Mild Cognitive Impairment (MCI) has gained prominence as a clinically and biologically meaningful stage between normal ageing and dementia. Individuals with MCI, particularly the amnestic subtype, exhibit objective cognitive deficits while maintaining relative functional independence, yet face a substantially increased risk of progression to Alzheimer’s disease and related dementias. Importantly, MCI represents a window of opportunity during which interventions may meaningfully alter disease trajectory.

Despite extensive research, pharmacological approaches to MCI have produced limited and inconsistent results. Cholinesterase inhibitors and memantine have not demonstrated reliable efficacy in preventing progression to dementia, and disease-modifying therapies targeting amyloid or tau pathology have shown modest benefit at best, often accompanied by safety concerns. These limitations have shifted attention toward non-pharmacological strategies that enhance brain resilience rather than targeting isolated pathological substrates.

Among lifestyle interventions, physical activity—and aerobic exercise in particular—has emerged as one of the most promising strategies for cognitive preservation. Epidemiological studies consistently associate higher levels of aerobic fitness with reduced cognitive decline and lower dementia risk. Randomized controlled trials increasingly demonstrate that aerobic exercise improves cognitive performance in older adults and individuals with early cognitive impairment. However, the mechanisms underlying these benefits are complex and multifactorial, extending beyond simple cardiovascular conditioning.

This paper aims to synthesize clinical evidence with mechanistic insights to conceptualize aerobic exercise as a multilevel neuroprotective strategy in MCI. By integrating findings from a randomized controlled trial with existing literature, we explore how aerobic exercise influences vascular, neurotrophic, metabolic, inflammatory, and neurodegenerative pathways, and discuss its translational relevance for preventive neurology.

This study was a prospective, randomized controlled trial conducted over 18 months, including participant recruitment, intervention, and follow-up. Study Setting and Participants Participants were recruited from the Neurology and Psychiatry outpatient departments of a tertiary care teaching hospital. Individuals aged 55–75 years were screened for eligibility. Inclusion Criteria Participants were included if they met criteria for amnestic MCI, defined by: • Subjective memory complaint reported by the participant or informant • Objective impairment in episodic memory (≥1.5 SD below age- and education-adjusted norms) • Preserved basic activities of daily living • Clinical Dementia Rating (CDR) global score of 0.5 • MMSE score 24–28 or MoCA score 18–25 • Medical clearance for physical activity Exclusion Criteria Exclusion criteria included: • Diagnosis of dementia • Major psychiatric illness • Uncontrolled cardiovascular, respiratory, or musculoskeletal disease • Participation in structured exercise programs within the previous six months Sample Size Based on an assumed effect size of 0.5, α = 0.05, and power = 0.8, a minimum of 64 participants was required. Accounting for potential attrition, 80 participants were enrolled. Randomization Participants were randomized using block randomization into AET or SAT groups in a 1:1 ratio. Intervention Aerobic Exercise Training Group: Participants engaged in supervised aerobic exercise five days per week for 12 weeks. Each session consisted of warm-up, 30–40 minutes of brisk walking or treadmill exercise, and cool-down. Exercise intensity was maintained at 60–75% of age-predicted maximum heart rate and progressively increased during the initial weeks. Stretching and Toning Control Group: The control group participated in supervised stretching, balance, and light toning exercises matched for frequency and duration but maintained below aerobic intensity (<50% HR reserve). Outcome Measures Cognitive Assessment: • Global cognition: MoCA, MMSE • Executive function: Trail Making Test-A and B, Stroop Test • Attention and working memory: Digit Span forward and backward Cardiorespiratory Fitness: • Six-minute walk test (6-MWT) Assessments were conducted at baseline, 6 weeks, and 12 weeks. Statistical Analysis Data were analyzed using SPSS version 31.0. An intention-to-treat approach was employed. Baseline differences were assessed using independent t-tests and chi-square tests. Between-group comparisons of post-intervention outcomes were conducted using ANCOVA with baseline values as covariates. Effect sizes were calculated using partial eta squared (ηp²). A p-value <0.05 was considered statistically significant. TABLE 1. Post-Intervention Global Cognitive Outcomes (ANCOVA) Outcome AET Group Control Group p-value ηp² MoCA score 24.3 ± 2.0 22.0 ± 2.4 <0.001* 0.32 MMSE score 27.4 ± 1.3 26.3 ± 1.5 0.002* 0.21 *Adjusted for baseline values TABLE 2. Executive Function Outcomes at 12 Weeks Test AET Group Control Group p-value ηp² Trail Making Test–A (sec) 44.1 ± 8.2 51.7 ± 9.4 <0.001* 0.29 Trail Making Test–B (sec) 121.5 ± 19.8 139.6 ± 23.1 <0.001* 0.34 Stroop interference score 34.6 ± 6.9 40.1 ± 7.8 0.001* 0.26 TABLE 3. Attention and Working Memory Outcomes Parameter AET Group Control Group p-value Digit Span – Forward 6.2 ± 1.0 5.5 ± 0.9 0.003* Digit Span – Backward 4.4 ± 0.8 3.7 ± 0.9 0.002* TABLE 4. Interim (6-Week) Cognitive Changes Outcome AET Group Control Group p-value Change in MoCA score +1.6 ± 0.9 +0.4 ± 0.8 <0.001* Improvement in TMT–B (sec) −9.8 ± 6.4 −2.1 ± 5.9 <0.001* TABLE 5. Change in Cardiovascular Fitness at 12 Weeks Parameter AET Group Control Group p-value Increase in 6-MWT distance (m) +58.4 ± 21.3 +11.6 ± 18.7 <0.001* Reduction in resting HR (bpm) −6.1 ± 3.4 −1.2 ± 2.8 <0.001* TABLE 6. Correlation Between Fitness Improvement and Cognitive Gain (AET Group) Variables Compared Correlation (r) p-value Δ 6-MWT vs Δ MoCA 0.62 <0.001* Δ 6-MWT vs Δ TMT–B −0.58 <0.001* Δ Resting HR vs Δ Stroop score −0.46 0.003*

