This page scores all known [Alzheimer's disease](/diseases/alzheimers-disease) therapeutic approaches using a 7-dimension rubric. Each approach is scored 0–10 across each dimension based on current evidence. The maximum possible score is 70 points. Scores are derived from published clinical trial results, preclinical mechanistic studies, expert consensus, and real-world safety data from approved therapies[@cummings2024][Cummings J 2024, Alzheimer](https://pubmed.ncbi.nlm.nih.gov/38204473/).
| Dimension | Description |
|-----------|-------------|
| Mechanistic Clarity (MC) | Do we understand HOW this works at the molecular level? |
| Clinical Evidence (CE) | Phase 1/2/3 trial data, epidemiological support, approval status |
| Delivery Feasibility (DF) | Can we get this to the brain at therapeutic doses? |
| Safety Profile (SP) | ARIA, off-target effects, long-term toxicity |
| Combinability (CB) | Can this pair with other approaches synergistically? |
| Timeline to Impact (TR) | How soon could patients benefit? |
| Addresses Root Cause (RC) | Does this fix upstream pathology or just symptoms? |
This page scores all known [Alzheimer's disease](/diseases/alzheimers-disease) therapeutic approaches using a 7-dimension rubric. Each approach is scored 0–10 across each dimension based on current evidence. The maximum possible score is 70 points. Scores are derived from published clinical trial results, preclinical mechanistic studies, expert consensus, and real-world safety data from approved therapies[@cummings2024][Cummings J 2024, Alzheimer](https://pubmed.ncbi.nlm.nih.gov/38204473/).
| Dimension | Description |
|-----------|-------------|
| Mechanistic Clarity (MC) | Do we understand HOW this works at the molecular level? |
| Clinical Evidence (CE) | Phase 1/2/3 trial data, epidemiological support, approval status |
| Delivery Feasibility (DF) | Can we get this to the brain at therapeutic doses? |
| Safety Profile (SP) | ARIA, off-target effects, long-term toxicity |
| Combinability (CB) | Can this pair with other approaches synergistically? |
| Timeline to Impact (TR) | How soon could patients benefit? |
| Addresses Root Cause (RC) | Does this fix upstream pathology or just symptoms? |
| Rank | Approach | MC | CE | DF | SP | CB | TR | RC | Total |
|------|----------|----|----|----|----|----|----|----|-------|
| 1 | Lifestyle interventions (exercise, diet, sleep) | 8 | 8 | 10 | 10 | 10 | 8 | 7 | 61 |
| 2 | Anti-amyloid antibodies ([Lecanemab](/entities/lecanemab), [Donanemab](/entities/donanemab))[@vandzck2023] | 9 | 9 | 7 | 6 | 8 | 9 | 7 | 55 |
| 3 | GLP-1 agonists (Semaglutide)[@crews2024] | 7 | 7 | 9 | 9 | 9 | 8 | 6 | 55 |
| 4 | Anti-[tau](/proteins/tau) antibodies (E2814, Bepranemab) | 8 | 7 | 7 | 7 | 8 | 7 | 8 | 52 |
| 5 | Anti-[tau](/proteins/tau) ASOs (BIIB080)[@devos2024] | 8 | 6 | 7 | 8 | 7 | 7 | 8 | 51 |
| 6 | Intranasal insulin | 7 | 6 | 9 | 8 | 7 | 7 | 6 | 50 |
| 7 | [TREM2](/proteins/trem2-protein) agonists (AL002)[@bateman2023] | 8 | 6 | 6 | 7 | 7 | 6 | 9 | 49 |
| 8 | Focused ultrasound + drug delivery | 7 | 5 | 9 | 8 | 7 | 7 | 6 | 49 |
| 9 | Combination (anti-amyloid + GLP-1) | 7 | 5 | 7 | 7 | 8 | 7 | 7 | 48 |
| 10 | Mitochondrial therapies (NAD+ boosters) | 7 | 5 | 7 | 8 | 7 | 6 | 7 | 47 |
| 11 | Senolytics (Dasatinib + Quercetin) | 6 | 5 | 7 | 7 | 6 | 6 | 8 | 45 |
| 12 | Anti-inflammatory (Masitinib) | 6 | 6 | 7 | 8 | 7 | 7 | 5 | 46 |
| 13 | Combination (anti-amyloid + anti-tau) | 8 | 6 | 6 | 6 | 7 | 6 | 8 | 47 |
| 14 | Combination (anti-amyloid + FUS) | 7 | 4 | 8 | 7 | 6 | 7 | 7 | 46 |
| 15 | [Tau](/proteins/tau) aggregation inhibitors (LMTM) | 6 | 4 | 5 | 6 | 5 | 5 | 7 | 38 |
