Adult Cognitive Disease

The load-bearing concepts most referenced

A 87

Abeta aggregation as necessary initiating event10 Abeta as molecular prime mover2 Abeta as physiological modulator of synaptic homeostasis4 Abeta as stress response marker6 Activated microglia imaging for treatment guidance3 Acyloxyacyl Hydrolase Neuroprotection6 AD as a double prion disorder5 AD as accelerated aging of Abeta management3 AD as accelerated normal aging3 AD as accumulation of insults exceeding homeostasis4 AD as addiction-like circuit pathology3 AD as autoimmune disorder6 AD as clinical syndrome not disease3 AD as multiple diseases3 AD as systemic disease not limited to brain3 AD caused by APP dysregulation not Abeta per se5 AD-diabetes shared mechanism3 Adrenergic Signaling21 Adult hippocampal neurogenesis restoration10 Adult Neurogenesis11 Age-dependent feedback loops in neurodegeneration9 Age-dependent threshold model5 Age-related immune dysfunction enables neurotropic viruses10 Aging accelerators and decelerators3 Aging as Mechanism3 Aging as root cause of AD4 Aging-epigenetic-genetic interaction3 AI Disease Model Discovery2 AI Neurotherapeutic Discovery6 AI-based early diagnosis5 Alpha-sheet toxicity in disease pathogenesis5 Aluminum as primary environmental cause4 Aluminum driving amyloid production4 Amyloid and tau as secondary byproducts3 Amyloid and tau as secondary phenomena3 Amyloid as age-related phenomenon5 Amyloid as antimicrobial defense10 Amyloid as compensatory mechanism8 Amyloid as defense mechanism against parasites3 Amyloid as downstream secondary3 Amyloid as innate immune defense gone awry3 Amyloid as secondary to synaptic dysfunction3 Amyloid clearance as important as deposition3 Amyloid Clinical Disconnect4 Amyloid Nucleation5 Amyloid plaques as fibrotic scar tissue from BBB repair9 Amyloid structural diversity and toxicity5 Amyloid-beta as innate immune defense5 Anti Ferroptotic Botanicals7 Anti-prion therapeutics as novel drug strategy9 Anti-TNF-alpha therapeutic strategy4 Antibody Target Specificity9 Antimicrobial Defense10 Antimicrobial hypothesis of amyloid12 Antioxidant defense failure7 ApoE isoform-heparin binding differences14 ApoE-centric unified model8 APOE4 Endolysosomal Dysfunction4 APOE4 Pathogen Interaction7 ApoE4 structural vulnerability6 APP and tau pathology linked through transport disruption3 APP as dependence receptor5 APP processing pathway3 Astrocyte network management hypothesis6 Astrocyte-centric AD hypothesis9 Astrocyte-centric AD mechanism8 Astrocyte-driven amyloid buildup3 Asymptomatic AD Phenotyping2 Atherosclerosis as AD driver3 Atherosclerotic obstruction4 ATN biomarker classification system5 ATP depletion as direct trigger of tau pathology3 ATP-chaperone-protein folding axis7 Autoimmune contribution via BBB compromise3 Autoimmune Neurodegeneration4 Autophagic Collapse22 Autophagic Flux11 Autophagy51 Autophagy Dysfunction7 Autophagy-amyloid coupling5 Autophagy-lysosomal failure9 Autophagy-metabolism crosstalk in AD4 Axon initial segment as key disease locus6 Axonal atheroma hypothesis3 Axonal Transport10 Axonal transport failure as unifying mechanism4 Ayurvedic medicine approach3

B 28

Bacterial exudate-driven neurodegeneration9 Barrier dysfunction pathology5 BBB as gatekeeper failure3 BBB breakdown cascade9 BBB degradation and pathogen invasion3 BBB-mediated vascular contribution3 BCG Immune Checkpoint Modulation13 Beta Alanine Neurotransmission5 Bimodal brain (inference vs training)4 BIN1 Autophagic Regulation6 Bioenergetic Collapse16 Bioenergetic defects as early events4 Bioenergetics11 Biogenic amines disrupt cellular translation fidelity4 Biological spintronic sensing6 Biomarker gap in neurology3 Blood-based biomarker discovery3 Blood-based biomarker panels for preclinical detection4 Blood-based lipid and protein module biomarkers11 Brain buoyancy hypothesis3 Brain DNA blueprint is altered in AD neurons5 Brain hemisphere synchronization4 Brain Immune Interface10 Brain Lipid Homeostasis Restoration3 Brain plasticity decline driving AD progression3 Brain structure-function relationships3 Brain-glucose-steal as mechanism of cognitive impairment4 Brain-heart health connection6