At 12 weeks, the AET group demonstrated significant improvements in MoCA and MMSE scores compared to the control group (p < 0.01). Improvements were evident by 6 weeks and sustained through the intervention period (Table 5, Figure 5).

Significant reductions in completion times for TMT-A and TMT-B were observed in the AET group, indicating improved executive processing speed and cognitive flexibility. Stroop interference scores also improved significantly compared to controls (Table 6, Figure 6).

Digit Span forward and backward scores improved significantly in the AET group, reflecting enhanced attention and working memory capacity (Table 7, Figure 7).

The AET group demonstrated significant increases in 6-MWT distance and reductions in resting heart rate, while the control group showed minimal change (Table 9, Figure 9).

Improvements in cardiorespiratory fitness were strongly correlated with improvements in global cognition and executive function (r = 0.62 for MoCA change; p < 0.001) (Figure 10).

Future research should focus on long-term randomized trials incorporating biomarker and neuroimaging endpoints to establish disease-modifying effects of aerobic exercise. Precision approaches tailoring exercise prescription based on genetic, metabolic, and psychosocial factors may enhance efficacy. Exploration of combined interventions integrating aerobic exercise with cognitive training or dietary modification is also warranted.

Aerobic exercise functions as a multilevel neuroprotective strategy in Mild Cognitive Impairment, influencing vascular, neurotrophic, metabolic, inflammatory, and neurodegenerative pathways. By enhancing brain resilience rather than targeting isolated pathological processes, aerobic exercise offers a powerful and practical approach to preserving cognitive health. Incorporation of structured aerobic exercise into preventive neurology frameworks has the potential to meaningfully alter the trajectory of cognitive ageing and reduce the global burden of dementia.