TyG (Triglyceride-Glucose)

Monitoring and lowering the TyG index through interventions like aerobic exercise may reduce the risk or slow the progression of Alzheimer’s by improving insulin sensitivity and supporting brain health.

The TyG (Triglyceride-Glucose) index is calculated as:

TyG = (Triglycerides × Fasting Glucose) / 2

Where:

•  Triglycerides are measured in mg/dL.

•  Fasting Glucose is measured in mg/dL.

The result is often expressed as the natural logarithm (ln) of the product for better normalization in some studies, i.e., ln[(Triglycerides × Fasting Glucose) / 2].

This index is used as a marker for insulin resistance, with higher values indicating greater risk.

“Higher TyG index values may contribute to conditions (e.g., impaired glucose metabolism, reduced IDE activity, inflammation) that accelerate Alzheimer’s pathology.”

1. Insulin Resistance and Brain Metabolism: A high TyG index (typically >8, depending on the scale) reflects elevated fasting triglycerides and glucose, signaling insulin resistance. This impairs glucose uptake in the brain, particularly in insulin-sensitive regions like the hippocampus, leading to reduced neuronal energy availability. This “brain energy deficit” is a key factor in cognitive decline and Alzheimer’s pathology.

2. Amyloid-Beta Accumulation: As discussed, insulin resistance can overwhelm insulin-degrading enzyme (IDE), reducing its ability to clear amyloid-beta, a toxic protein that forms plaques in Alzheimer’s. A high TyG index correlates with this mechanism, increasing amyloid-beta buildup.

3. Supporting Evidence: Studies, such as those published in Journal of Diabetes Research (2020) and Frontiers in Aging Neuroscience (2021), have linked elevated TyG index values with higher Alzheimer’s risk. For example, a 2021 study found that individuals with a TyG index in the highest quartile had a significantly greater risk of cognitive impairment and dementia compared to those in the lowest quartile.

4. Additional Mechanisms: A high TyG index is also associated with systemic inflammation, oxidative stress, and vascular damage, all of which exacerbate Alzheimer’s pathology by promoting neuroinflammation and impairing cerebral blood flow.

5. Implications for Prevention: As you suggested earlier, interventions like aerobic exercise can lower the TyG index by improving insulin sensitivity, potentially reducing amyloid-beta accumulation and Alzheimer’s risk. Other strategies, such as a low-glycemic diet or weight management, also help.

1. Aerobic Exercise and Insulin Resistance:

• Aerobic exercise (e.g., running, cycling, swimming) enhances insulin sensitivity by increasing glucose uptake in muscles (via GLUT4 translocation) and reducing systemic inflammation. This can lower the TyG index (Triglyceride-Glucose index), a marker of insulin resistance.

• Studies show that regular aerobic exercise reduces fasting glucose and triglyceride levels, directly impacting the TyG index and improving metabolic health.

2. Impact on Amyloid-Beta Accumulation:

• Improved insulin sensitivity reduces the burden on insulin-degrading enzyme (IDE), which degrades both insulin and amyloid-beta. When insulin levels are lower due to better insulin sensitivity, IDE can more effectively clear amyloid-beta, reducing its accumulation in the brain.

• Aerobic exercise also promotes neurogenesis (growth of new neurons), increases brain-derived neurotrophic factor (BDNF), and enhances cerebral blood flow, all of which support brain health and may reduce amyloid-beta plaques and tau pathology.

• Exercise reduces neuroinflammation and oxidative stress, which are linked to amyloid-beta buildup and Alzheimer’s progression.

3. Evidence Linking Exercise to Reduced Dementia Risk:

• Research, including studies from journals like Neurology and Journal of Alzheimer’s Disease, shows that regular aerobic exercise is associated with lower amyloid-beta levels, improved cognitive function, and reduced dementia risk in older adults.

• A 2019 meta-analysis found that aerobic exercise interventions (e.g., 150 minutes per week of moderate-intensity exercise) significantly improved cognitive outcomes in individuals with mild cognitive impairment, partly by addressing metabolic dysfunction and amyloid pathology.

4. Practical Implications:

• Engaging in 150–300 minutes per week of moderate aerobic exercise (e.g., brisk walking, jogging, or cycling) is recommended by guidelines like those from the WHO for improving metabolic and brain health.

