PLMI Blog

Alzheimer’s disease is a prevalent and often devastating neurodegenerative disorder, currently affecting over six million individuals in the U.S., with research indicating it is now the third leading cause of mortality (1). An imbalance between amyloid β-protein (Aβ) production and clearance has been demonstrated to drive AD pathology, preceding its manifestation of pronounced cognitive symptoms (2).

A number of clinical trials involving anti–β-amyloid (Aβ) drugs have yielded some, but limited, progress in mitigating cognitive decline and are further compounded by side effects (including brain edema and atrophy), underscoring the need for improved therapeutic treatments. In fact, researchers predict that by 2050, if more preventive, efficacious treatments are not discovered, 50 million individuals will be diagnosed with Alzheimer’s Disease (3).

A Closer Look at Early Dementia & Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia, a broad term describing a group of symptoms that impede memory, cognition, and social abilities to the point of interfering with daily life functions. Dementia can arise from various diseases, including AD, vascular dementia, and Lewy body disease. It is a debilitating neurological condition associated with damage to brain cells, and symptoms vary depending on the extent and region of impact. Dementia represents a persistent decline in cognitive abilities and memory, often advancing to significant impairments in one’s daily functioning. Mild cognitive impairment (MCI) describes deficits in memory and cognition and increases the risk of these conditions.

The Need for Improved Treatment

Despite its prevalence, Alzheimer’s remains one of the most complex neurodegenerative diseases, with its etiology still unfolding. While various theories have linked AD to factors including diabetes, Herpes simplex infections, amyloid-β plaques, tau misfolding, and prions, no single theory has yielded efficacious solutions (4-8). A growing body of research underscores additional underlying contributors such as neuroinflammation, insulin resistance, and reduced trophic support for neurons (9-11).

This emerging model of research suggests that Alzheimer’s results from a mismatch between cerebral network support—such as blood flow, oxygen, and nutrients—and the increased demands placed on the brain due to inflammation, toxins, and stress. This network insufficiency leads to synapse loss and cognitive decline, with amyloid-β playing a central role in a chronic, low-grade encephalitis response (12). Genetic, lifestyle, and environmental factors are also demonstrated to influence onset and progression.

Research continues to focus on early detection, the identification of improved biomarkers, and advances in multifaceted treatment options that address underlying contributing factors to these conditions.

Personalized & Precision Medicine

A bio-individual approach to AD and early dementia offers promise in tackling these prevalent conditions by targeting the root causes of its etiology, including reduced network support or increased demands on the brain. Recent anecdotal reports and proof-of-concept trials (POCs) have shown cognitive improvement in patients with mild cognitive impairment (MCI) or even advanced dementia using these tailored approaches (13-15).

The four major contributors to cognitive decline that precision medicine targets include:

• Pro-inflammatory agents and signals
• Toxins and toxicants (including metals, organics, and biotoxins)
• Energetic support (cerebral blood flow, oxygen saturation, mitochondrial function)
• Trophic support (neurotrophic factors, nutrients, hormones)

Evaluation & Diagnostics

A thorough and comprehensive diagnostic process is pivotal to uncovering these underlying contributors of network insufficiency in AD, impeding the brain’s connections. Laboratory assessments focus on inflammatory markers (CRP, homocysteine, fibrinogen, tumor necrosis factor alpha, omega-6:omega-3 ratio, albumin:globulin ratio), immune system biomarkers (immunoglobulins and lymphocyte subsets), intestinal permeability, and autoimmune biomarkers (anti-thyroglobulin, anti-thyroid peroxidase, and anti-nuclear antigen), as well as causes of recurring chronic infections (Herpes, Toxoplasma, SARS-CoV-2). Further evaluations assess energetic factors, including cerebral blood flow,  mitochondrial function (Organic Acids Test), oxygen saturation, sleep apnea, insulin resistance, lipid profiles, and toxicant exposure (metals, biotoxins) (16).

Additionally, trophic support is assessed through testing for neurotrophins (e.g., BDNF), key nutrients, and hormones that influence brain health. Genetic testing helps to identify variants related to inflammation, detoxification, mitochondrial function, and other possibly impeded metabolic processes—such as nutrient and hormone metabolism and methylation. For such, APOE4, a variant of the APOE gene, has been associated with an increased risk of AD by altering the brain’s metabolism of lipids and impeding the blood-brain barrier, resulting in oxidative stress and increased risk of cognitive decline (17). Genes alone, however, do not cause AD; rather, the combination of genes and lifestyle factors has the most profound impact in terms of etiology.

Imaging techniques such as brain MRI with volumetrics (measuring the volume of different brain regions) and electrophysiological tests (EEG) may be recommended to monitor disease progression and identify abnormalities.

Targeted Interventions

Once potential contributors are identified, patients are categorized into AD subtypes based on the primary, underlying impeded pathophysiological processes, which can include inflammatory, glycotoxic, atrophic, toxic, vascular, and traumatic. Most patients exhibit multiple contributing factors, making treatment complex, however purposeful, personalized, and efficient.

Innovative Trials & Treatment Framework

Emerging clinical trials, such as those looking at biomarkers—p-tau, amyloid-β ratios, and neurofilament light—aim to improve diagnostic accuracy and offer improved monitoring for future treatments. These trials, along with more comprehensive testing methods (e.g., epigenetic evaluation), hold promise for more efficient, individualized approaches to reversing cognitive decline by addressing the interplay of underlying contributors (such as inflammation, toxins, energetic imbalances, and trophic support), rather than solely addressing presenting symptoms.

This treatment framework for Alzheimer’s disease (AD) goes beyond traditional treatments by targeting systemic factors that influence brain health and cognitive function, focusing on both common and individual-specific impacted pathways (18).

