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Review Open access Sep 2026

Experience-Dependent Plasticity of Large-Scale Brain Networks in Aging: How Different Training Modalities Shape Neural Connectivity.

Brain regions are organized into large-scale networks through dynamic functional connections that support sensorimotor and cognitive processes across the lifespan. Age-related disruptions of these functional systems are associated with cognitive and motor decline and increased risk of neurocognitive disorders. A growing body of evidence suggests that structured physical training can modulate resting-state functional connectivity within these networks, offering a potential neuroprotective strategy. However, the relative efficacy of different training modalities, and the mechanisms by which simultaneous cognitive loading during motor training may confer neuroplastic benefits, remain incompletely characterized. This narrative review critically integrates evidence on network-level changes following cardiorespiratory, resistance and balance training, cognitive stimulation, and combined motor-cognitive interventions (with exergames (i.e., interactive physical and/or motor-cognitive exercises to control traditional or extended reality games) and mind-body practices) in older adults. We critically appraise evidence strength across three methodological tiers: direct neuroimaging (i.e., rs-fMRI), indirect measures (i.e., EEG and fNIRS), and conceptual frameworks, and apply this hierarchy to critically evaluate the guided-plasticity facilitation framework, a working hypothesis proposing synergistic neuroplastic effects when motor and cognitive demands overlap, for which direct neuroimaging support in humans remains limited. Key methodological gaps are identified: scarcity of direct comparison trials, inadequate dose-matching, limited long-term data, and near-absence of dynamic functional connectivity analyses. We outline research priorities to advance a mechanistic, individualized understanding of experience-dependent brain network plasticity in aging and neurocognitive disorders and propose network-level biomarkers as a candidate direction for future personalized training prescriptions. We also outline a prospective precision-medicine framework for exercise prescription in neurocognitive disorders, noting that prospective validation studies are needed before network-level biomarkers can inform clinical decision-making.

F. Gennaro, L. Pini, Maurizio Corbetta et al. · 0 citations
Review Open access Sep 2026

Rethinking tau-targeted therapy in Alzheimer's disease: Toward a dual biomarker strategy.

Tau pathology is more closely associated with cognitive deterioration than amyloid burden in symptomatic Alzheimer's disease (AD), yet tau-targeted trials have often interpreted decreases in soluble phosphorylated tau (p-tau) as evidence of therapeutic success. Emerging data argue for a more biology-informed framework. P-tau262 and p-tau356 identify sites within soluble pre-tangle tau assemblies, and cerebrospinal (CSF) p-tau262 may decline as neurofibrillary pathology advances. Conversely, marked p-tau217 lowering with posdinemab was not accompanied by clinical benefit. The amyloid field offers a useful but incomplete analogy. Amyloid plaques are extracellular whereas tau misfolding and fibrillization occur predominantly intracellularly, so equivalent relationships among imaging, fluid biomarkers, and clinical outcomes should not be assumed. A recent preprint describing a functional plasma assay of pathologically active tau reported high discrimination of tau positron emission tomography (PET) positivity, particularly at early tau PET stages, illustrating how seeding-related activity may add information beyond p-tau concentration. We propose a dual-domain framework in which tau-targeted therapies are evaluated using complementary measures of aggregated tau burden and biologically defined soluble tau states. P-tau262 is one candidate within the soluble domain, but treatment-induced increases should be considered favorable only when they accompany aggregate reduction and evidence of a less pathogenic soluble state. This framework applies across antibodies, antisense oligonucleotides, and other biologic tau-directed strategies. Future trials should test joint biomarker-clinical response functions rather than importing thresholds from anti-amyloid therapy, and should prespecify adequately powered analyses of sex, population background, disease stage, and other potential modifiers.

C. Teunissen, L. Pini, B. Imbimbo · 0 citations

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