At the molecular level, many dietary compounds modulate oxidative stress and inflammatory signaling, two critical pathways involved in neurodegeneration. Polyphenols—including resveratrol, curcumin, and flavonoids from fruits, tea, and cocoa—scavenge ROS and activate Nrf2, thereby enhancing endogenous antioxidant defense [37]. Concurrently, these compounds suppress NF-κB activation, leading to reduced expression of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and inducible nitric oxide synthase (iNOS) [38, 39].

Omega-3 polyunsaturated fatty acids, particularly docosahexaenoic acid and eicosapentaenoic acid, play pivotal roles in membrane fluidity, synaptic transmission, and the resolution of inflammation via specialized pro-resolving mediators such as resolvins and protectins [40]. Omega-3 supplementation attenuates β-amyloid deposition, improves dopaminergic signaling, and modulates microglial polarization toward neuroprotective phenotypes [41].

Vitamins and minerals—notably vitamins E, C, D, and B-complex, as well as zinc and selenium—also contribute to neuroprotection through antioxidant mechanisms, homocysteine metabolism regulation, and modulation of neurotransmitter synthesis [11, 42]. Deficiencies in these micronutrients have been associated with increased oxidative stress and accelerated cognitive decline [43].

Beyond individual nutrients, dietary patterns provide a more holistic framework for understanding nutritional neuroprotection. The Mediterranean diet, characterized by a high intake of fruits, vegetables, whole grains, olive oil, legumes, and fish, has consistently been linked to a reduced risk of AD, PD, and HD [44, 45]. Its neuroprotective benefits are attributed to the synergistic effects of antioxidants, healthy fats, and anti-inflammatory components, which collectively improve vascular function and reduce neuroinflammation [46].

The ketogenic diet (KD), high in fats and low in carbohydrates, promotes the production of ketone bodies, which serve as alternative energy substrates for neurons and exhibit antioxidant and anti-apoptotic properties [47, 48]. Emerging evidence suggests that KD may improve mitochondrial function, stabilize neuronal networks, and attenuate seizure activity and neuroinflammatory processes [49].

Similarly, the MIND [Mediterranean-Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay] diet, explicitly designed to support cognitive function, emphasizes green leafy vegetables, berries, and whole grains. Prospective studies indicate that greater adherence to MIND diet recommendations is associated with slower cognitive decline and improved memory performance [50].

Recent research highlights the gut–brain axis as a crucial mediator of diet-induced neuroprotection. The gut microbiota communicates with the central nervous system via immune, endocrine, and neural pathways, influencing neuroinflammation, stress reactivity, and neurotransmitter synthesis [51]. Diets rich in prebiotics and probiotics enhance microbial diversity and promote the production of short-chain fatty acids such as butyrate, which possess anti-inflammatory and epigenetic regulatory properties. Dysbiosis, in contrast, has been linked with neuroinflammatory priming and blood–brain barrier disruption in neurodegenerative diseases [52, 53].

Clinical trials and longitudinal cohort studies reinforce the potential of dietary modulation for the prevention and management of neurodegenerative diseases. In AD, adherence to the Mediterranean or MIND diet is associated with delayed onset and slower progression of cognitive impairment [54, 55]. In PD and HD, diets enriched with antioxidants and omega-3 fatty acids correlate with improved motor and non-motor symptoms [56, 57]. Despite these promising findings, heterogeneity in dietary assessment methods, small sample sizes, and short intervention durations limit the generalizability of current results.

Future research should integrate nutrigenomic and metabolomic approaches to elucidate individualized responses to diet and optimize personalized nutritional interventions. Combining dietary modification with other lifestyle strategies—such as physical activity or mindfulness—may yield synergistic effects on neuroprotection, providing a foundation for integrative therapeutic models in neurodegenerative disease care. Within a vitactions framework, dietary patterns are not merely nutritional prescriptions but represent culturally and personally meaningful practices that can support sustained behavioral change and metabolic resilience.

Although epidemiological and longitudinal studies support nutritional strategies such as the Mediterranean and MIND diets, the level of clinical evidence remains heterogeneous. While some interventional studies suggest beneficial effects on cognitive decline and disease progression, others report limited or inconsistent findings, partly due to differences in dietary assessment methods, adherence, and population characteristics. Evidence for specific dietary interventions, such as the KD or micronutrient supplementation, is still emerging and often derived from small-scale or short-term studies. Furthermore, isolating the effects of individual nutrients from broader lifestyle factors remains challenging. These limitations highlight the need for well-controlled clinical trials and standardized dietary intervention protocols.