Core Considerations

While personalized protocols are developed based on evaluation results, certain core strategies are foundational for all individuals:

• Insulin Sensitivity & Metabolic Flexibility: Restoring the ability to efficiently switch between glucose and ketone utilization is pivotal. Research shows that impaired glucose utilization in regions including the temporal and parietal brain areas is associated with cognitive decline, while exogenous ketones have been demonstrated to improve cognitive function in Mild Cognitive Impairment (MCI) patients (18).
• Nutritional Protocol: A plant-rich, high-fiber, mildly ketogenic diet is recommended, emphasizing leafy greens, non-starchy vegetables, and unsaturated fats, while avoiding processed foods and grains. Regular blood ketone monitoring is recommended.
• Exercise: Both aerobic and strength training are encouraged (16). Exercise has been demonstrated to improve cardiovascular and endothelial functions, enhance ketosis, increase brain-derived neurotrophic factor (BDNF), boost cerebral blood flow, and enhance sleep.
• Sleep Hygiene: Obtaining sufficient quality and quantity of sleep is significant, with assessment for sleep apnea or upper airway resistance syndrome (UARS), if necessary. Sleep stages, particularly deep sleep and REM sleep, are monitored for optimal cognitive recovery and are necessary to augment glymphatic system function, helping the brain to detoxify harmful waste substances.

Personalized Protocols: Addressing Specific Contributing Factors

A more extensive evaluation of each individual uncovers specific contributors to cognitive decline, which are then addressed through a targeted treatment regimen (16). Key therapeutic interventions include:

• Energetic Support:
  • Enhance oxygenation, cerebral blood flow, and mitochondrial function to ensure optimal brain energy.
  • Treat metabolic issues, such as insulin resistance, to improve glucose utilization, metabolic flexibility, and overall brain function.
• Inflammation:
  • If systemic or neuroinflammation is detected, pro-resolving mediators and anti-inflammatory supplements (liposomal glutathione, fish oil, turmeric, and resveratrol) are often recommended. Low-dose naltrexone may be prescribed for those with autoimmune issues to regulate immune responses and reduce inflammation.
• Pathogens:
  • Treat identified pathogens that could be contributing to cognitive decline, including Herpes simplex virus, Epstein-Barr virus (EBV), or tick-borne infections, such as Lyme disease. Targeted herbal treatments and antiviral drugs (valacyclovir) may be utilized as needed.
• Trophic Support:
  • Neurotrophic factors, such as promoting BDNF, are enhanced through exercise, ketosis, and supplementation with whole coffee fruit extract.
  • Sufficient nutrients (vitamin D, vitamin E, omega-3s, B vitamins, lipoic acid, magnesium, CoQ10, and neurosteroids if necessary) to support brain health. For women with suboptimal hormone levels, appropriate supplements and bioidentical hormone replacement to optimize sex hormones may be recommended. Similarly, addressing suboptimal thyroid function with thyroid medication and nutritional support.
• Toxins & Detoxification:
  • For patients exposed to harmful substances including mercury, lead, or biotoxins, detoxification is initiated. This includes identification of exposure, avoidance strategies, and the utilization of binding agents (activated charcoal), sauna therapy, and herbal detoxifiers.
• Gastrointestinal Health:
  • For individuals with gastrointestinal hyperpermeability or digestive issues, a gut-healing protocol is implemented, including dietary restrictions, digestive enzyme support, and treatment of dysbiosis.
  • Microbiome optimization is also an integral focus, as gut health is associated with inflammation and cognitive function.

Additional Interventions

• Brain Training: Evidence suggests that cognitive exercises can support neuroplasticity. A validated brain training platform is included as part of the protocol, with a minimum of 15 minutes of daily training targeting information processing speed and accuracy.
• Stress Management: Techniques including yoga, meditation, and biofeedback are integrated to reduce stress and enhance vagal tone and heart-rate variability (HRV), which support cognitive function. In fact, vagus nerve stimulation has been suggested for the treatment of dementia–associated memory impairments, underscoring these body-mind connections (19).
• Lifestyle Support: A multidisciplinary approach to body and brain health is significant in reducing and reversing cognitive decline of early dementia and Alzheimer’s. Movement, stress reduction, and nutrition are all imperative. Moderate-intensity exercise has been shown to inhibit inflammatory markers, including IFN-γ, IL-1β, IL-6, CRP, TNF-α, sTNFR1, COX-2, and NF-κB. In addition to significantly increasing plasma levels of BDNF, aerobic exercise has been shown to also enhance nerve growth factor, synaptic plasticity and motor activity, exploratory behavior, and spatial memory in AD subjects, as evidenced by a 2023 study published in Frontiers in Aging Neuroscience (20).

This personalized, multi-faceted approach to early dementia and Alzheimer’s disease treatment emphasizes addressing the root, systemic causes of cognitive decline rather than just managing symptoms. By optimizing energy metabolism, reducing inflammation, supporting neurotrophic factors, detoxifying the body and brain, and enhancing brain function through nutrition and lifestyle interventions, individuals can experience a more efficacious strategy for preventing and potentially reversing cognitive decline in early dementia and AD.

Join us on March 4th from 5-7 PM PST for a groundbreaking event, Reversing Cognitive Decline at Scale hosted by PLMI Founder Dr. Jeffrey Bland, featuring internationally recognized neurologist Dr. Dale Bredesen and TruNeura Co-Founder Dr. Kristine Burke. Dr. Bredesen will explore the root cause approach to reversing cognitive decline correlated with these conditions, while Dr. Burke will share insightful strategies for scaling successful brain health programs. This event is vital for those interested in the future of cognitive health and personalized medicine.

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