Active and passive immunotherapy for neurodegenerative disorders has been a focus of research since successful mouse models of Alzheimer's disease (AD) showed promise. Early human trials of active amyloid-beta (Aβ) vaccination faced safety issues, including meningoencephalitis in 6% of participants. However, preliminary data and ongoing research have led to alternative, potentially safer immunotherapeutic approaches for various neurodegenerative conditions. Despite progress, the mechanisms underlying these therapies remain unclear, with potential roles for antibody-induced phagocytosis, direct disruption of aggregates, neutralization of toxic proteins, and immune responses. Active Aβ vaccination in transgenic mice showed benefits in reducing plaque pathology and improving behavior. However, human trials, such as the AN1792 trial, faced safety concerns, including meningoencephalitis. Although some patients showed cognitive stabilization, the trial was halted due to adverse events. Passive vaccination using monoclonal antibodies also showed promise in reducing Aβ plaques and improving behavior in mice, but effects on plaque pathology and behavior were not always correlated. Potential mechanisms of immunotherapy include antibody-mediated phagocytosis, direct disruption of Aβ aggregates, and neutralization of toxic soluble Aβ species. Some studies suggest that anti-Aβ antibodies may act as peripheral sinks, preventing Aβ transport into the brain. Other mechanisms, such as cell-mediated immune responses, may also contribute to plaque clearance. Passive vaccination strategies, such as using monoclonal antibodies, have shown promise in preclinical models, but safety concerns, including intracerebral hemorrhage, remain. Active vaccination strategies are still considered viable, with ongoing trials. FDA-approved immunotherapeutics, such as intravenous immunoglobulin, have been explored for AD treatment. Future directions include identifying preclinical models that predict clinical efficacy, accelerating clinical trials, and understanding the economic feasibility of long-term immunotherapy. The field of neurodegenerative immunotherapy is still in its early stages, with much research needed to develop safe and effective treatments.Active and passive immunotherapy for neurodegenerative disorders has been a focus of research since successful mouse models of Alzheimer's disease (AD) showed promise. Early human trials of active amyloid-beta (Aβ) vaccination faced safety issues, including meningoencephalitis in 6% of participants. However, preliminary data and ongoing research have led to alternative, potentially safer immunotherapeutic approaches for various neurodegenerative conditions. Despite progress, the mechanisms underlying these therapies remain unclear, with potential roles for antibody-induced phagocytosis, direct disruption of aggregates, neutralization of toxic proteins, and immune responses. Active Aβ vaccination in transgenic mice showed benefits in reducing plaque pathology and improving behavior. However, human trials, such as the AN1792 trial, faced safety concerns, including meningoencephalitis. Although some patients showed cognitive stabilization, the trial was halted due to adverse events. Passive vaccination using monoclonal antibodies also showed promise in reducing Aβ plaques and improving behavior in mice, but effects on plaque pathology and behavior were not always correlated. Potential mechanisms of immunotherapy include antibody-mediated phagocytosis, direct disruption of Aβ aggregates, and neutralization of toxic soluble Aβ species. Some studies suggest that anti-Aβ antibodies may act as peripheral sinks, preventing Aβ transport into the brain. Other mechanisms, such as cell-mediated immune responses, may also contribute to plaque clearance. Passive vaccination strategies, such as using monoclonal antibodies, have shown promise in preclinical models, but safety concerns, including intracerebral hemorrhage, remain. Active vaccination strategies are still considered viable, with ongoing trials. FDA-approved immunotherapeutics, such as intravenous immunoglobulin, have been explored for AD treatment. Future directions include identifying preclinical models that predict clinical efficacy, accelerating clinical trials, and understanding the economic feasibility of long-term immunotherapy. The field of neurodegenerative immunotherapy is still in its early stages, with much research needed to develop safe and effective treatments.