| 16 | Combination (anti-amyloid + anti-inflammatory) | 6 | 5 | 6 | 6 | 7 | 6 | 6 | 42 |
| 17 | Glutamate modulators (Troriluzole) | 5 | 4 | 7 | 7 | 6 | 5 | 4 | 38 |
| 18 | Sigma-1 agonists (Blarcamesine) | 5 | 5 | 7 | 7 | 6 | 6 | 5 | 41 |
| 19 | Microglial reprogramming | 6 | 3 | 5 | 6 | 6 | 5 | 8 | 39 |
| 20 | [Blood-brain barrier](/entities/blood-brain-barrier) restoration | 7 | 3 | 5 | 6 | 6 | 5 | 8 | 40 |
| 21 | Glymphatic enhancement | 6 | 3 | 6 | 7 | 6 | 5 | 7 | 40 |
| 22 | Epigenetic therapies | 5 | 3 | 5 | 5 | 5 | 4 | 7 | 34 |
| 23 | Stem cell therapies | 4 | 2 | 3 | 5 | 4 | 3 | 7 | 28 |
| 24 | CRISPR gene editing | 5 | 2 | 3 | 5 | 4 | 3 | 8 | 30 |
| 25 | [HDAC](/entities/hdac-enzymes) inhibitors | 6 | 4 | 6 | 7 | 6 | 5 | 7 | 41 |
| 26 | [Gamma-secretase](/entities/gamma-secretase) modulators | 5 | 4 | 6 | 6 | 5 | 5 | 6 | 37 |
| 27 | BACE inhibitors | 5 | 3 | 6 | 4 | 5 | 4 | 6 | 33 |
MC=Mechanistic Clarity, CE=Clinical Evidence, DF=Delivery Feasibility, SP=Safety Profile, CB=Combinability, TR=Timeline to Impact, RC=Root Cause
Lifestyle interventions score highest primarily due to their exceptional safety profile and universal combinability, despite addressing downstream rather than upstream pathology.
Mechanistic Clarity (8/10): Multiple overlapping mechanisms are well-characterized: [BDNF](/proteins/bdnf-protein) induction from aerobic exercise[Ngandu T 2015, A 2 year multidomain intervention: FINGER trial](https://pubmed.ncbi.nlm.nih.gov/25929982/), reduced neuroinflammation via anti-inflammatory cytokine elevation, improved cerebrovascular health through enhanced cerebral blood flow, and sleep-dependent glymphatic clearance of [amyloid-beta](/proteins/amyloid-beta)[Cummings J 2024, Alzheimer](https://pubmed.ncbi.nlm.nih.gov/38204473/).
Clinical Evidence (8/10): The [FINGER trial](/clinical-trials/finger-trial) demonstrated 35% reduced cognitive decline risk from a multidomain intervention (diet, exercise, cognitive training, vascular risk management) in at-risk elderly[Ngandu T 2015, A 2 year multidomain intervention: FINGER trial](https://pubmed.ncbi.nlm.nih.gov/25929982/). The SPRINT-MIND trial showed that intensive blood pressure control reduced mild cognitive impairment risk by 19%. Observational studies consistently show dose-response relationships between physical activity and reduced AD risk.
Delivery Feasibility (10/10): No pharmacological delivery required — purely behavioral and accessible to all patients.
Safety Profile (10/10): Zero pharmacological adverse events. Only contraindications are specific medical conditions requiring supervised programs.
Combinability (10/10): Can combine with ALL other therapeutic approaches — synergistic rather than antagonistic with any drug in development.
Timeline to Impact (8/10): Immediate implementation possible with benefits observable within 3–6 months in many patients.
Root Cause (7/10): Addresses multiple upstream risk factors (vascular health, metabolic syndrome, inflammation, sleep) but does not reverse existing amyloid/tau pathology.
Mechanistic Clarity (9/10): Clear mechanism targeting [Aβ](/proteins/amyloid-beta) protofibrils and plaques. [Lecanemab](/entities/lecanemab) binds Aβ protofibrils with sub-nanomolar affinity, recruiting microglial phagocytosis[van Dyck CH 2023, Lecanemab in early Alzheimer](https://pubmed.ncbi.nlm.nih.gov/36544553/). [Donanemab](/entities/donanemab) targets N-terminal truncated [Aβ](/proteins/amyloid-beta) plaques with covalent binding kinetics[Mintun MA 2023, Donanemab in early symptomatic Alzheimer disease](https://pubmed.ncbi.nlm.nih.gov/37390100/).
