Type 1 Alzheimer’s – Inflammatory
Posted on February 21st, 2017
Alzheimer’s disease (AD) is not one disease but more of a gradual change in many inputs – a network effect – similar to the downward slide a regional economy might experience during a recession. Alzheimer’s involves progressive neurodegeneration in the presence of misfolded proteins, poorly-understood inflammatory changes. So, Alzheimer’s a uniquely personalized degenerative condition: genetically, clinically, and pathologically heterogeneous (Sudduth et al) [R]. One clear marker of of Alzheimer’s is high levels of inflammation comorbid with cognitive impairment (often referred to as “brain fog” in the young) advancing to intermittent amnesia leading to true dementia.
Inflammatory markers such as Phospho-tau and anti-amyloid-beta (Abeta) CSF levels are useful markers of neurodegeneration but not diagnostic of a process leading to neurodegeneration.
Indications of Inflammatory Alzheimer’s Disease
- Increase in C-reactive protein and other inflammatory markers like IL-6, IL-8, IL-12, tumor necrosis factor (TNF-alpha)
- Hippocampal atrophy. Early diagnosis will rarely include visible cerebral volume atrophy on MRI. A PET scan may show decreases hippocampal activity. However, PET scans involve radiation in the brain which can aggravate inflammatory Alzheimers.
- Reduction in A/G ratio. A low Albumin/Globulin ratio may reflect overproduction of globulins, such as seen in multiple myeloma or autoimmune diseases, or underproduction of albumin, such as may occur with cirrhosis [R], or selective loss of albumin from the circulation, as may occur with kidney disease (nephrotic syndrome). [R]
- Increase in M1/M2 ratio. Tumor-associated macrophages (TAMs) are classified into two major phenotypes, M1 and M2. M1/M2 describes the two major and opposing activities of macrophages. M1 “killer” macrophages inhibit cell proliferation and causes tissue damage (inflammatory) while M2 “repair” macrophages promote cell proliferation and tissue repair (anti-inflammatory). [W] Polarization of M1/M2 ratio has been shown to be a reliable early indicator of inflammatory-driven Alzheimer’s Disease. [R] Interferon regulatory factor (IRF), signal transducers and activators of transcription (STAT) and suppressor of cytokine signaling (SOCS) proteins all play a role in skewing macrophage function towards either the M1 or M2 phenotype. The IRF/STAT pathways, activated by IFNs and toll-like receptor (TLR) signaling, polarize macrophages to the M1 activation state via STAT1. On the other hand, IL-4 and IL-13 skew macrophages toward the M2 activation state via STAT 6 (Sica et al). [R]
– M1 macrophages secrete high levels of IL-12 and low levels of IL-10.
– M2 macrophages produce high levels of IL-10, TGF-beta and low levels of IL-12.
- Reduced MFI. Alzheimer disease patients have an impairment of anti-amyloid-beta (Abeta) innate immunity and a defect in immune gene transcription. [R]
- APOE4 genetics. APOE4 is a leading risk factor but is not a diagnostic. Inflammation can drive degenerative Alzheimer’s with or without the accelerant of APOE4 genetics.
- MTHFR polymorphism genetics. MTHFR polymorphism results in reduced bioavailability of B12 and folate, essential brain and central nervous system nutrients, leading to inflammation and reduced cognitive function.
- Depression or Anxiety. A history of depression or anxiety may indicate cerebral inflammation. [R]
- Recent or History of Infection. Central nervous system or systemic infections may contribute to the pathogenesis or pathophysiology of AD, and chronic infection with several pathogens should be considered a risk factor for sporadic AD (Sonjo et al). [R]
Lab Tests to Order
- High Sensitivity CRP (hs-CRP)
- Vitamin B-12
- Vitamin D3, 25-Hydroxy
- Hormones: estradiol, free and total testosterone
- Free T3, Free T4, TSH
- Fasting glucose and insulin
- Hemoglobin A1C
- Complete Blood Count with Diff
- Comprehensive Metabolic Panel
- ALCAT Micronutrients
- APOE Genetics
- MTHFR Genetics
Identify Causes of Inflammation
- Poor liver function
- Poor kidney function
- Advanced Glycation Endproducts (AGEs)
- Gut tissue permeability or connective tissue problems (joint hyperextension, stretchy skin, Ehlers Danlos Syndrome, etc.)
- Inflammatory bowel disease, Krohn’s disease, celiac
- Poor oral hygiene. High levels of plaque and biofilm build up in the brain, often due to the same phenotype in the mouth. High levels of plaque build up can also be symptomatic of disregulated mouth microbiome. The ears, nose and throat are highly connected to the brain.
- Obesity. Obesity can be an outcome of inflammation as well as a cause. [R]
- Diabetes or glycemic cause. Fasting glucose and Hemoglobin A1C are second stage indicators.
- History of infection, especially chronic infection
- Immune dysfunction or autoimmune syndromes
- Food sensitivity
- Exposure to toxins: multi-valent metals (mercury, aluminum, etc), mold mycotoxins (history of flooding in home)
Please contact us for evidence-based personalization consultation.
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- Lai, M. K. P., et al. “Psychosis of Alzheimer’s disease is associated with elevated muscarinic M2 binding in the cortex.” Neurology 57.5 (2001): 805-811. [R]
- Sudduth, Tiffany L., et al. “Neuroinflammatory phenotype in early Alzheimer’s disease.” Neurobiology of aging 34.4 (2013): 1051-1059. [R]
- Ship, Jonathan A., and Scott A. Puckett. “Longitudinal study on oral health in subjects with Alzheimer’s disease.” Journal of the American Geriatrics Society 42.1 (1994): 57-63. [R]
- Avagyan, Hripsime, et al. “Immune blood biomarkers of Alzheimer disease patients.” Journal of neuroimmunology 210.1 (2009): 67-72. [R]
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- Gray, Seymour J., and ES Guzman Barron. “The electrophoretic analyses of the serum proteins in diseases of the liver.” Journal of Clinical Investigation 22.2 (1943): 191. [R]
- Kibrick, Andre C., and Alfred B. Clements. “A comparative study of the serum albumin-globulin ratio, the cephalin-cholesterol flocculation, and the thymol turbidity tests for liver function.” The Journal of laboratory and clinical medicine 33.6 (1948): 662-671. [R]
- Leonard, Brian E. “Inflammation, depression and dementia: are they connected?.” Neurochemical research 32.10 (2007): 1749-1756. [R]
- Dantzer, Robert, et al. “From inflammation to sickness and depression: when the immune system subjugates the brain.” Nature reviews neuroscience 9.1 (2008): 46-56. [R]
- Honjo, Kie, Robert van Reekum, and Nicolaas PLG Verhoeff. “Alzheimer’s disease and infection: do infectious agents contribute to progression of Alzheimer’s disease?.” Alzheimer’s & Dementia 5.4 (2009): 348-360. [R]