A scoping review of the wide array of Alzheimer’s disease theories and hypotheses supports a multifactorial etiology
Bibliographic record
Abstract
BACKGROUND: There is a common agreement that Alzheimer's disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed. Our objective was to perform a scoping review of original manuscripts describing hypotheses and theories of AD published in past decades. METHODS: We reviewed 127 original manuscripts that fulfilled our inclusion criteria out of more than 13,807 references extracted from open databases (from inception to 14 Sept 2023). Each entry was characterized as having a single or multifactorial focus and assigned to one of 15 theoretical groupings. Impact was tracked using open citation tools. RESULTS: We found that three quarter of studies proposed a hypothesis characterized as being single-focus (97/127), with the most important theoretical groupings being the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Infection and Cerebrovascular. Three stages can be discerned in terms of hypotheses generation. The first phase (∼1980-1995) included the establishment of the main thrusts that have endured to this day (Amyloid, Glial, Infection, Inflammation, Metabolism, Oxidative stress, and Proteinopathies hypotheses; multifactoriality; and neurotoxicity). In the second phase (1995-2005), the importance of the Cerebrovasculature, Mitochondrial dysfunction, and Neurotransmitters were recognized. Lately (2005-2023), evidence towards Genetics (outside of the autosomal dominant form of AD), and especially Gut/Brain interactions came to the fore. Impact, as measured by total citations count, followed a similar pattern. Out of a total of 19,996 citations for the 127 papers, the most cited single-focused grouping was Amyloid (52%), followed by Mitochondrial dysfunction (6%, reaching 10.0% when adding Metabolism articles), then Cerebrovascular (5%) and Oxidative Stress (4%). CONCLUSION: When viewed together, these multi-faceted reports reinforce the notion that AD affects multiple sub-cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. Future work should integrate these competing views into a comprehensive, systemic framework able to capture individual and combinatorial factor evolutions and interactions, to manage its inherent complexity.
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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 | 0.036 | 0.142 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.004 | 0.005 |
| Bibliometrics | 0.038 | 0.035 |
| Science and technology studies | 0.002 | 0.003 |
| Scholarly communication | 0.007 | 0.006 |
| Open science | 0.003 | 0.003 |
| Research integrity | 0.004 | 0.002 |
| Insufficient payload (model declined to judge) | 0.009 | 0.002 |
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".