Page 39 - Summer2014

MODERN WESTERN DIET & LIFESTYLE
• High Refined Carbohydrate Intake
• Low Anti-Oxidant Intake
• Skewed n-6/n-3 Ratio
• Sedentism/Lack of Physical Activity

SETTING THE STAGE: DECADES PRIOR TO AD DIAGNOSIS
• Peripheral Hyperinsulinemia
• Insulin Resistance at Blood-Brain Barrier
• Possible Brain "Hyperglycemia"
• Membrane Fatty Acid Imbalance
• Lipid Peroxidation
VERY EARLY STAGE: DAMAGE ACCRUING SLOWLY & SILENTLY
• Mitochondrial Dysfunction (Altered Permeability & Transporter Function)
• ROS Generation/Oxidative Damage
• i CMRglu (Slight)
EARLY STAGE: NO SYMPTOMS PRESENT – BRAIN IS COMPENSATING
• h Aβ Accumulation (Slight)
• h NFT Formation (Slight)
• hAPOE Glycation
• iBrain Insulin Receptor Function
• iDelivery of Cholesterol & Fatty Acids to Brain (Slight)
• iATP Production in Brain (Slight)
• iAcetylcholine Production in Brain (Slight)

MILD COGNITIVE IMPAIRMENT: SYMPTOMS BEGINNING TO MANIFEST
• h AGE Formation
• ii Delivery of Cholesterol & Fatty Acids to Brain (Worsening)
• ii CMRglu (Worsening)
• ii ATP Production in Brain (Worsening)
• ii Acetylchoine Production in Brain (Worsening)
• Regression of Axons & Dendrites – Loss of Synapses
BRAIN IN “PROTECTION MODE”: SEEKING ALTERNATIVE FUELS & ANTIOXIDANTS
• i Glycolysis
• h Pentose PO4 Pathway: h NADPH
• h Lactate Shuttle
• Peripheral Insulin Levels High g No Ketone Formation g Neuronal Cells "Starving"

DAMAGE SEVERE, WIDESPREAD, AND INTERFERING WITH DAILY LIFE
• hhh Aβ Plaques
• hhh NFTs
• iiiDelivery of Cholesterol & Fatty Acids to Brain (Severe)
• iii ATP Production in Brain (Severe)
• iii Acetylcholine Production in Brain (Severe)

WIDESPREAD NEURONAL DEATH
ALZHEIMER’S DISEASE

Figure.1: The Alzheimer’s disease cascade: Dietary imbalances cause mitochondrial dysfunction, oxidative damage,
peripheral hyperinsulinemia, and insulin resistance at the BBB. Decades prior to clinical disease manifestation, the brain
shows a decreased ability to metabolize glucose. Insulin dysregulation causes Aβ plaques to accumulate, NFTs to form,
and glycated ApoE particles fail to deliver cholesterol and fatty acids to the brain. Axons and dendrites recede; synapses
are lost. High peripheral insulin levels inhibit ketogenesis and starve the struggling brain of an alternative fuel. The brain
upregulates pathways to protect and feed itself. A lack of substrates for these pathways results in widespread neuronal
death and overt Alzheimer’s disease. Aβ: beta-amyloid; CMRglu: cerebral metabolic rate of glucose; NFT: neurofibrillary
tangles; ROS: reactive oxygen species.

Wise Traditions SUMMER 2014 Wise Traditions 39

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