C 62

Ca2+-cAMP signaling convergence in neurodegeneration3 Calcium dyshomeostasis as upstream AD mechanism5 Calcium Homeostasis7 Calcium signaling disruption3 Calcium-mediated tauopathy3 Cannabinoid Neuroprotection1 Cannabis as primary environmental AD cause3 Causation pyramid model3 CD74 Microglial Signaling2 CDK3 Cell Cycle Toxicity5 Cellular Identity5 Cellular Senescence45 Cellular Vectors3 Cerebral Self-Management Process3 Childhood experience shaping AD vulnerability4 Cholesterol deficiency driving AD pathology18 Cholesterol Homeostasis23 Cholesterol Transport14 Cholinergic network failure in AD13 Cholinergic neuron vulnerability11 Cholinergic primacy in AD13 Chronic Excitatory Insufficiency16 Chronic intracellular infection model5 Chronic intracellular pathogen-driven neurodegeneration3 Chronic intranasal infection explaining slow AD progression3 Chronic mild hypothermia as AD cause3 Chronic neuroinflammation from infection3 Chronic neuroinflammation from periphery7 Chronobiologic neuroprotection via melatonin7 Circadian disruption as cause not consequence5 Circadian Immune Regulation8 Circadian regulation of glial function5 Clearance failure vs. overproduction3 Cognitive fitness as disease-modifying factor5 Cognitive reserve building11 Cognitive reserve hypothesis9 cognitive resilience26 Cognitive resilience as dynamic protective concept6 Community-based dementia support model3 Compensatory Homeostasis5 Computational AD Subtyping2 Computational disease subtyping3 Computational models of associative memory3 Continuum of senile cognitive decline14 Convergent risk factor pathways6 Convergent signaling through Wnt-PCP-RhoA-ROCK5 Convergent Synaptic Collapse12 Cortisol-driven secretase dysfunction10 Coverage Fraction4 Cranial bone compression causing brain atrophy9 CRISPR-like protein immunity model4 Critique of amyloid dogma3 Critique of mono-causal therapeutics4 Cross Disease Prion Mechanisms5 Cross-disease protein aggregation parallels3 CSF flow dynamics4 Culturally adapted dementia care3 Cumulative axonal defect accumulation8 Cumulative inflammation threshold for neurodegeneration4 Curcumin multi-target action4 Cytoskeletal disorder as core pathology5 Cytoskeletal Dynamics7

D 17

Dark Genome Variation13 Dehydration as AD risk factor3 Denervation supersensitivity4 Destructive emotions as root cause of all disease8 Dietary Fatty Acid APOE4 Rescue3 Dietary intervention as primary prevention6 Dietary neuroprotection3 Dietary neurotoxin exposure as modifiable risk factor5 Dietary Sodium Neurodegeneration6 Disease as behavioral feedback mechanism5 Disorientation vs memory loss distinction4 Dose-dependent mitochondrial dysfunction determines pathology type6 Double-hit mutation hypothesis6 Dual Pathogen AD Pathogenesis5 Dynamic and region-independent disease mechanisms5 Dynamic neural circuit failure model5 Dysregulated homeostatic units6

