Model of Alzheimer’s Disease

Longitudinal Characterization of Cerebral Hemodynamics in the TgF344-AD Rat Model of Alzheimer’s Disease

An electrostatic cluster guides Aβ40 fibril formation in cerebral amyloid angiopathy

Aβ42 oligomer-specific antibody ALZ-201 reduces the neurotoxicity of Alzheimer’s disease brain extracts

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