{"id":11022,"date":"2025-11-23T17:09:50","date_gmt":"2025-11-24T01:09:50","guid":{"rendered":"https:\/\/www.telemedical.com\/wordpress\/?page_id=11022"},"modified":"2026-02-20T20:17:57","modified_gmt":"2026-02-21T04:17:57","slug":"hypotheses-molecular-and-cellular","status":"publish","type":"page","link":"https:\/\/www.telemedical.com\/wordpress\/home\/alzheimers\/hypotheses-molecular-and-cellular\/","title":{"rendered":"Molecular and Cellular Basis of AD."},"content":{"rendered":"\n

MCI and All Dementias<\/a> : EOAD and LOAD<\/h2>\n\n\n\n
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Genetically defined types of A<\/a>lzheimer\u2019s disease can be subtyped  into either early or late onset. All of the reported genetically defined types  share the common endpoint pathology of Neurofibrillary Tangles, Lipid inclusions in Microglia, and Extracellular Amyloid Plaques. Both LOAD and EOAD <\/a>are heterogeneous  diseases that are caused by specific genetic and exposome factors (, medical history, diet, exercise, and environmental factors). EOAD has about 90 % sporadic component and 10% familial,   while LOAD has a 70% Polygenic component and a 30 % Sporadic  subtype.<\/p>\n\n\n\n

Framework 1- Complex Biological System Model<\/strong><\/a>s with AD subtypes<\/strong><\/p>\n\n\n\n

Framework 2 –AD as an offshoot of the Biology of Aging<\/a><\/p>\n\n\n\n

Framework 3 <\/a>– The Multiple hit theory <\/strong><\/a> of Genetics, Oxidative stress, chronic inflammation, and disrupted electron energy  homeostasis <\/a><\/p>\n\n\n\n

LOAD<\/h2>\n\n\n\n
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Leading frameworks for the pathology of AD<\/p>\n\n\n\n

Tau Predominant seen in microglial methylome data, brain transcriptome signatures, and Tau PET Scan analysis<\/p>\n\n\n\n

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33% A <\/strong>Neuronal dysfunction predominant<\/a> – Most likely connected to Infection Related Sporadic AD of both Late and Early versions.  May be related to Exitotoxicity – Mitochondrial dysfunction  and Apoptosis pathway contributions.<\/strong><\/p>\n\n\n\n

33% <\/strong>B1<\/strong><\/a> Astrocyte Predominant – Blood Brain Barrier and Glymphatic Flow – Amyloid Clearance connected   and<\/strong><\/p>\n\n\n\n

        <\/strong>B2<\/strong><\/a> Endothelial then Astrocyte Predominant – CardioVascular Disease and Vascular Dementia connected<\/strong><\/p>\n\n\n\n

Amyloid Predominant seen in microglial methylome data  and brain transcriptome signatures<\/p>\n\n\n\n

\"\"<\/a><\/figure>\n\n\n\n

33% <\/strong>C1<\/strong><\/a> – OPC with High Microglial Contribution – Involving pathogenic CD8 T Cells and APoE4 influenced<\/strong><\/p>\n\n\n\n

C2<\/strong><\/a> – OPC with Low Microglial Contribution – A primary Oliodendrocytopathy – not involving CD8 T cells.<\/strong><\/p>\n\n\n\n

ApoE genotype stratified patients differentially express proteomes leading to different LOAD Neuropathology Types depending on their Exposome and Polygenic Risk Factors. Exposome factors include  HSV1, Lithium in diet, Mediterranean diet, Coffee consumption, High Fat Cream Consumption, Microbial Ferulic Acid Production in the Intestine, Physical Activity Level, Medications including <\/strong> levetiracetam- Keppra<\/strong>, Education Level, Social Experiences, Brain Exercises, Periodontitis, and\/or other Risk Factors .<\/strong><\/p>\n\n\n\n

Pan ApoE genotype or ApoE independent Proteome Biomarkers<\/strong><\/p>\n\n\n\n

    \n
  1. Inflammation- ? IL-6 or interferon gamma  from Local CD8 T cells  or Senescent Astrocytes  communicating with  Microglia, and OPCs.<\/strong><\/li>\n\n\n\n
  2. Mitochondrial dysfunction- Due to ApoE4 and Hyperactivity of Excitotoxic Glutamate Neurons and Locus Ceruleus noradrenergic Neurons impacted by CD8 T cell binding to HLA 1<\/strong><\/li>\n\n\n\n
  3. Dyslipidemia- due to faulty transfer of FFA from ApoE4 to a FFA binding protein in late endosomes or mitochondria.<\/strong><\/li>\n<\/ol>\n\n\n\n

    Th1 like app recognizing  senescent CD8 T cells TREMs  >>>> Traverse Blood Brain Barrier initially as CEMs  –  They then migrate into CSF accessible tissues to cause Neurodegeneration through binding to  MHC Class 1 expressing Neurons located in Locus Ceruleus, Hippocampus  and other Areas.<\/strong><\/p>\n\n\n\n

    Pathological mechanisms and treatment progression of Alzheimer\u2019s disease | European Journ<\/a><\/p>\n\n\n\n

    All Pathways<\/p>\n\n\n\n

    \"\"<\/a><\/figure>\n\n\n\n

    Biomarker Evolution and Staging<\/strong><\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

    MCI and All Dementias : EOAD and LOAD Genetically defined types of Alzheimer\u2019s disease can be subtyped  into either early or late onset. All of the reported genetically defined types  share the common endpoint pathology of Neurofibrillary Tangles, Lipid inclusions in Microglia, and Extracellular Amyloid Plaques. Both LOAD and EOAD are heterogeneous  diseases that are […]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":7860,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"class_list":["post-11022","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/www.telemedical.com\/wordpress\/wp-json\/wp\/v2\/pages\/11022","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.telemedical.com\/wordpress\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/www.telemedical.com\/wordpress\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/www.telemedical.com\/wordpress\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.telemedical.com\/wordpress\/wp-json\/wp\/v2\/comments?post=11022"}],"version-history":[{"count":51,"href":"https:\/\/www.telemedical.com\/wordpress\/wp-json\/wp\/v2\/pages\/11022\/revisions"}],"predecessor-version":[{"id":11478,"href":"https:\/\/www.telemedical.com\/wordpress\/wp-json\/wp\/v2\/pages\/11022\/revisions\/11478"}],"up":[{"embeddable":true,"href":"https:\/\/www.telemedical.com\/wordpress\/wp-json\/wp\/v2\/pages\/7860"}],"wp:attachment":[{"href":"https:\/\/www.telemedical.com\/wordpress\/wp-json\/wp\/v2\/media?parent=11022"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}