E 43

Early-life neuroinflammatory priming8 ECM remodeling in neurodegeneration6 Eight factors of dementia framework3 Electrochemical basis of cognitive decline3 Emotional transformation as therapeutic approach3 Endocrine-circadian-inflammation axis3 Endolysosomal Dysfunction10 Endosomal Lysosomal Network1 Endosomal Trafficking9 Energy failure as primary AD driver3 Energy failure as root cause3 Energy Metabolism6 Energy metabolism decline3 Energy metabolism failure drives neurodegeneration3 Entropy acceleration from maladaptive thinking7 Entropy as organizing principle10 Environmental and emotional risk factors3 Environmental and socioeconomic risk factors3 Environmental CxI inhibitors as AD etiological agents4 Environmental neurotoxicology3 Environmental Toxicology3 Environmental toxicology of neurodegeneration3 Environmental toxin contribution3 Environmental vs. genetic causation3 Epidemiological correlation argument5 Epigenetic and genetic interplay4 Epigenetic Regulation5 Epigenetic regulation of AD genes3 Epigenetic Repression6 Equilibrium at criticality5 ER Stress10 ESCRT III Membrane Scission6 Evolutionary biochemistry of disease3 Evolutionary framework for AD causation3 Evolutionary mismatch between genes and modern lifestyle15 Evolutionary mismatch hypothesis6 Evolutionary vulnerability of brain structures4 Excitatory Neurotransmission4 Exercise as cognitive catalyst9 Existing HIV RT inhibitors as potential AD therapeutics6 Expanded Prion Paradigm7 Exponential exposure-prevalence correlation3 Extracellular Matrix Pathology3

F 9

Factor classification and connectivity7 Familial vs sporadic AD4 Ferroptosis16 Ferroptosis as implicated pathway11 Ferroptosis in Neurodegeneration10 Ferroptosis Phase II Oligodendrocyte11 Five-factor quintet model of AD causation3 Folate-B12 therapeutic intervention4 Functional model of neuron-glia interaction3

G 27

GAG-driven AD pathogenesis3 Gene dosage of APP directly causes pathogenesis4 Gene Environment Interaction6 Genetic evidence as gold standard for causality5 Genetic shortcuts in FAD vs LOAD3 GI-tract microbiome neurotoxicity8 Glia-neuron interaction dysfunction3 Glial Biology2 Glial contribution to neurodegeneration3 Glial inflammatory response3 Glial-driven neuroinflammatory disease model3 Gliotransmitter dysregulation3 Glycobiology3 Glycolysis-fat oxidation metabolic switch11 Glymphatic Clearance9 Glymphatic clearance failure10 Glymphatic clearance failure amplifies pathology11 GlyNAC as novel nutritional therapeutic for AD4 Gravity and cerebral perfusion4 Gravity-dependent brain perfusion4 Gravity-dependent brain vulnerability4 GSH deficiency as root cause of multiple AD defects9 Gut Brain Axis6 Gut Microbiome Lipid AD Axis8 Gut-brain axis in AD3 Gut-brain axis in neuroinflammation3 Gut-brain axis via tryptamine production4

H 10

Head-down time and dementia3 Head-down time hypothesis3 Health disparities in AD4 Hippocampal hyperexcitability as pre-AD state4 Hippocampal neuron vulnerability3 Holistic multi-level therapeutic approach3 Homeostatic disruption model of AD2 Homeostatic Microglial Collapse12 Host Defense Peptides6 Human-germ interaction model6

I 35

Iatrogenic contribution via medications3 IDE-insulin-Abeta competition10 Immediate preventive interventions4 Immune Checkpoint Therapy12 Immune-pathogen interaction model6 Immunometabolic Checkpoints7 Immunometabolism7 Immunosenescence as central aging mechanism3 Inciting injury model3 Infection as co-factor in neurodegeneration3 Infection-triggered epigenetic cascade model3 Infectious etiology of AD2 Infectious etiology of late-onset AD8 Infectious etiology of LOAD3 Infectious origin of Alzheimer's disease3 Infectious-toxic-genetic synergy3 Inflamm-aging as disease driver6 Inflammaging integrates hallmarks of aging7 Information Theoretic Transcriptomics6 Innate immune function of amyloid proteins3 Innate immune-mediated plaque formation3 Innate Immunity19 Innate immunity failure in sporadic AD5 Innate immunity network dysregulation in AD3 Inside Out Plaque19 Integrated molecular-to-network perspective5 Integrative complementary therapy approach9 Integrative treatment across medical traditions8 Interconnected homeostatic disruption3 Interlinked pathological cascades3 Intracellular Amyloid9 Intraneuronal amyloid accumulation as primary event10 Iron Brain Paradox4 Iron Dyshomeostasis4 iron dyshomeostasis in AD3

