Alzheimer’s Disease as an Autoimmune Disease
Bibliographic record
Abstract
Abstract Background The identification of new exploitable molecular pathogeneses (beyond the conventional amyloid hypothesis) for Alzheimer’s disease (AD) is a continuing neurotherapeutic priority, and has yielded a range of mechanistic proposals including immunopathy, gliopathy, mitochondriopathy, synaptopathy. However, as these new hypotheses emerge, they are often regarded as mutually exclusive and even in competition. Rather than unconditionally rejecting the role of amyloid‐β (Aβ) (or any other proposed mechanism), the need for a broadly‐encompassing model of AD, which harmonizes multiple divergent theories into a single unified explanation emerges as a much‐needed goal. Method We performed a comprehensive series of in silico, in vitro and in vivo studies explicitly evaluating the atomistic‐molecular mechanisms of cytokine‐mediated and Aβ‐mediated neurotoxicities in AD. Next, new chemical entities were synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small molecule therapeutics. Result In response to various stimuli (e.g. infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon ‘self’ neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane‐penetrating attack by antimicrobial peptides (AMPs) such as Aβ. Following this self‐attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self‐perpetuating autoimmune cycle. AD thus emerges as a brain‐centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti‐Alzheimer’s molecules capable of chemical modification into multi‐site therapeutic modulators targeting AD’s complex immunopathic‐proteopathic pathogenesis. Conclusion Conceptualizing AD as a brain‐centric autoimmune disease of innate immunity (with Aβ as an immunopeptide), and identifying endogenous regulators of this autoimmunity, represents a novel comprehensive conceptualization approach to AD with therapeutic implications.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".