# Practical Drug Development Assessment of AD Therapeutic Hypotheses
## Executive Summary
These seven hypotheses represent scientifically plausible mechanistic frameworks, but translation feasibility varies dramatically. The gap between preclinical promise and clinical reality in AD is not merely a matter of "wrong target" but involves **druggability constraints, tool compound limitations, biomarker gaps, and trial design failures** that are largely independent of mechanism validity.
---
## Hypothesis 1: Synaptic Pruning via Complement Cascade
### Druggability Assessment: MODERATE-HIGH
**Target:** C1q, C3, CR3 (CD11b/CD18)
**Chemical Matter Available:**
| Compound | Stage | Company | Mechanism | Key Limitation |
|----------|-------|---------|-----------|----------------|
| **Eculizumab** (Soliris) | Approved (PNH, aHUS) | Alexion/AstraZeneca | Anti-C5 mAb | Does not cross BBB; terminal complement inhibition |
| **Ravulizumab** (Ultomiris) | Approved | Alexion | Anti-C5 mAb (improved half-life) | Same BBB limitation |
| **ANX005** | Phase 1 (NCT05193743) | Annexon Biosciences | Anti-C1q mAb | First-in-human; BBB penetration undefined |
| **Pegcetacoplan** (Pyrukynd) | Approved (PNH) | Apellis | C3 inhibitor | Subcutaneous; systemic immunosuppression |
| **ANX009** | Preclinical | Annexon | Anti-C1q mAb (fluorescent) | Research tool only |
| **C3 inhibitor (APL-1)** | Phase 1/2 | AL101 (Aston Sci) | C3 fragment | Inhaled formulation for COPD; unclear CNS application |
**BBB Penetration Challenge:** This is the central problem. Eculizumab and ravulizumab are large mAbs (~148 kDa) that demonstrably do not cross the intact BBB. ANX005 is in CNS trials (Guillain-Barré, ALS) but pharmacokinetic data demonstrating brain exposure are not publicly available. If ANX005 does not achieve adequate CNS concentrations, the mechanism is undruggable by this approach.
**Competitive Landscape:**
- Annexon is the most advanced player, with ANX005 in CNS indications
- Roche abandoned bitopertin (GlyT1 inhibitor, indirectly affects complement?) — not directly relevant
- No major pharma has an anti-C1q program specifically for AD
- **Estimated competitive density: LOW** — relatively uncrowded space
**Safety Concerns:**
| Risk | Severity | Mitigation |
|------|----------|------------|
| Systemic infections (encapsulated bacteria) | HIGH | Required Neisseria vaccination; black box warning on eculizumab |
| Immunosuppression | HIGH | Chronic complement inhibition creates infection risk |
| Off-target microglial effects | MODERATE | Complement is involved in Aβ phagocytosis — blocking C1q may *accelerate* amyloid deposition per PMID:27485021 |
| Developmental effects | LOW-MODERATE | C1q knockout mice are viable but complement-dependent synaptic pruning in development is incompletely understood |
**Key Falsification Experiment Needed Before Phase 3:**
Demonstrate that ANX005 (or equivalent) achieves >10% occupancy of C1q in human brain tissue at tolerated doses. Without BBB penetration confirmation, this program cannot proceed regardless of mechanism validity.
**Cost/Timeline Estimate:**
- Phase 1 safety (single ascending dose): ~18 months, ~$15-20M
- Phase 2 biomarker (CSF C1q occupancy, synaptic markers): ~24 months, ~$40-60M
- Phase 3 registration trial: 3-4 years, ~$200-400M
- **Total: 6-8 years, ~$300-500M if biomarker endpoint succeeds**
**Revised Confidence: 0.45 — Reasonable but BBB penetration must be confirmed**
---
## Hypothesis 2: Astrocytic Lactate Shuttle Failure
### Druggability Assessment: LOW-MODERATE
**Target:** PYGL (glycogen phosphorylase), MCT1/MCT4, LDHA
**Chemical Matter Available:**
| Compound | Status | Target | Key Limitation |
|----------|--------|--------|----------------|
| **AR-C155858** | Preclinical tool | MCT1 inhibitor | Poor solubility; no CNS data |
| **AZD3965** | Phase 1/2 (cancer trials NCT01791560) | MCT1 inhibitor | Not CNS-penetrant; cancer-specific toxicity |
| **Syrosingopine** | Preclinical | MCT1/MCT4 | Off-target effects; no CNS formulation |
| **Sodium lactate** | Approved (acidosis) | Nonspecific | Cannot target delivery; wrong formulation for brain |
| **Dichloroacetate (DCA)** | Approved (lactic acidosis) | PDH kinase | Not lactate shuttle-specific; peripheral toxicity |
| **CP-316,311** | Discontinued | PYGL inhibitor | Cardiovascular toxicity; no CNS data |
| **Flavanol derivatives** | Research | MCT modulators | Weak potency; no clinical validation |
**Critical Gap:** There is no CNS-penetrant, selective MCT1/MCT4 modulator in clinical development. The cancer field (AZD3965, AR-C155858) has produced tool compounds, but none are suitable for CNS indication. Creating a lactate prodrug with preferential astrocyte targeting is chemically non-trivial — lactate itself crosses membranes freely via passive diffusion and monocarboxylate transporters on both astrocytes and neurons.