K 2

Ketogenic diet as primary AD therapy4 Kinase Inhibitor Neuroprotection5

L 25

L-type CCB neuroprotective strategy8 LC Morphology What is Established7 Lifestyle and behavioral factors4 Lifestyle as causal anchor10 Lifestyle intervention for cognitive reversal3 Lifestyle intervention for neurodegeneration3 Lifestyle Microglial Modulation5 Lifestyle-based AD prevention6 Limbic brain as circavital clock locus5 Lipid Dysregulation3 Lipid homeostasis as AD driver3 Lipid Metabolism10 Lipid Peroxidation13 Lipid peroxidation cascade at synapse12 Lipid Transport8 Lipid-driven neurodegeneration3 Lipid-glycan crosstalk in AD5 Liver-brain metabolic axis3 Lock and Key memory reactivation7 Locus coeruleus as ground zero12 Long preclinical phase of AD pathology5 Longitudinal observational evidence6 Lysosomal Acidification21 Lysosomal Dysfunction18 Lysosomal Storage Disease6

M 61

Matrix Sulfation Node12 Mechanical risk factor for AD3 Meditation as neuroprotective intervention6 Membrane Biology3 Membrane Biophysics9 Membrane Lipid Dysregulation2 Membrane lipid pathology in AD3 Memory building framework4 Memory construction disease model3 Memory encoding-retrieval interference3 Meningeal T Cell Regulation8 Mercury as primary AD cause5 Metabolic dysfunction as AD driver3 Metabolic dysfunction in neurodegeneration3 Metabolic origin of amyloid and tau3 Metabolic-neurodegenerative disease axis3 Metabolic-neurodegenerative disease connection4 Metal-protein interaction in disease3 Microbial Pathogenesis5 Microbiome-immune-brain integration11 Microbleeds as initiating vascular event in AD5 Microglial cytokine storm12 Microglial dysfunction as early event3 Microglial Immunometabolism2 Microglial Lipid Regulation2 Microglial Protein Biomarkers11 Microglial senescence as AD trigger10 Micronutrient therapeutic potential3 Microtubule quantum information processing8 Mind-body causation in neurodegeneration3 Mind-body correspondence in disease formation4 Mind-body-soul integration for treatment7 miRNA as mechanistic link3 Mitochondrial Dysfunction21 Mitochondrial inheritance and AD3 Mitochondrial theory of aging4 Modifiability of AD risk6 Modifiable risk factor intervention5 Morphological analysis methodology13 Mosaic model of aging brain6 Moving brain hypothesis5 MTHFR as catalytic pre-existing factor10 Multi-cellular pathology6 Multi-factorial etiology of AD3 Multi-level heterogeneity of AD3 Multi-omics network approach to AD3 Multi-pathway AD pathophysiology review4 Multi-system medicine approach to AD3 Multi-target vs mono-target3 Multi-targeting the amyloid hypothesis4 Multidomain AD Intervention6 Multifactorial causal network3 Multifactorial convergence model3 Multifactorial etiology3 Multifactorial modulation of disease trajectory5 Multifactorial prevention through modifiable risk factors6 Multifactorial risk accumulation model3 Multipathology convergence theory3 Multiple chronic stressors3 Multiple converging factors in unified tauopathy framework4 Musical reminiscence as neurological intervention3

N 38

NAD+ depletion drives neurodegeneration3 Natural product polytherapy4 Navigable database of AD factors3 NbM as origin of sporadic AD3 Necrotic Cell Death4 Need to understand normal APP function6 Network-based combination therapy7 Network-based neurodegeneration3 Neural circuit breakdown model4 Neural Oscillations4 Neurodegeneration as aberrant development5 Neuroendocrine shift at menopause4 Neuroimmune Surveillance11 Neuroimmunology9 Neuroinflammation39 Neuroinflammation as primary driver connecting all AD subsystems3 Neuroinflammatory disequilibrium4 Neuronal activity as survival factor5 Neuronal Excitability5 Neuronal lysis forming extracellular plaques8 Neuronal maturation context in disease6 Neuronal network degradation as substrate of dementia5 Neuroplasticity-based cognitive enhancement4 Neurotransmitter disruption cascade3 Neurovascular dysfunction as initiating event12 Neurovascular injury-repair cycle driving disease progression11 Neurovascular unit as disease origin8 NF-kB-miRNA inflammatory cascade5 Non-dimensional quantum pathway3 Non-enzymatic AChE signaling7 Non-invasive thermal therapy3 Non-optimal aging rather than normal aging process3 Non-pharmacological cognitive enhancement4 Novel systems analysis approach3 Nuclear pathology as early AD mechanism11 Nutritional deficiency as AD cause6 Nutritional modulation of neuroinflammation3 Nutritional rebalancing over pharmacological intervention3