Current evidence suggests a stronger role in prevention and risk reduction, with more limited and heterogeneous data supporting disease-modifying effects in clinical populations.

Mind–body practices exert neuroprotective effects primarily by regulating the HPA axis and balancing the autonomic nervous system [59]. Chronic stress and hyperactivation of the HPA axis contribute to hippocampal atrophy, neuroinflammation, and glucocorticoid-mediated neurotoxicity—processes that exacerbate neurodegenerative pathology. Mindfulness and meditative practices reduce cortisol secretion, enhance parasympathetic activity (as reflected by increased heart rate variability), and promote functional connectivity within fronto-limbic networks involved in emotion regulation and cognitive control [60, 61].

Functional magnetic resonance imaging (MRI) studies reveal that long-term meditation is associated with increased gray matter density in the hippocampus, prefrontal cortex, and anterior cingulate cortex—regions critical for memory, attention, and executive function [62]. These structural adaptations are accompanied by improved synaptic efficiency and upregulation of neurotrophic factors, such as BDNF, which support neuronal survival and synaptic plasticity. Furthermore, psychosocial interventions can attenuate systemic inflammation by downregulating NF-κB-related pathways and decreasing circulating levels of IL-6, TNF-α, and C-reactive protein [63, 64].

In AD, HD and MCI, mindfulness-based stress reduction (MBSR) and yoga interventions have demonstrated improvements in working memory, processing speed, and emotional well-being. These effects may be mediated by reduced stress reactivity and improved attentional control [65, 66]. In PD, Tai Chi and Qigong enhance balance, motor coordination, and postural stability while reducing fatigue and depressive symptoms. Such multimodal benefits reflect the integration of motor training with proprioceptive feedback and cognitive engagement, which collectively strengthen cortico-striatal connectivity and motor planning circuits [67, 68].

Music therapy has also shown promise as a non-invasive neuromodulatory tool. Listening to or producing music activates dopaminergic reward pathways and sensorimotor networks, leading to improvements in gait rhythm, mood, and motivation in PD, HD, and post-stroke rehabilitation [69, 70]. These effects underscore the role of audiovisual and rhythmic stimulation in enhancing neuroplasticity and functional recovery.

Psychosocial stress, social isolation, and mood disturbances are recognized risk factors for neurodegenerative disease onset and progression [71]. Interventions fostering social engagement, emotional expression, and cognitive stimulation can mitigate these risks and improve quality of life. Group-based mindfulness or movement programs, for example, not only provide cognitive and physical benefits but also enhance perceived social support, reducing loneliness and anxiety—factors closely associated with neuroinflammation and accelerated cognitive decline [72, 73].

Recent studies suggest that positive psychosocial experiences influence epigenetic mechanisms, such as histone acetylation and DNA methylation patterns in genes regulating inflammation and neurotrophic signaling [74]. These findings highlight the potential for mind–body interventions to exert long-term genomic and immunomodulatory effects relevant to neuroprotection.

Studies provide growing evidence that mind–body and psychosocial interventions yield clinically meaningful benefits in patients with AD, PD, and MS. Reported outcomes include improved mood, cognition, motor performance, and sleep quality. However, heterogeneity in study designs, intervention duration, and outcome measures limits direct comparisons across trials [75–77].

Future research should emphasize multimodal approaches that combine mind–body practices with physical exercise, nutritional modification, or sensory therapies to harness synergistic mechanisms. Incorporating digital tools, such as mobile mindfulness applications or virtual reality-based movement therapy, may enhance accessibility and adherence, facilitating the translation of psychosocial interventions into standard neurorehabilitative care. This aligns closely with the vitactions perspective, in which mind–body practices are embedded as intrinsically rewarding activities that reinforce emotional regulation and long-term engagement.