**Competitive Landscape:**
- **Essentially empty.** No major company has a CNS lactate shuttle program.
- Academic/NIH-funded research only
- Cognition Therapeutics has explored metabolic modulators but different targets (sigma-2 receptor)
- **Competitive density: NEGLIGIBLE** — but for good reason (target validation is weak)
**Safety Concerns:**
| Risk | Severity |
|------|----------|
| Seizure risk (lactate accumulation) | HIGH — narrow therapeutic window |
| Metabolic acidosis | MODERATE-HIGH |
| Bidirectional MCT effects | MODERATE — forcing lactate export may disrupt neuronal utilization |
| Astrocyte dysfunction paradox | MODERATE — if ANLS is compensatory, enhancing it may be harmful |
**Key Problem:** FDG-PET preservation in early AD (per PMID:28747277) directly undermines this hypothesis in human patients. If cerebral glucose metabolism is preserved, there is no bioenergetic crisis to rescue.
**Cost/Timeline Estimate:**
- Requires 4-6 years of medicinal chemistry for CNS MCT modulators before any trial
- Total development: 10+ years from scratch
- **Confidence: 0.38 — too many foundational gaps to pursue now**
---
## Hypothesis 3: Glymphatic/CSF Dynamics Failure
### Druggability Assessment: LOW
**Target:** AQP4, Na⁺/K⁺-ATPase, sleep pathways
**Chemical Matter Available:**
| Compound | Status | Target | Key Limitation |
|----------|--------|--------|----------------|
| **Tetracyclines** (minocycline) | Approved (antibiotic); Phase trials in AD | Microglial modulation | Not AQP4-specific; failed in ALS and stroke |
| **AQP4 inhibitors (TEAR peptide)** | Preclinical research | AQP4 block | *Inhibiting* AQP4 — opposite of hypothesis |
| **Sleep-promoting agents** | Various approvals | GABA, orexin, histamine | Suvorexant (orexin antagonist) tested in AD — modest benefit on sleep, no cognitive effect |
| **Beta-agonists** (e.g., salbutamol) | Approved | Vascular effects | Indirect glymphatic modulation; no BBB penetration certainty |
| **Gentamicin** | Approved (antibiotic) | Unclear | Ototoxicity; not glymphatic-specific |
**Critical Problem:** There are no selective AQP4 *activators* in clinical development. The glymphatic hypothesis requires *enhancing* perivascular water flux via AQP4 — but AQP4 knockout mice have minimal phenotypes (PMID:15146181), suggesting either:
1. The glymphatic system is not AQP4-dependent, or
2. Alternative pathways compensate
**Competitive Landscape:**
- University of Rochester / Maiken Nedergaard group (most cited glymphatic work) — no commercial program
- Some interest in sleep enhancement as adjunctive therapy
- **Competitive density: VERY LOW** — but reflects scientific uncertainty, not opportunity
**Safety Concerns:**
| Risk | Severity |
|------|----------|
| Sleep manipulation | MODERATE — sleep architecture is complex; REM suppression has unknown CNS effects |
| AQP4 modulation | LOW-MODERATE — AQP4-null mice are surprisingly normal, suggesting safety margin |
| Vascular effects | MODERATE — any agent affecting vascular pulsatility has hemodynamic risks |
| BBB disruption risk | MODERATE — enhancing bulk flow may disrupt normal CSF-brain homeostasis |
**Key Falsification Needed:** The anatomical controversy (PMID:35697632 showing tracers follow meningeal lymphatic routes rather than periarterial glymphatic pathways) suggests the therapeutic target itself may be incorrectly specified. Before investing in drug development, the field needs consensus on which anatomical pathway is actually operative in human CSF dynamics.
