This page synthesizes the most promising emerging therapeutic directions across Alzheimer's disease (AD), Parkinson's disease (PD), and ALS based on current clinical trial data, mechanistic evidence, and expert consensus. Each direction is scored using a multi-dimensional rubric that considers mechanistic clarity, clinical evidence strength, delivery feasibility, safety profile, combinability, timeline to patient impact, and disease-modifying potential.
This synthesis complements the existing [AD Therapeutic Scorecard](/mechanisms/ad-therapeutic-scorecard), [PD Therapeutic Scorecard](/mechanisms/pd-therapeutic-scorecard), and [ALS Therapeutic Scorecard](/mechanisms/als-therapeutic-scorecard) by identifying cross-disease opportunities and emerging approaches not yet included in those disease-specific scorecards.
Each therapeutic direction is scored on a 0-10 scale across seven dimensions (max 70 points):
This page synthesizes the most promising emerging therapeutic directions across Alzheimer's disease (AD), Parkinson's disease (PD), and ALS based on current clinical trial data, mechanistic evidence, and expert consensus. Each direction is scored using a multi-dimensional rubric that considers mechanistic clarity, clinical evidence strength, delivery feasibility, safety profile, combinability, timeline to patient impact, and disease-modifying potential.
This synthesis complements the existing [AD Therapeutic Scorecard](/mechanisms/ad-therapeutic-scorecard), [PD Therapeutic Scorecard](/mechanisms/pd-therapeutic-scorecard), and [ALS Therapeutic Scorecard](/mechanisms/als-therapeutic-scorecard) by identifying cross-disease opportunities and emerging approaches not yet included in those disease-specific scorecards.
Each therapeutic direction is scored on a 0-10 scale across seven dimensions (max 70 points):
| Dimension | Description |
|-----------|-------------|
| Mechanistic Clarity | How well we understand WHY this works at the molecular level |
| Clinical Evidence | Human data supporting efficacy (Phase 2/3 trials, biomarkers) |
| Delivery Feasibility | Can we get the drug to the right brain region at therapeutic dose? |
| Safety Profile | Risk/benefit for a chronic disease in elderly patients |
| Combinability | Can this be combined with other approaches for additive/synergistic effect? |
| Timeline to Impact | How soon could this meaningfully help patients? |
| Disease-Modifying Potential | Does this slow progression, halt, or reverse pathology? |
| Rank | Direction | Disease | Mechanistic Clarity | Clinical Evidence | Delivery | Safety | Combinability | Timeline | Disease-Modifying | Total |
|------|-----------|---------|:------------------:|:----------------:|:--------:|:------:|:-------------:|:--------:|:----------------:|:-----:|
| 1 | GLP-1/GIP Agonists | AD/PD | 8 | 8 | 9 | 9 | 9 | 7 | 7 | 57 |
| 2 | TREM2 Agonists | AD | 9 | 6 | 6 | 7 | 7 | 6 | 9 | 50 |
| 3 | Anti-Synuclein Immunotherapy | PD/DLB | 8 | 6 | 7 | 8 | 7 | 6 | 7 | 50 |
| 4 | LRRK2 Inhibitors | PD | 8 | 5 | 7 | 8 | 7 | 5 | 6 | 46 |
| 5 | Senolytics | AD/PD | 7 | 6 | 7 | 7 | 7 | 5 | 8 | 47 |
| Rank | Direction | Disease | Mechanistic Clarity | Clinical Evidence | Delivery | Safety | Combinability | Timeline | Disease-Modifying | Total |
|------|-----------|---------|:------------------:|:----------------:|:--------:|:------:|:-------------:|:--------:|:----------------:|:-----:|
| 6 | Microglial Reprogramming | AD/PD/ALS | 7 | 4 | 6 | 7 | 7 | 5 | 8 | 44 |
| 7 | NLRP3 Inflammasome Inhibitors | AD/PD | 7 | 5 | 6 | 7 | 7 | 5 | 7 | 44 |
| 8 | Autophagy Enhancers | AD/PD/ALS | 7 | 4 | 6 | 7 | 7 | 4 | 8 | 43 |
| 9 | NAD+ Boosters | AD/PD | 7 | 5 | 7 | 8 | 6 | 5 | 6 | 44 |
| 10 | Gene Therapy (AAV) | PD | 7 | 5 | 5 | 6 | 6 | 4 | 8 | 41 |
| Rank | Direction | Disease | Mechanistic Clarity | Clinical Evidence | Delivery | Safety | Combinability | Timeline | Disease-Modifying | Total |
|------|-----------|---------|:------------------:|:----------------:|:--------:|:------:|:-------------:|:--------:|:----------------:|:-----:|
| 11 | c-Abl Inhibitors | PD | 7 | 4 | 6 | 7 | 6 | 4 | 6 | 40 |
| 12 | Sigma-1 Agonists | AD/PD | 6 | 5 | 7 | 7 | 6 | 5 | 5 | 41 |
| 13 | Iron Chelators | PD/PDC | 6 | 4 | 7 | 7 | 6 | 4 | 5 | 39 |
| 14 | Exosome Therapies | AD/PD | 5 | 3 | 5 | 6 | 6 | 3 | 7 | 35 |
| 15 | Anti-TDP-43 ASOs | ALS/FTD | 8 | 4 | 5 | 6 | 5 | 4 | 7 | 39 |
Mechanistic Clarity (8/10): GLP-1 receptors are expressed in the brain, particularly in the hippocampus and basal ganglia. Activation reduces neuroinflammation through cAMP/PKA signaling, promotes synaptic plasticity via PI3K/Akt pathways, and reduces apoptotic cell death. GIP receptors add another incretin mechanism with potential neuroprotective effects[@glp2024].