Mind–body interventions demonstrate promising effects on cognitive function, emotional regulation, and quality of life; however, the overall strength of evidence is variable. Many studies are based on small sample sizes, short intervention periods, and heterogeneous methodologies, limiting generalizability. While randomized controlled trials exist for interventions such as MBSR and Tai Chi, findings are not always consistent, and effect sizes are often modest. Additionally, outcomes are frequently based on subjective measures, such as self-reported well-being or mood, which may introduce bias. The lack of standardized intervention protocols and long-term follow-up data further constrains the interpretation of their sustained neuroprotective effects.

These interventions are primarily supported for their symptomatic benefits, with neuroprotective effects inferred largely from mechanistic and preclinical findings.

Sensory stimulation interventions act through multimodal mechanisms involving both bottom-up sensory inputs and top-down cortical modulation. Peripheral sensory activation—via tactile, olfactory, auditory, or visual pathways—elicits widespread neural responses in limbic, hypothalamic, and cortical regions [81, 82]. These responses modulate stress signaling, enhance dopaminergic and serotonergic transmission, and support neurovascular coupling.

Acupuncture, one of the most extensively studied sensory interventions, exerts neuroprotective effects by activating the vagal–adrenal anti-inflammatory axis and modulating microglial polarization [83]. Experimental studies demonstrate that electroacupuncture reduces neuroinflammation, oxidative stress, and neuronal apoptosis by regulating the phosphoinositide 3-kinase Akt signaling (PI3K/Akt) and the Nrf2/HO-1 (heme oxygenase-1) pathways. Moreover, acupuncture enhances cerebral blood flow and synaptic plasticity, thereby improving motor and cognitive performance in animal models of PD and AD [84–86].

Aromatherapy and olfactory stimulation influence neurocognitive and emotional processes via direct projections from the olfactory bulb to limbic structures such as the amygdala and hippocampus [24, 87]. Essential oils rich in monoterpenes (e.g., linalool, 1,8-cineole, limonene) have demonstrated antioxidant, anti-inflammatory, and cholinergic-modulating properties. Studies suggest that inhalation of lavender, rosemary, or bergamot essential oils can reduce anxiety, improve sleep, and enhance cognitive performance in individuals with MCI, effects that may reflect modulation of GABAergic and serotonergic systems [88–91].

Massage therapy and tactile stimulation are associated with reduced stress, anxiety, and cortisol levels, contributing to improved relaxation and overall well-being in clinical populations [92, 93]. These effects can enhance sleep quality, relieve anxiety, and attenuate pain perception—symptoms that commonly worsen neurodegenerative disease burden. Mechanistically, tactile input activates C-tactile afferents, triggering oxytocin release and promoting neuroendocrine stability and emotional well-being [94].

In addition to traditional sensory therapies, non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are gaining attention as potential neuroprotective tools [95]. TMS induces electric currents that modulate cortical excitability and promote synaptic plasticity, particularly in motor and prefrontal regions. Repetitive TMS has demonstrated improvements in motor function and mood in PD and HD, and may enhance cortical connectivity in AD [96, 97].

The therapeutic effects of these techniques are highly dependent on stimulation parameters. In repetitive TMS (rTMS), low-frequency stimulation (≤ 1 Hz) is generally associated with inhibitory effects on cortical excitability, whereas high-frequency stimulation (≥ 5 Hz) enhances excitability [98]. Stimulation intensity is typically defined relative to the individual motor threshold, ensuring both safety and reproducibility. In contrast, tDCS modulates neuronal membrane potentials via weak electrical currents, with anodal stimulation increasing cortical excitability and cathodal stimulation decreasing it [99]. Treatment protocols vary widely in terms of session duration, number of sessions, and cumulative exposure, contributing to heterogeneity in clinical outcomes.

Targeted brain regions play a crucial role in determining therapeutic outcomes. In neurodegenerative disorders, the dorsolateral prefrontal cortex (DLPFC) is frequently targeted to improve cognitive function and mood regulation, particularly in AD and MCI [100]. Stimulation of the primary motor cortex and supplementary motor area has been explored in PD to enhance motor performance and reduce bradykinesia [101]. These region-specific approaches reflect attempts to modulate dysfunctional neural circuits, although optimal targeting strategies remain under investigation.