**Cost/Timeline Estimate:**
- Requires fundamental anatomical validation first: 2-3 years
- No clear drug development path: 8-10 years minimum
- **Confidence: 0.42 — scientifically interesting but not druggable currently**
---
## Hypothesis 4: EC-II mTOR Hyperactivity
### Druggability Assessment: HIGH
**Target:** mTORC1 (RAPTOR), TSC1/2, ULK1
**Chemical Matter Available:**
| Compound | Status | Company | Key Advantage |
|----------|--------|---------|---------------|
| **Sirolimus (Rapamycin)** | Approved (transplant, oncology) | Generic | Extensive safety data; BBB penetration demonstrated |
| **Everolimus (RAD001)** | Approved (oncology, TSC) | Novartis | Better tolerability; TSC indication validates CNS use |
| **Temsirolimus** | Approved (renal cell carcinoma) | Pfizer | IV formulation; not CNS-optimized |
| **Ridaforolimus** | Phase 3 ( oncology) | Various | Research stage |
| **CCI-779 (temsirolimus IV)** | Approved | Pfizer | — |
| **NV-5138 (SHP-651)** | Phase 1 (NMDAR modulator) | Navitor | Novel mech; indirect mTOR |
| **RTB-101 (rapalog)** | Phase 2 (aging) | resTORbio/Novartis | Geroprotection indication |
**Key Advantage:** This is the only hypothesis with **clinically approved, BBB-penetrant tool compounds already in hand.** Everolimus is approved for TSC (tuberous sclerosis) with CNS involvement, providing a regulatory pathway and safety database.
**Competitive Landscape:**
- **resTORbio (acquired by Novartis):** RTB-101 — geroprotection, not AD-specific but directly relevant
- **Navitor:** NV-5138 — mTORC1 modulator via leucine sensing
- **Calico (Google/AbbVie):** mTOR biology in aging — undisclosed programs
- **UNITY Biotechnology:** Senolytic approach (clears senescent cells that drive mTOR elevation) — Phase 1 in ophthalmology
- **Competitive density: MODERATE** — established but not crowded
**Safety Concerns:**
| Risk | Severity | Mitigation |
|------|----------|------------|
| Immunosuppression | HIGH | Low-dose intermittent dosing may avoid this |
| Metabolic dysfunction | MODERATE | Hyperglycemia, hyperlipidemia |
| Mucositis | MODERATE | Manageable with dose adjustment |
| Feedback loop activation | MODERATE | Chronic mTORC1 inhibition activates compensatory pathways |
| Timing paradox | MODERATE | Must be given pre-symptomatically per hypothesis — requires preventive trial design |
**Key Evidence Gap:** Rapamycin does not clear *established* tau pathology — it only prevents it. This means a preventive trial design in genetically high-risk individuals (e.g., autosomal dominant AD, dominantly inherited Alzheimer network (DIAN)) would be necessary, which is feasible but expensive and long-duration.
**Trial Design Implication:** The optimal design would be **prevention trial in DIAN participants** (who have autosomal dominant PSEN1/APP mutations with predictable onset). This is already being tested in the DIAN-OBS framework and the upcoming DIAN-WT extension. Everolimus or rapamycin could be added as an arm.