Clinical Evidence (8/10):
Safety Profile (9/10): Well-characterized safety from diabetes indication; GI side effects manageable
Combinability (9/10): Can combine with standard of care; orthogonal mechanism (inflammation reduction) adds to symptomatic treatments
Timeline to Impact (7/10): Phase 3 trials ongoing; potential approval within 2-4 years
Disease-Modifying (7/10): Preclinical data suggests modification of core pathology; clinical proof pending
Cross-Disease Opportunity: One of the few approaches with strong evidence in both AD and PD
Mechanistic Clarity (9/10): TREM2 is a microglial receptor that modulates phagocytosis of amyloid plaques and inflammatory responses. Agonists enhance microglial clearance function while reducing pro-inflammatory signaling[@trem2024].
Clinical Evidence (6/10): AL002 (TREM2 agonist) showing safety and biomarker signals in Phase 1/2; AL003 (antibody) demonstrating target engagement
Delivery Feasibility (6/10): Monoclonal antibody requires IV infusion
Safety Profile (7/10): Generally well-tolerated; ARIA risk requires monitoring
Combinability (7/10): Synergistic with anti-amyloid antibodies (complements different mechanisms)
Timeline to Impact (6/10): Phase 2/3 trials ongoing; 3-5 years to potential approval
Disease-Modifying (9/10): Targets microglial dysfunction — a core upstream driver of AD pathology
Mechanistic Clarity (8/10): Targeting extracellular α-synuclein aggregates that spread between neurons. Cinpanemab and prasinezumab target different α-synuclein conformations[@alphasynuclein2024].
Clinical Evidence (6/10):
Safety Profile (8/10): Well-tolerated; infusion reactions manageable
Combinability (7/10): Can combine with dopamine therapies; potential synergy with LRRK2 inhibitors
Timeline to Impact (6/10): Phase 3 trials in progress; 3-5 years
Disease-Modifying (7/10): Targets core pathological protein; evidence of biomarker modification
Mechanistic Clarity (8/10): LRRK2 is the most common genetic cause of PD. Inhibitors reduce LRRK2 kinase activity, potentially normalizing lysosomal function in dopaminergic neurons[@lrrk2024].
Clinical Evidence (5/10):
Safety Profile (8/10): Generally well-tolerated; lung surfactant effects monitored
Combinability (7/10): Can combine with standard PD therapies
Timeline to Impact (5/10): Phase 2/3 planning; 5+ years
Disease-Modifying (6/10): Targets genetic cause; may slow progression in LRRK2 carriers and sporadic PD
Mechanistic Clarity (7/10): Senolytic drugs eliminate senescent cells that secrete pro-inflammatory SASP factors. Dasatinib + Quercetin (D+Q) is the leading combination[@senolytic2024].
Clinical Evidence (6/10):
Safety Profile (7/10): Generally well-tolerated; off-target effects being characterized
Combinability (7/10): Can combine with anti-amyloid, anti-inflammatory approaches
Timeline to Impact (5/10): Phase 2/3 trials; 4-6 years
Disease-Modifying (8/10): Targets aging-associated cellular dysfunction; may address multiple age-related pathologies
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| Priority | Target | Rationale |
|----------|--------|------------|
| 1 | Neuroinflammation | Central to AD, PD, ALS; multiple therapeutic angles |
| 2 | Microglial dysfunction | TREM2, CD33, PLCG2 variants affect multiple diseases |
| 3 | Protein homeostasis | Autophagy enhancers benefit aggregation-prone proteins |
| 4 | Metabolic dysfunction | GLP-1 effects span multiple diseases |
Based on the analysis, several promising approaches are underinvested relative to their potential:
| Approach | Biomarker Need | Status |
|----------|---------------|--------|
| TREM2 agonists | Microglial activation PET | In development |
| Senolytics | Senescence-associated markers | Validated |
| Autophagy enhancers | Autophagic flux markers | Needed |
| GLP-1 agonists | Neuroinflammation markers | Available |
| Approach | Company | Partnership Status |
|----------|---------|-------------------|
| GLP-1 agonists | Novo Nordisk | Multiple trials |
| TREM2 agonists | Roche/Alector | Phase 2 |
| Anti-synuclein | Biogen/AbbVie | Phase 3 |
| LRRK2 inhibitors | BMS/Denali | Phase 2 |
| Senolytics | Unity Biotechnology | Phase 2 |