• Combining aerobic exercise with a healthy diet (e.g., Mediterranean or low-glycemic diet) can further enhance insulin sensitivity and reduce the TyG index, amplifying protective effects against amyloid-beta accumulation

Mechanisms Linking Aerobic Exercise to Reduced Amyloid-Beta Accumulation and Alzheimer’s Prevention

1. Brain-Derived Neurotrophic Factor (BDNF):

• Role in Alzheimer’s:

BDNF is a neurotrophin critical for synaptic plasticity, neuronal survival, and neurogenesis, all of which are disrupted in Alzheimer’s disease. Low BDNF levels are associated with cognitive decline and increased amyloid-beta accumulation, as BDNF promotes non-amyloidogenic processing of amyloid precursor protein (APP), reducing amyloid-beta production. It also enhances neuronal resilience against neurotoxic insults.

• Exercise-Induced Effects:

Aerobic exercise significantly increases BDNF levels in the hippocampus and cortex, key brain regions affected in Alzheimer’s. This upregulation occurs through several pathways:

• Muscle-Brain Crosstalk:

Exercise stimulates the release of myokines like irisin (from FNDC5) and cathepsin-B from skeletal muscle, which cross the blood-brain barrier (BBB) and upregulate BDNF expression via the cAMP/PKA/CREB pathway.

• Ketone Bodies:

Aerobic exercise increases production of β-hydroxybutyrate in the liver, which inhibits histone deacetylases in the brain, promoting BDNF gene expression.

• Lactate:

Exercise-induced lactate from muscles enhances BDNF production by stimulating neuronal signaling pathways, improving memory and neuronal function.

• Impact on Amyloid-Beta: BDNF reduces amyloid-beta by:

• Activating SORL1 (Sortilin-Related Receptor 1) via the ERK pathway, which shifts APP processing toward a non-amyloidogenic pathway, decreasing amyloid-beta production.

• Reducing BACE1 activity (a β-secretase enzyme that cleaves APP into amyloid-beta), inhibiting amyloid-beta formation.

• Enhancing synaptic plasticity and neurogenesis, counteracting amyloid-beta-induced synaptic loss.

• Evidence: A 2021 study found that aerobic exercise increases hippocampal BDNF by up to 200%, correlating with improved memory and reduced amyloid-beta deposition in animal models. In humans, regular aerobic exercise (30 minutes, 3–5 times/week) boosts BDNF levels, enhancing cognitive function and neuroprotection.

2. Insulin-Degrading Enzyme (IDE):

• Role in Alzheimer’s: IDE is a protease that degrades both insulin and amyloid-beta. In insulin-resistant states (high TyG index), elevated insulin levels compete with amyloid-beta for IDE, reducing amyloid-beta clearance and promoting its accumulation in the brain, a hallmark of Alzheimer’s.

• Exercise-Induced Effects: Aerobic exercise improves insulin sensitivity, lowering circulating insulin levels and reducing the TyG index. This alleviates the competitive burden on IDE, allowing it to more effectively degrade amyloid-beta.

　Mechanisms:

• Improved Insulin Sensitivity:

Aerobic exercise enhances glucose uptake in muscles via GLUT4 translocation, reducing systemic insulin resistance. This lowers insulin levels, freeing IDE to target amyloid-beta.

• Anti-Inflammatory Effects:

Exercise reduces pro-inflammatory cytokines (e.g., TNF-α, IL-6), which can inhibit IDE activity in insulin-resistant states. By lowering inflammation, exercise supports IDE function.

• Impact on Amyloid-Beta: By reducing insulin resistance, aerobic exercise enhances IDE’s ability to clear amyloid-beta, decreasing plaque formation. Animal studies show that exercise reduces amyloid-beta levels (e.g., Aβ40 and Aβ42) in transgenic AD models, partly through enhanced IDE activity.

• Evidence:

A 2023 study noted that exercise-induced improvements in insulin sensitivity correlate with reduced amyloid-beta deposition in AD mouse models, likely due to increased IDE availability.

3. Inflammation:

• Role in Alzheimer’s: Chronic neuroinflammation, driven by activated microglia and peripheral immune cell infiltration, promotes amyloid-beta deposition and tau hyperphosphorylation, accelerating Alzheimer’s pathology. Insulin resistance exacerbates inflammation, as seen in high TyG index individuals.

• Exercise-Induced Effects: Aerobic exercise exerts potent anti-inflammatory effects by:

• Reducing pro-inflammatory cytokines (e.g., TNF-α, IL-6, hs-CRP) and increasing anti-inflammatory mediators (e.g., IL-10).

• Enhancing clusterin and other blood factors that dampen brain inflammation and improve neurogenesis.