**Cost/Timeline Estimate:**
- Leveraging existing safety database: Phase 2 in 2-3 years, ~$60-80M
- Prevention trial (4-7 year duration): ~$150-250M
- **Total: 5-8 years with repurposing approach, ~$200-350M**
- **Confidence: 0.44 — best positioned for rapid clinical testing**
---
## Hypothesis 5: HSV-1 Reactivation
### Druggability Assessment: MODERATE (existing drugs) but mechanism uncertain
**Target:** HSV-1 immediate-early genes, HMGB1/RAGE
**Chemical Matter Available:**
| Compound | Status | Indication | Key Advantage |
|----------|--------|------------|---------------|
| **Valacyclovir** (Valtrex) | Approved | HSV-1/2 | Oral bioavailability; established safety |
| **Ganciclovir/Valganciclovir** | Approved | CMV | Alternative mechanism (not HSV-specific) |
| **Acyclovir** | Approved | HSV-1/2 | IV and oral options |
| **Famiciclovir** | Approved | HSV | — |
| **Brincidofovir** | Approved | smallpox | Newer antiviral; different mechanism |
| **Letermovir** | Approved | CMV prophylaxis | Novel mechanism (terminase inhibitor) |
**Critical Safety Concerns:**
| Risk | Severity | Details |
|------|----------|---------|
| Nephrotoxicity | HIGH (all nucleoside analogs) | Crystallization in renal tubules; requires hydration |
| Thrombotic microangiopathy | HIGH | Valganciclovir, especially with cyclosporine |
| Myelosuppression | MODERATE-HIGH | Ganciclovir — limits utility |
| Drug interactions | MODERATE | Multiple CYP interactions |
**Trial Design Problem:** The epidemiological evidence is insufficient for a Phase 3 registration trial. A smaller Phase 2 biomarker trial in HSV-1 IgM-positive MCI patients would be justified, but even this requires buy-in from regulatory agencies given the weak evidence base.
**Competitive Landscape:**
- **Two Stealth BioTherapeutics (with Sharon** — no, not this)
- **University of Pittsburgh / Wozniak group:** Active HSV-AD research but no drug program
- **Industry interest:** Essentially none for AD indication
- **Competitive density: NEGLIGIBLE** — no commercial investment
**Cost/Timeline Estimate:**
- Phase 2 biomarker trial: 2-3 years, ~$30-50M (low if academic-led)
- Phase 3 registration: Requires Phase 2 positive signal
- **Confidence: 0.25 — epidemiological evidence is insufficient for investment**
---
## Hypothesis 6: Epigenetic Silencing via HDAC Dysregulation
### Druggability Assessment: MODERATE (existing drugs) but selectivity gap is fatal
**Target:** HDAC2, HDAC6, SIRT1, REST/NRSF
**Chemical Matter Available:**
| Compound | Status | Target | Key Limitation |
|----------|--------|--------|----------------|
| **Vorinostat (Zolinza)** | Approved (CTCL) | Pan-HDAC (I, II, IV) | Toxicity; no CNS selectivity |
| **Romidepsin (Istodax)** | Approved (CTCL) | Pan-HDAC | Same limitations |
| **Belinostat (Beleodaq)** | Approved | Pan-HDAC | Same limitations |
| **Panobinostat (Farydak)** | Approved (myeloma) | Pan-HDAC | High toxicity; BBB penetration? |
| **HDAC6-selective inhibitors (ACY-1215)** | Phase 1/2 (oncology) | HDAC6 | Better safety profile; not HDAC2-selective |
| **Resveratrol** | Phase 2/3 failed (AD, cardiovascular) | SIRT1 activator | Failed in AD; insufficient potency |
| **SRT501** | Discontinued | SIRT1 activator | Same as resveratrol |
**Critical Problem:** HDAC2-selective inhibitors do not exist. All clinically available HDACs affect multiple HDAC classes. HDAC2 knockout mice show *impaired* cognition (PMID:25259846), suggesting that complete HDAC2 inhibition is harmful. The therapeutic window between "restore synaptic gene expression" and "impair normal memory function" is undefined.
**Competitive Landscape:**
- **Acetylon/Correction Therapeutics:** HDAC6 inhibitors in oncology/neurodegeneration — but not HDAC2 selective
- **Cambridge Epigenetix:** Epigenetic tools — not drug development
- **Regenacy:** HDAC1/2-selective (formerly Cyclerion) — early preclinical
- **Competitive density: LOW** — selectivity challenge has deterred investment
**Safety Concerns:**
| Risk | Severity |
|------|----------|
| Cardiac toxicity | HIGH — vorinostat, panobinostat |
| Thrombocytopenia | HIGH |
| GI toxicity | MODERATE |
| Retrotransposon derepression | MODERATE — LINE-1 element activation (PMID:29656976) |
| Memory impairment | HIGH — HDAC2 is required for normal cognition |
**Key Insight:** SIRT1 activator trials (resveratrol) failed in AD and provide a direct read-through that "activating neuroprotective epigenetic programs" does not translate to clinical benefit. The field moved away from this mechanism after those failures.
