{"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":"2026-08-03T11:19:31","modified_gmt":"2026-08-03T18:19:31","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
\"\"<\/a><\/figure>\n\n\n\n

Genetically defined types of A<\/a>lzheimer\u2019s disease can be subtyped\u00a0 into either early or late onset. All of the reported genetically defined types\u00a0 share the common endpoint pathology of Neurofibrillary Tangles, Lipid inclusions in Microglia, and Extracellular Amyloid Plaques. Both LOAD and EOAD <\/a>are heterogeneous\u00a0 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, \u00a0 while LOAD has a 70% Polygenic component and a 30 % Sporadic\u00a0 subtype. Multiple frameworks to describe AD have been proposed including, Complex Biological System Model<\/strong><\/a>s with AD subtypes<\/strong> , AD as an offshoot of the Biology of Agin<\/a>g, The Multiple hit theory <\/strong><\/a>\u00a0of Genetics, Oxidative stress, chronic inflammation, and disrupted electron energy\u00a0 homeostasis\u00a0<\/a><\/p>\n\n\n\n

LOAD – Late Onset Alzheimer’s Disease<\/h2>\n\n\n\n
\"\"<\/a><\/figure>\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, Infant exposure to added sugar, Mediterranean diet, Coffee consumption, High Fat Cream Consumption, Microbial Ferulic Acid Production in the Intestine, Physical Activity Level, Medications including  levetiracetam- Keppra, Education Level, Social Experiences, Brain Exercises, Periodontitis, and\/or other Risk Factors .<\/strong><\/p>\n\n\n\n

Amyloid Predominant C1\/C2 <\/p>\n\n\n\n

\n
\n
<\/tr>
Stage<\/td>Event <\/td>Key Consequences<\/td><\/tr>
0<\/td>Genetics for Amyloid predominant – = ApoE4, Amyloid gene duplication\/Down’s Syndrome, Presenilin 1,2 . <\/td>Dysfunctional amyloid 42 production

<\/td><\/tr>
1<\/td>Innate Metabolic Cascades and Mitochondrial Dysfunction<\/td>Reduced ATP\/NADH Energy Production<\/td><\/tr>
2<\/td>Aging- decreased DNA methylation —> Line-1 \/SVA activation<\/td>Retrotransposon derepression, cGAS-STING overactivation– Senescence<\/td><\/tr>
3<\/td>Pathogenic App specific CD8 T cell and Monocyte-Microglial brain infiltration<\/td>Interferon gaama, perforin, SASP factors, Chronic Neuroinflammation<\/td><\/tr>
4<\/td>Neuronal\/Astrocyte\/OPC-OL\/Microglial Cell Death and Neuronal Network Failure<\/td>Karyoptosis, Apoptosis, synaptic loss, Progressive Neurodgeneration<\/td><\/tr>
<\/td><\/td><\/td><\/tr><\/tbody><\/table><\/figure>\n<\/div><\/div>\n<\/div><\/div>\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

<\/p>\n\n\n\n

Tau Predominant Types A, B1, B2<\/p>\n\n\n\n

Stage<\/td>Event<\/td>Consequence<\/td><\/tr>
0<\/td>Birth – HLA-DR risk genes for neurotropic infections<\/td>Tau and Amyloid production<\/td><\/tr>
1<\/td>HSV1 in hippocampal glutamatergic neurons or other brain cell infection<\/td>Chronic neuronal\/astrocyte\/microglial\/OPC stress and oxidative environment<\/td><\/tr>
2<\/td>Oxidized alpha MIF Signaling<\/td>Tau phosphorylation and oligomer formation<\/td><\/tr>
3<\/td>Tau oligomers activation of Transposons<\/td>cGAS-STING activation by LINE-1 elements and senescence induction<\/td><\/tr>
4<\/td>anti neurotropic CD8 T cell infiltration into brain<\/td>Either protective or destructive T cells impact on the brain<\/td><\/tr>
5<\/td>Cell Death and Network Failure<\/td>Apoptosis, necroptosis, synaptic loss, progressive neurdegeneration<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n

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

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

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

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\n\n\n

<\/p>\n","protected":false},"excerpt":{"rendered":"

MCI and All Dementias : EOAD and LOAD Genetically defined types of Alzheimer\u2019s disease can be subtyped\u00a0 into either early or late onset. All of the reported genetically defined types\u00a0 share the common endpoint pathology of Neurofibrillary Tangles, Lipid inclusions in Microglia, and Extracellular Amyloid Plaques. Both LOAD and EOAD are heterogeneous\u00a0 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":66,"href":"https:\/\/www.telemedical.com\/wordpress\/wp-json\/wp\/v2\/pages\/11022\/revisions"}],"predecessor-version":[{"id":11582,"href":"https:\/\/www.telemedical.com\/wordpress\/wp-json\/wp\/v2\/pages\/11022\/revisions\/11582"}],"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}]}}