• Modulating the gut-brain axis by increasing short-chain fatty acids (SCFAs) and gut biodiversity, which reduce systemic inflammation.

• Impact on Amyloid-Beta: Lower inflammation reduces microglial activation, which decreases amyloid-beta production and enhances its clearance. Exercise also downregulates NF-κB signaling, a key driver of inflammation in Alzheimer’s.

• Evidence: A 2024 study in Journal of Neuroinflammation found that 5 months of voluntary wheel running in AD mouse models significantly reduced neuroinflammation, amyloid-beta plaques, and tau phosphorylation, with effects mediated by exercise-induced anti-inflammatory molecules.

Recent Studies on Exercise and Alzheimer’s Prevention (2020–2025)

Here’s a summary of recent studies, focusing on aerobic exercise, BDNF, IDE, inflammation, and Alzheimer’s prevention, drawing from available sources and general research trends:

1. 2024:

Exercise Mimetics and Neuroinflammation (Journal of Neuroinflammation)

• Findings:

This study explored exercise mimetics (compounds mimicking exercise effects) in AD mouse models. Five months of treadmill running reduced amyloid-beta (Aβ40 and Aβ42) and tau phosphorylation in APP/PS1 mice. Exercise lowered neuroinflammation by modulating immune function and increased BDNF levels via lactate secretion, enhancing memory and neuronal function.

• Relevance:

Supports your hypothesis that aerobic exercise reduces amyloid-beta via anti-inflammatory effects and BDNF upregulation. It also suggests that exercise mimetics could benefit those unable to exercise.

2. 2023:

Mechanisms of Exercise-Induced BDNF in AD (MDPI)

• Findings:

Aerobic exercise increased BDNF through molecules like osteocalcin, irisin, and lactate, which activate pathways (e.g., CREB/BDNF) to enhance neurogenesis and reduce amyloid-beta. In AD mouse models, exercise protected synaptic function and reduced early BDNF losses due to oxidative stress.

• Relevance:

Highlights BDNF as a key mediator of exercise’s neuroprotective effects, directly linking it to reduced amyloid-beta accumulation.

3. 2022:

BDNF and Lifestyle in AD (Frontiers in Aging Neuroscience)

• Findings:

A Mediterranean diet and aerobic exercise increased BDNF levels, reduced inflammation, and improved insulin sensitivity in humans. These lifestyle interventions were associated with lower AD risk by enhancing synaptic plasticity and reducing amyloid-beta via BDNF-mediated SORL1 activation.

• Relevance:

Reinforces the role of aerobic exercise in upregulating BDNF and improving insulin regulation, supporting IDE’s amyloid-beta clearance.

4. 2021:

BDNF and Type 2 Diabetes (Scientific Reports)

• Findings:

A meta-analysis showed that individuals with type 2 diabetes (often linked to high TyG index) had lower serum BDNF levels (-1.12 ng/mL) compared to healthy controls. Lower BDNF was correlated with higher inflammation (hs-CRP) and worse glycemic control, increasing AD risk.

• Relevance:

Connects insulin resistance (high TyG index) to reduced BDNF, supporting the idea that exercise-induced BDNF upregulation could mitigate AD risk in insulin-resistant individuals.

5. 2020:

BDNF and Memory Impairment (Scientific Reports)

• Findings:

In 256 older adults, lower BDNF levels, less physical activity, and hippocampal atrophy were independently associated with memory impairment. Aerobic exercise was linked to higher BDNF and better cognitive outcomes.

• Relevance:

Confirms that aerobic exercise boosts BDNF, protecting against cognitive decline and potentially amyloid-beta accumulation.

Practical Implications for Reducing Alzheimer’s Risk

Based on these mechanisms and studies, aerobic exercise is a powerful tool for reducing Alzheimer’s risk in individuals with a high TyG index. Here’s how it ties together:

• BDNF Upregulation: Aerobic exercise (e.g., 30–60 minutes of moderate-intensity activity like brisk walking or cycling, 3–5 times/week) boosts BDNF, promoting non-amyloidogenic APP processing and synaptic health.

• IDE Enhancement: By improving insulin sensitivity, exercise reduces insulin levels, allowing IDE to prioritize amyloid-beta clearance.

• Anti-Inflammatory Effects: Exercise lowers systemic and neuroinflammation, reducing amyloid-beta production and enhancing clearance via microglia and blood factors like clusterin.

• TyG Index Reduction: Aerobic exercise lowers triglycerides and fasting glucose, reducing the TyG index and mitigating insulin resistance, which supports both IDE and BDNF pathways.