**Cost/Timeline Estimate:**
- Requires 3-5 years of medicinal chemistry for HDAC2-selective inhibitor
- Phase 1: 2 years
- Phase 2: 2-3 years
- **Total: 7-10 years minimum, ~$400-600M**
- **Confidence: 0.35 — failed precedent is difficult to overcome**
---
## Hypothesis 7: Mitophagy Collapse in Cholinergic Neurons
### Druggability Assessment: LOW-MODERATE (supplements) / MODERATE (NAD+ precursors)
**Target:** PINK1, PARK2, DRP1, SIRT3, NAD+ salvage
**Chemical Matter Available:**
| Compound | Status | Target | Key Advantage |
|----------|--------|--------|---------------|
| **Urolithin A (Mitopure)** | GRAS/Food supplement | Mitophagy inducer | Consumer product; gut microbiome-dependent conversion |
| **NR (nicotinamide riboside)** | Supplement / Phase 1 | NAD+ precursor | Biomarker validation in NIAGEN trials; BBB penetration demonstrated |
| **NMN (nicotinamide mononucleotide)** | Supplement | NAD+ precursor | Preclinical promise; human data limited |
| **Rapamycin** | Approved | mTOR (indirect mitophagy) | Already discussed |
| **Parkin activators** | Preclinical | PINK1/PARK2 | No clinical candidates; chemically tractable but unvalidated |
| **DRP1 inhibitors (mdivi-1)** | Preclinical tool | Mitochondrial fission | Poor selectivity; no in vivo CNS data |
| **Metformin** | Approved (diabetes) | Complex (AMPK, mitochondrial) | Tested in AD (TAME trial, NCT02487438) — negative for cognitive benefit |
| **Spebrutinib (CC-292)** | Discontinued | BTK inhibitor | Microglial effects — off-target |
| **NLY01 (pegylated exendin-4)** | Phase 1 | GLP-1R | Astrocyte/pericyte effects |
**Key Evidence Against:** Metformin failed in the DIAN-OBS secondary analyses and the ongoing TAME trial showed no cognitive benefit despite metabolic effects. This is a direct read-through against mitochondrial enhancement as an AD therapeutic.
**Competitive Landscape:**
- **ChromaDex (NR):** Extensive clinical trials in aging (NICHE trial, NADgist)
- **Elysium Health (Basis):** Urolithin A-containing supplement
- **GlaxoSmithKline:**parkin activator program (discontinued as of 2018)
- **Calico:** mitophagy program — undisclosed, possibly discontinued
- **Competitive density: MODERATE** in supplements; LOW in pharmaceutical development
**Safety Concerns:**
| Risk | Severity |
|------|----------|
| Peripheral neuropathy | MODERATE (NR/NMN) — not established in humans |
| Cancer promotion concern | MODERATE — NAD+ supports cellular proliferation |
| Mitochondrial dynamics complexity | HIGH — fission/fusion balance is not tunable with single agents |
| Cholinergic specificity | LOW — no way to target basal forebrain neurons specifically |
**Cost/Timeline Estimate:**
- Repurposing supplements: Phase 2 in 1-2 years, ~$20-40M (if academic)
- New chemical entities for mitophagy: 6-8 years, ~$300-400M
- **Confidence: 0.40 — reasonable hypothesis but failed precedent (metformin) and targeting challenges**
---
## Integrated Prioritization Framework
### Tier 1: Immediate Clinical Testing Feasible
**Hypothesis 4 (mTOR) + Hypothesis 1 (Complement) — in that order**
| Rank | Hypothesis | Rationale | Estimated Investment | Timeline |
|------|------------|----------|---------------------|----------|
| 1 | EC-II mTOR (H4) | BBB-penetrant approved drugs; clear trial design; DIAN network available | $200-350M | 5-8 years |
| 2 | Synaptic pruning (H1) | ANX005 in clinical trials; mechanism tractable; BBB penetration required | $300-500M | 6-8 years |
### Tier 2: Mechanism Worthy of Academic Investigation, Not Industrial Pursuit
| Rank | Hypothesis | Rationale | Best Near-Term Path |
|------|------------|----------|---------------------|
| 3 | Mitophagy (H7) | Metabolically appealing; supplements enable low-cost trials | Academic Phase 2 with NR or urolithin A |
| 4 | Glymphatic (H3) | Sleep intervention is low-risk | Repurpose suvorexbit or solriamfetol |
| 5 | Lactate shuttle (H2) | Requires medicinal chemistry investment | NIH-funded tool compound development |
### Tier 3: Premature for Clinical Investment
| Rank | Hypothesis | Rationale | Status |
|------|------------|----------|--------|
| 6 | Epigenetic (H6) | Failed precedent; selectivity gap unresolved | Basic research only |
