Oxidative Stress & Neural Network Changes 

Alzheimer’s disease sits at the intersection of multiple biological pathways. Five major hypotheses attempt to explain its pathogenesis: the amyloid cascade hypothesis, tau protein hypothesis, inflammation hypothesis, metal ions hypothesis, and the oxidative stress hypothesis (Bai et al., 2022). Among these, oxidative stress is emerging as a central mechanism—and one that interacts with all the others.

Oxidative stress occurs when the body’s balance tips: too many pro-oxidants, not enough antioxidants (Bai et al., 2022). Pro-oxidants increase Reactive Oxygen Species (ROS), which can come from environmental toxins, medications, or normal metabolism. While ROS are essential signaling molecules, excessive ROS become toxic. Key ROS include Hydroxyl Radical (OH), Hydrogen Peroxide (H2O2), Singlet Oxygen (1O2), and Superoxide Anion (O2) (Bai et al., 2022).

High ROS levels damage cell membranes, proteins, and DNA—disrupting mitochondrial function. Once the mitochondria falter, the electron transport chain produces even more ROS, creating a destructive feedback loop (Bai et al., 2022). This cascade pushes neurons toward apoptosis. Not surprisingly, people with Alzheimer’s show:

1. Fewer intact mitochondria, and

2. Higher oxidative markers across multiple brain regions (Bai et al., 2022).

These findings are why antioxidant-based strategies are under investigation both as early interventions and as potential therapeutic agents in pre-clinical and clinical trials.

Neural Network Changes in Aging & Early Dementia

Even in typical aging, the brain’s energy machinery gradually weakens. Mitochondria decline by ~8% per decade (Watanabe et al., 2021), and oxidative stress accelerates this process (Bai et al., 2022). With less ATP available, synapses struggle to function efficiently. Watanabe et al. (2021) note that this mismatch between energy supply and demand may contribute to pathological protein accumulation and set the stage for dementia.

To distinguish normal aging from early dementia, researchers examined structural and functional brain changes across adulthood. In MRI studies of 1,500 healthy volunteers (ages 20–80), 192 brain regions (“nodes”) were identified. Of these, 174 regions (90.6%) showed age-related volume decline, particularly in the central gyrus, cerebellum, and inferior frontal gyrus (Watanabe et al., 2021). Some structures—such as the medial and superior frontal regions—were more resilient. The para-hippocampal gyrus and putamen peaked at ages 45–50 before declining.

White matter followed a classic inverted U-shaped curve: increasing through midlife, then decreasing (Watanabe et al., 2021). The rate of decline varies by tract, suggesting some pathways may preserve cognitive resilience—the concept underlying “SuperAgers,” adults in their 80s with memory performance equal to those decades younger.

Functionally, resting-state fMRI revealed that within-network connectivity decreases with age, while compensatory strengthening may occur across networks (Watanabe et al., 2021). The preserved connections—especially in the dorsal attention network—may offer clues for maintaining cognition across the lifespan.

Why This Matters for OT Practice 

1. Oxidative stress is not abstract neuroscience—it’s a functional barrier.

More ROS → fewer viable mitochondria → less ATP → reduced synaptic efficiency → impaired memory, attention, processing speed.
This shows up in everyday function: fatigue, slowed problem-solving, decreased dual-tasking, and difficulty learning new routines.

2. “SuperAging” isn’t magic—it’s a blueprint.

If certain networks and regions are preserved longer, OT interventions targeting attention, aerobic capacity, and cognitive challenge may help maintain or extend these protective patterns.

3. Early detection = early intervention.

Changes in oscillations, connectivity, and white-matter integrity appear long before functional decline. OTs working in neurology, geriatrics, or primary care can use screening tools, functional assessments, and occupational history to flag risk earlier.

4. Lifestyle and occupation directly influence oxidative stress.

Meaningful occupation encourages movement, social connection, cognitive stimulation, and stress reduction—all of which impact cellular health. OT is uniquely positioned to integrate these protective habits into everyday life.

5. Evidence like this strengthens OT’s role in precision brain health.

As neuromodulation, biomarkers, and oscillation-based interventions expand, OT practitioners who understand underlying mechanisms will be equipped to lead—not follow—the next decade of dementia care.

References

Bai, R., Guo, J., Ye, X. Y., Xie, Y., & Xie, T. (2022). Oxidative stress: The core pathogenesis and mechanism of Alzheimer's disease. Ageing Res Rev, 77, 101619. doi:10.1016/j.arr.2022.101619

Watanabe, H., Bagarinao, E., Maesawa, S., Hara, K., Kawabata, K., Ogura, A., . . . Sobue, G. (2021). Characteristics of Neural Network Changes in Normal Aging and Early Dementia. Front Aging Neurosci, 13, 747359. doi:10.3389/fnagi.2021.747359