O 17

Olfactory Route Neuroinvasion8 Olfactory vector hypothesis10 Oligomer hypothesis of neurotoxicity6 Omics Driven Profiling2 Omnigenic AD architecture5 Onset vs Progression6 Oral Microbiome5 Oral-brain infection axis3 Oskar Fischer Founder20 Oxidative and nitrative stress as primary driver3 Oxidative Stress13 Oxidative stress and apoptosis pathways4 Oxidative stress as trigger3 Oxidative stress as unifying mechanism3 Oxygen as fundamental homeostatic mediator4 Oxygen deficiency as root cause7 Oxygenation-based therapeutic approach2

P 53

P. gingivalis as keystone pathogen5 PANTHOS26 Parasitic mite infestation as AD cause3 Pathogen Driven Neurodegeneration2 Pathogen-specific AD subtypes5 Pathological supersystem model3 Peptide Neurotherapeutics5 Perineuronal Nets21 Peripheral Immunocyte Regulation4 Peripheral Lipid Biomarkers7 PERK DLX1 Tau Axis5 Peroxidized ApoE as proximate cause11 Peroxynitrite-mediated neurodegeneration3 Personalized multifactorial etiology4 Phagocytic Clearance9 Pharmacological neuroprotection3 Phase Measurability13 Physics of organisms approach4 Plaque IgG Sequestration4 Plaque Origin What is Established26 Plaque-cognition dissociation6 Polymicrobial brain infection2 Polymicrobial causation of AD3 Polytherapeutic natural product approach4 Population-specific AD genetic signatures3 Post-translational modification as prion trigger3 Post-translational modification dysregulation6 Precision genomics approach3 Precision Medicine AD5 Precision medicine approach3 Precision medicine for AD3 Precision medicine protocol8 Preclinical Phase Activity5 Presymptomatic Lipidomic Signatures3 Prion infectivity distinct from insoluble protein accumulation6 Prion-like disease propagation18 Probabilistic multi-cause disease etiology3 Production-clearance equilibrium5 Programmed aging clock model of AD3 Proteasome Tau Feedback18 Protein biosynthesis interference as root cause4 Protein denaturation as disease driver3 Protein Misfolding7 Protein templating and seeding10 Proteoglycan role in amyloid formation6 Proteostasis15 Proteostasis Collapse3 Proteostasis disruption5 Psychological origins of neurodegeneration4 Psychology as primary disease trigger3 Psychosocial Risk Factors4 Psychosomatic cascade to neurodegeneration3 Psychosomatic model of Alzheimer's disease3

Q 2

Quality Control Collapse11 Quantum consciousness in neurons3

R 17

Reasoning-numerical cognitive separation6 Receptor-based therapeutic approach3 Receptor-mediated amyloid internalization6 Redox chemistry therapeutic approach3 Redox signaling as central mechanism3 Reelin-ApoE receptor axis disruption38 Region-selective neuronal vulnerability6 Repurposing antihypertensives for AD4 Resilience as key to understanding AD clinical expression3 Retrogenesis model4 Retrotransposon Activation5 Retroviral-like mechanisms drive disease propagation18 Revisiting failed drug trials3 Risk factor convergence3 RNA-based diagnostics and therapeutics5 ROS-calcium signaling axis3 Runaway synaptic modification hypothesis3