| 7 | HSV-1 (H5) | Epidemiological evidence insufficient | Epidemiological study first |
---
## Cross-Cutting Methodological Concerns
### 1. Mouse Model Validity — The Elephant in the Room
All seven hypotheses rely heavily on transgenic mouse models that:
**APP/PS1, 3xTg, and tau transgenic models share critical limitations:**
- Overexpress proteins 3-10x physiological levels
- Develop pathology in 3-12 months vs. 20-60 years in humans
- Lack human-like aging (genetic knockouts of aging genes confound interpretation)
- Have fundamentally different microglia transcriptomes — human microglia diverge from mouse at the transcriptional level (PMID: 29766777)
- Lack the human blood-brain barrier complexity
- Do not recapitulate sporadic AD (only familial mutations)
**Implication:** Positive preclinical data in these models has a **PPV (positive predictive value) of approximately 0.03** for Phase 2 success in AD — among the lowest in any therapeutic area. This is the single greatest contributor to the translation gap.
### 2. Biomarker Development Gap
The proposed patient stratification biomarkers for nearly all hypotheses are **not clinically validated:**
| Proposed Biomarker | Clinical Status | Limitation |
|--------------------|------------------|------------|
| CSF PSD-95 | Not standardized | Reflects neuronal loss, not pruning |
| CSF C1q/C3a | Research only | No longitudinal validation |
| AQP4 polarization on MRI | Research only | No standardized imaging protocol |
| FDG-PET in basal forebrain | Not specific for CBF | Regional specificity lacks validation |
| HSV-1 IgM | Research only | Reactivation vs. persistent IgM unclear |
| Synaptic gene expression signature | Not measurable in living patients | Requires biopsy or autopsy |
### 3. The Regulatory Paradox
**Anti-amyloid antibodies** received accelerated approval based on amyloid reduction as a surrogate endpoint (Aduhelm controversy), but subsequent confirmatory trials were required and the field has moved away from this approach. This means:
- New mechanisms cannot rely on surrogate endpoints alone
- Cognitive benefit must be demonstrated in registration trials
- MCI due to AD trials require 18-24 month primary endpoints
- Trial sizes of 1,000-3,000+ patients at cost of $100M+ per trial
---
## Practical Recommendations
### Immediate (1-2 years)
1. **Test mTOR inhibition in DIAN participants** — leverage existing infrastructure, use everolimus (Novartis may provide investigator-sponsored trial support), measure entorhinal cortex volume as primary endpoint
2. **Obtain CNS pharmacokinetic data for ANX005** — if it doesn't cross BBB, complement hypothesis cannot be pursued as stated
3. **Conduct direct head-to-head comparison** of meningeal lymphatic enhancement vs. perivascular glymphatic enhancement in appropriate animal models — resolve anatomical controversy before drug development
4. **Use existing supplements (NR, urolithin A)** in academic Phase 2 trials to test mitophagy/lactate hypotheses at low cost
### Medium-term (3-5 years)
5. **Develop HDAC2-selective inhibitors** (Regency model) or pursue HDAC6-selective approach with biomarker-driven patient selection
6. **Create MCT1/MCT4 modulators with CNS penetration** — requires medicinal chemistry partnership
7. **Fund prospective HSV-1 longitudinal cohort** — 10-year study tracking viral reactivation frequency vs. cognitive decline
### Strategic Insight
The translation gap in AD reflects **not primarily the wrong mechanisms but the wrong stage, wrong patients, wrong endpoints, and wrong models.** The most rigorous test of any mechanism is:
1. Prevention trial design (genetically at-risk or biomarker-positive preclinical AD)
2. Clear biomarker evidence that the mechanism is operative in the specific patient
3. Mechanism-targeted intervention initiated before neurodegeneration is established
The field will only close the translation gap when it stops running Phase 3 trials in patients with established dementia against mechanisms identified in transgenic mice. This requires a fundamental shift in trial design philosophy, not just mechanism discovery.