Unravelling the power of Gender and BDNF: Preventing Chronic traumatic Encephalopathy

Figure 1: Major reason for CTE

Are men and women at equal risk?

Although men and women are vulnerable, there is an increase in evidence that shows male and female brain can react differently on a molecular level to the same injury and that differences can identify both recovery and risk of chronic neurological diseases.(Jansen et al., 2021) (Spychala et al., 2017).Recent research has pointed to an important sex based differences, Female athletes may report severe acute symptoms after concussion but the study data suggests men have higher risk of tau aggregation.(Makhoul et al., 2025) Hormones add a lot of difference. The female hormones, estrogen and progesterone are superheroes of brain cells. They assist diminishing destructive inflammation and enhance self-restoration by decreasing the damage in the brain. The estrogen appears to protect neurons but declining level after the menopause may make older women more vulnerable towards the CTE studies in rodent that has shown males are more likely to develop extensive tau tangles while females exhibit unique molecule responses and immune profiles.

Molecular Cascade:

A concussion triggers wave of damage: Shearing of axons, ionic imbalance excitotoxicity with glutamate and microvascular stress that interact to activate microglia and astrocytes, upsurge cytokines and activate tau kinases such as GSK3β and CDK5 leading towards hyper-polarization and aggregation around the small cortical vessels at depth of the sulcal a feature of CTE. Perivascular p-tau transfers to limbic and cortical circuit of memory, mood and executive functions. It aligns with clinical phases that attenuate from headache and attention loss to depression impulsivity cognitive decline and ultimate dimension many patients have also faced endocrine depression disruption from pituitary injury, inflammation, energy failure and mood symptoms.

BDNF is the factor that helps to break down the cascade that derives CTE pathology. Brain-derived-neurotrophic-factor (BDNF) is a neuroprotective molecule which plays a crucial role in decreasing the progression from concussion or TBI to severe stages of CTE. By supporting neuronal survival, promoting synaptic plasticity and reducing neuroinflammation.

Figure 2: Factors in CTE and brain injury include axonal stretch causing calcium influx and cytoskeletal damage, tau hyperphosphorylation disrupting neural networks, mitochondrial dysfunction leading to energy deficits, hypothalamic-pituitary injury affecting hormones and mood, and chronic neuroinflammation via NF-κB, NLRP3 inflammasome, and cytokines.

BDNF breaking the cascade:

BDNF reduces apoptosis and promotes repair after shearing of axons. (Wang et al., 2024). It suppresses neuro inflammation by modulating the active stage of microglia and astrocytes , by reducing the release of damaging cytokines (Wurzelmann et al., 2017a). BDNF inhibits hyper-polarization through regulating tau kinases and clearing out the toxic tau aggregates. It also supports mitochondrial function, counteracting the chronic energy failure seen in post-concussion states and CTE.

In humans, BDNF levels are more variable some regions like prefrontal cortex have higher level of BDNF while hippocampal region shows little difference. Some studies show higher level in women, particularly in younger or premenopausal women , menopausal women tends to have decrease level of BDNF, showing a strong role of hormones in regulation. (Zanesco and Velloso, 2025)

Enhancing BDNF level

Hormonal therapies, such as estrogen, progesterone, and growth hormone show promising neuroprotection and pre-emptive intervention in concussion and CTE but are not yet standard for prevention in athletes. In clinical practice, hormone therapy is typically used only after an injury when endocrine dysfunction has been diagnosed, rather than as a preventive measure. However, emerging research on its neuroprotective benefits suggests a promising future were personalized screening and early, targeted interventions could be used for people at high risk. Such strategies might combine hormone support with lifestyle approaches that naturally enhance the body's ability to release own neuro-steroids and boost.(Wurzelmann et al., 2017b)

BDNF level, offering most holistic way to protect the brain from injury occurs. in experimental studies it has been found that supplementing BDNF via different therapies including hormonal therapies gene therapies nanoparticles or neuronal stem cells has improved cognitive functions rand recovery in animal models. Dietary supplements Omega-3-fatty acids have shown with improved outcomes and higher BDNF level in TBI rat model.(Korley et al., 2016).

Multiple research has been done to enhance BDNF, and some are under clinical trials such as Neuroelectronic and endogenous enhancement via norsteroidal modulation (Lim, 2024).

Future perspective and research Gaps:

The optimal timing, delivery method, and combination strategies for BDNF enhancement still need rigorous human trials. most data come from pre-clinical model and need more participation of athletes for early detection. So, translating these approaches into real world care- especially people suffering from CTE remains a major focus for future. he future lies in personalized, multi-modal interventions that optimize BDNF for neurodegenerations, prevention, and lifelong brain health after trauma.