S 53

Selective Tau Disruption4 selective vulnerability of PV interneurons1 Self-DMN dysfunction hypothesis3 Sense-making failure and cellular conflict7 Sensory Loss Dementia Correlation5 Sex Differences in Tauopathy2 Sex Dimorphic AD Mechanisms3 Sex Specific MiRNA Signatures3 Sex-based hemoglobin differential4 Sex-specific AD vulnerability3 Sex-specific disease mechanisms5 Sigma-1 receptor-mediated neuroprotection3 Signal Insufficiency Model (SIM)10 Silica water as protective intervention4 Single Cell AD Signatures5 Sinus-brain barrier breach enabling neurodegeneration5 SIRT1 neuroprotection3 Sleep position and brain maintenance3 Sleep posture and brain maintenance3 Sleep timing and gravitational stretching8 Sleep-AD connection4 Small molecule polypharmacology3 Small ncRNA regulation of neurodegeneration5 Solar gravitational muscle constriction theory6 Somatic Mosaicism in AD11 Somatic mutations as novel therapeutic targets9 Somatic recombination creates pathogenic gene variants25 SORL1 Lysosomal Function6 SorLA Lipid ER Regulation6 Sphingolipid Signaling5 Spiritual and karmic etiology3 SSRI repurposing for neurodegeneration4 Staged anatomical progression7 Substance abuse and neurodegeneration9 Sundowner symptoms from evening muscle constriction6 SuperAgers demonstrate pathology-cognition dissociation5 Synapse loss as primary event3 Synaptic Competition5 Synaptic dysfunction as primary driver3 Synaptic impairment as primary pathomechanism3 Synaptic Pathology13 Synaptic Physiology2 Synaptic Plasticity12 Synaptic plasticity failure3 Synaptoblastic vs synaptoclastic balance5 Syndromic Complexity3 Systemic circulating factors governing neurodegeneration5 Systemic disease beyond CNS3 Systemic disease interaction model3 Systemic to Central Immune Signaling3 Systems approach to interconnected AD pathological hallmarks3 Systems Biology9 Systems thinking and feedback loops3

T 31

T14 feedforward toxicity cascade5 T14 Toxin Antagonism7 Tau as conditional prion8 Tau as primary causative factor over amyloid3 Tau Biomarkers9 Tau Pathology22 Tau prions drive disease more than Abeta prions5 Tau Propagation27 Tau Scaffolding Interactions5 Tauopathy primacy over amyloidopathy6 Tauopathy Sleep Disruption2 Temperature-dependent protein misfolding6 Terminal thoughts and genetic change3 Theoretical brain cognition framework3 Theory integration across domains7 Three-actor-group pathogenesis3 Threshold and set point model for neurodegeneration3 TNF-alpha as central AD mediator4 TOMM40 Import Gate22 Torsion field theory of AD3 Toxic Abeta species and PTMs3 Traditional medicine integration4 Trained Immunity9 Transcriptional Pause Release6 Transcriptomic Isoform Complexity8 Translational Regulation in Tauopathy5 Transsulfuration pathway dysfunction4 Transsynaptic tau propagation15 Trauma Induced Viral Reactivation6 TXNIP as therapeutic target3 Type 2 diabetes as AD risk factor3

U 2

Understanding Abeta function key to early identification4 Unified theory of AD etiology5

V 13

Vascular Amyloid Interaction5 Vascular and inflammatory contributions3 Vascular dysfunction as earliest detectable change3 Vascular insufficiency hypothesis6 Vascular-mechanical etiology3 Vascular-metabolic-infectious convergence3 Vascular-sleep interaction3 Vesicular Trafficking7 Vessel Associated Microglial Activation10 Viral infection triggers chronic brain inflammation3 Viral Pathogenesis3 Viral trigger hypothesis for neurodegeneration3 Vitamin E-miRNA-inflammation axis5

W 2

Wear and tear accumulation3 Wnt-GSK3-beta pathway integrating amyloid and tau pathology3

Z 1

Zeitgeber-driven neurodegeneration3

Concepts

The load-bearing concepts most referenced

Autophagy

Cellular Senescence

Neuroinflammation

Reelin-ApoE receptor axis disruption

Tau Propagation

cognitive resilience

PANTHOS

Plaque Origin What is Established

Somatic recombination creates pathogenic gene variants

Cholesterol Homeostasis

Autophagic Collapse

Tau Pathology

A 87

B 28

C 62

D 17

E 43

F 9

G 27

H 10

I 35

K 2

L 25

M 61

N 38

O 17

P 53

Q 2

R 17

S 53

T 31

U 2

V 13

W 2

Z 1

Discussion