Similarly, tDCS, by applying weak electrical currents to targeted cortical areas, facilitates long-term potentiation-like mechanisms and may enhance cognitive performance [102]. The neuroprotective potential of these modalities is supported by increased BDNF expression, reduced levels of neuroinflammatory cytokines, and restoration of disrupted neural networks. When combined with behavioral or rehabilitative therapies, NIBS may potentiate functional recovery through activity-dependent synaptic reinforcement [103].

Despite promising findings, several limitations constrain the clinical translation of these techniques. Considerable heterogeneity exists in stimulation protocols, including differences in frequency, intensity, electrode placement, and treatment duration, making comparisons across studies challenging [104]. Small sample sizes, short follow-up periods, and variability in outcome measures limit many clinical trials. Furthermore, inter-individual differences in brain anatomy and disease progression may influence responsiveness to stimulation. As a result, the long-term efficacy and optimal therapeutic parameters of TMS and tDCS remain to be fully established, highlighting the need for standardized, large-scale clinical trials [105].

Emerging research supports the use of multisensory stimulation, which combines visual, auditory, tactile, and olfactory cues to engage distributed brain networks simultaneously. In dementia care, multisensory environments (Snoezelen therapy) have been associated with improved mood, attention, and communication. Similarly, light therapy targeting circadian rhythms can improve sleep–wake regulation and cognitive alertness, particularly in AD and PD [106].

Combining sensory and neuromodulatory strategies with exercise, mindfulness, or nutritional interventions may amplify their effects by engaging overlapping neuroimmune and neuroendocrine pathways. These multimodal approaches can facilitate neuroplastic remodeling, stabilize affective states, and improve quality of life—aligning with a patient-centered model of integrative neuroprotection [8, 42].

While evidence from preclinical and clinical studies supports the neuroprotective potential of sensory and neuromodulatory interventions, methodological heterogeneity and limited sample sizes remain challenges. Standardization of protocols, identification of optimal stimulation parameters, and the use of objective biomarkers (e.g., neuroimaging, electrophysiology, and inflammatory markers) are essential to advancing translational validity.

Future directions should prioritize neurophenotyping approaches to identify responders to specific sensory modalities, leveraging wearable and digital technologies for real-time monitoring. Integration of these interventions into conventional neurorehabilitation could bridge mechanistic understanding and clinical application, positioning sensory and neuromodulatory therapies as valuable complements within comprehensive neuroprotective frameworks. From a vitactions standpoint, these interventions may be particularly valuable when tailored to individual sensory preferences, enhancing both adherence and therapeutic responsiveness.

The evidence supporting sensory and neuromodulatory interventions is evolving but remains less robust than that in other domains. While preclinical studies and early-phase clinical trials suggest beneficial effects on neuroinflammation, neurotransmission, and functional outcomes, high-quality randomized controlled trials are still limited. Techniques such as TMS and tDCS show promising but variable results, with outcomes highly dependent on stimulation parameters and target regions. Similarly, interventions such as aromatherapy, acupuncture, and multisensory stimulation are often supported by small-scale studies with heterogeneous designs and subjective endpoints. This variability underscores the need for standardized protocols, larger clinical trials, and objective biomarkers to establish efficacy and reproducibility better.

Evidence in this domain remains largely preclinical or based on small clinical studies, with symptomatic effects more consistently reported than disease-modifying outcomes.

A summary of the main non-pharmacological interventions, their mechanisms, target populations, and clinical outcomes is presented in Table 1.

Current studies are characterized by wide variability in intervention protocols, intensity, duration, and outcome measures. This heterogeneity limits the ability to compare results and draw firm conclusions regarding dose–response relationships or long-term efficacy [107]. Many trials rely on small samples, short follow-up periods, and subjective endpoints. The absence of standardized biomarkers for neuroprotection—such as validated imaging, electrophysiological, or molecular measures—further complicates interpretation [108]. Future research should adopt multicenter randomized designs, harmonized outcome measures, and biomarker-driven endpoints to enhance reproducibility and clinical relevance.

Another important consideration is the variability in the strength and type of evidence supporting different non-pharmacological interventions. While some approaches—such as physical exercise and certain dietary patterns—are supported by randomized controlled trials and longitudinal studies, others remain primarily grounded in preclinical research or small-scale clinical investigations. In addition, inconsistent findings and occasional negative or neutral results have been reported, often reflecting differences in study design, patient populations, and intervention protocols. This heterogeneity underscores the need for careful interpretation of current evidence and highlights the importance of distinguishing between well-established, emerging, and exploratory interventions in future research.

