The path to next-generation disease-modifying immunomodulatory combination therapies in Alzheimer’s disease

The cautious optimism following recent anti-amyloid therapeutic trials for Alzheimer's disease (AD) provides a glimmer of hope after years of disappointment. Although these encouraging results represent discernible progress, they also highlight the need to enhance further the still modest clinical efficacy of current disease-modifying immunotherapies. Here, we highlight crucial milestones essential for advancing precision medicine in AD. These include reevaluating the choice of therapeutic targets by considering the key role of both central neuroinflammation and peripheral immunity in disease pathogenesis, refining patient stratification by further defining the inflammatory component within the forthcoming ATN(I) (amyloid, tau and neurodegeneration (and inflammation)) classification of AD biomarkers and defining more accurate clinical outcomes and prognostic biomarkers that better reflect disease heterogeneity. Next-generation immunotherapies will need to go beyond the current antibody-only approach by simultaneously targeting pathological proteins together with innate neuroinflammation and/or peripheral–central immune crosstalk. Such innovative immunomodulatory combination therapy approaches should be evaluated in appropriately redesigned clinical therapeutic trials, which must carefully integrate the neuroimmune component. Looking beyond anti-amyloid immunotherapy in Alzheimer's disease, the authors discuss innovative next-generation immunomodulatory combination therapies jointly targeting pathogenic proteins and peripheral–central immune crosstalk.