A critical challenge lies in translating promising preclinical data into clinical practice. Animal models rarely replicate the full complexity of human neurodegenerative disease, and the physiological effects of lifestyle interventions often differ across species. Furthermore, non-pharmacological approaches do not fit neatly into traditional regulatory pathways for drug approval, posing barriers to standardization, quality control, and reimbursement [109, 110]. Collaboration between neuroscientists, clinicians, and regulatory authorities will be necessary to define evaluation frameworks that capture both functional and mechanistic outcomes of these interventions.

The integration of non-pharmacological interventions into standard neurological care remains inconsistent. Clinical implementation requires interdisciplinary models that combine neurology, rehabilitation, nutrition, psychology, and complementary medicine. Effective delivery also depends on training health professionals in evidence-based protocols and ensuring patient adherence through accessible, culturally adapted programs [111]. The incorporation of these interventions into multimodal care pathways could enhance treatment personalization and reduce reliance on pharmacological polytherapy.

Beyond mechanistic alignment and biomarker-driven precision, a patient-centered conceptual lens may further strengthen the translational integration of non-pharmacological therapies. The framework of “vitactions”, recently proposed in the context of neuroprotective therapy, conceptualizes structured, essential “life-actions” as foundational components of prevention and treatment. Rather than viewing non-pharmacological strategies merely as adjunctive prescriptions (e.g., exercise sessions or dietary plans), the vitactions perspective reframes them as inherently meaningful, intrinsically motivating activities embedded within the individual’s daily life context. This approach emphasizes alignment with patient preferences, emotional readiness, and existing routines—factors that critically influence adherence and long-term sustainability [10, 112].

From a translational standpoint, this framework complements mechanistic models by introducing an adherence-centered dimension. Conventional non-pharmacological interventions are often protocol-driven and condition-specific, potentially overlooking psychological engagement and reward pathways that modulate neuroplasticity and stress physiology. By integrating biologically informed selection (as outlined in Figure 2) with patient-valued, rewarding activities, vitaction-oriented strategies may enhance sustained behavioral change and amplify neuroprotective effects through reinforcement learning mechanisms and dopaminergic engagement [113].

The future of non-pharmacological neuroprotection lies in personalized and technology-supported interventions. Advances in digital health—such as wearable sensors, virtual reality rehabilitation, and mobile applications for mindfulness and exercise tracking—enable real-time monitoring of behavioral adherence and physiological responses. Integration of artificial intelligence and machine-learning algorithms can support individualized adaptation of interventions based on biomarkers, genetics, and digital phenotyping data [114, 115]. Moreover, combining multiple approaches (e.g., physical activity, dietary modulation, and stress-reduction practices) may achieve synergistic effects by targeting convergent neurobiological pathways.

To operationalize the integration of non-pharmacological strategies within clinical practice, a translational precision framework is proposed (Figure 2). This pipeline model emphasizes patient stratification based on clinical phenotype, disease stage, neuroimaging findings, and molecular biomarkers, followed by mechanism-matched selection of targeted interventions. Rather than applying uniform lifestyle recommendations, this approach aligns specific therapies—such as exercise, dietary modulation, mind–body practices, or neuromodulatory techniques—with dominant pathophysiological drivers, including neuroinflammation, mitochondrial dysfunction, or HPA axis dysregulation. The model further incorporates multimodal integration, objective monitoring through functional and biological markers, and adaptive personalization using digital tools and iterative feedback. By structuring integrative neuroprotection within a closed-loop, precision-based system, this framework bridges mechanistic insights and clinical implementation, advancing the field toward individualized, biomarker-informed therapeutic strategies. Within the proposed precision pipeline (Figure 2), the vitactions perspective may operate primarily at the levels of intervention selection and adaptive personalization, ensuring that mechanistically matched therapies are also intrinsically meaningful and behaviorally sustainable.

As integrative neuroprotective strategies become more widely promoted, ensuring equity of access and scientific integrity is paramount. Socioeconomic disparities, digital literacy gaps, and cultural factors may affect participation and adherence. Ethical frameworks must emphasize informed consent, realistic expectations, and transparency in communication of benefits and limitations.