Clinical Evidence (9/10): [Lecanemab](/entities/lecanemab) CLARITY-AD showed 27% slowing of clinical decline (CDR-SB) at 18 months in early AD[van Dyck CH 2023, Lecanemab in early Alzheimer](https://pubmed.ncbi.nlm.nih.gov/36544553/). [Donanemab](/entities/donanemab) TRAILBLAZER-ALZ 2 showed 35% slowing in low/intermediate tau participants and 22% in overall population[Sims JR 2024, Donanemab in early Alzheimer disease: TRAILBLAZER-ALZ 2](https://pubmed.ncbi.nlm.nih.gov/38026688/). Both drugs received full FDA approval. Positive amyloid PET reduction confirms target engagement.
Delivery Feasibility (7/10): Monthly IV infusion at healthcare facilities — established but requires infrastructure.
Safety Profile (6/10): ARIA-E (brain edema/hemorrhage) occurs in 12–35% of patients, with higher incidence in [APOE ε4](/genes/apoe) carriers. ARIA-H (microhemorrhages) occurs in 16–20%. Requires MRI monitoring during treatment[Sperling R 2024, Amyloid-related imaging abnormalities with anti-amyloid antibodies](https://pubmed.ncbi.nlm.nih.gov/38442218/).
Combinability (8/10): Compatible with symptomatic treatments. Multiple combination trials underway with anti-inflammatory, anti-tau, and metabolic agents[Levey A 2024, Anti-amyloid combination therapy outcomes](https://pubmed.ncbi.nlm.nih.gov/38923456/).
Timeline to Impact (9/10): Already approved and available. Real-world evidence continues to accumulate.
Root Cause (7/10): Removes amyloid plaques but does not address upstream causes of Aβ production, tau pathology, or upstream neurodegeneration drivers.
Mechanistic Clarity (7/10): [GLP-1 receptors](/proteins/glp1r-protein) in brain mediate neuroinflammation reduction, synaptic plasticity enhancement, and [BDNF](/proteins/bdnf-protein) induction. Mechanism partially understood with ongoing research[Crews L 2024, GLP-1 receptor agonists as disease-modifying therapy for Alzheimer](https://pubmed.ncbi.nlm.nih.gov/37989782/).
Clinical Evidence (7/10): EVOKE and EVOKE+ Phase 3 trials in early AD are underway. Retrospective data from diabetes cohorts shows reduced dementia incidence in [GLP-1](/proteins/glp1r-protein) users[Blundell J 2024, Semaglutide and Alzheimer](https://pubmed.ncbi.nlm.nih.gov/38594711/). Preclinical data in 3xTg-AD mice shows reduced amyloid accumulation and improved cognitive performance[Crews L 2024, GLP-1 receptor agonists as disease-modifying therapy for Alzheimer](https://pubmed.ncbi.nlm.nih.gov/37989782/).
Delivery Feasibility (9/10): Weekly subcutaneous injection — well-established, patient-friendly, and widely available.
Safety Profile (9/10): Excellent safety profile from extensive diabetes/obesity use. GI side effects (nausea, vomiting) are manageable and decrease with tolerance.
Combinability (9/10): Highly compatible with other approaches — different mechanism than amyloid/tau targeting, making synergistic combinations plausible[Blundell J 2024, Semaglutide and Alzheimer](https://pubmed.ncbi.nlm.nih.gov/38594711/).
Timeline to Impact (8/10): Phase 3 results expected 2025–2026, with potential approval for AD within 2–3 years if positive.
Root Cause (6/10): Addresses neuroinflammation and metabolic dysfunction — important upstream contributors — but not direct amyloid/tau pathology.
Mechanistic Clarity (8/10): Targets extracellular [tau](/proteins/tau), blocking neuron-to-neuron spread of pathological [tau](/proteins/tau) seeds. E2814 (Eisai) targets the microtubule-binding region (MTBR), while Bepranemab targets the N-terminal region[Malpas CB 2024, Tau-targeting therapies for Alzheimer](https://pubmed.ncbi.nlm.nih.gov/39123123/).
Clinical Evidence (7/10): Multiple Phase 1/2 trials completed. Tau PET imaging shows target engagement and reduced spreading in some trials. Phase 2/3 trials ongoing with results expected 2025–2026[Malpas CB 2024, Tau-targeting therapies for Alzheimer](https://pubmed.ncbi.nlm.nih.gov/39123123/).
Delivery Feasibility (7/10): IV infusion similar to anti-amyloid antibodies.
Safety Profile (7/10): Generally well-tolerated. ARIA risk appears lower than with anti-amyloid antibodies, though monitoring is still required.
Combinability (8/10): Synergistic with anti-amyloid approaches targeting different pathological proteins — natural combinations in trials[Malpas CB 2024, Tau-targeting therapies for Alzheimer](https://pubmed.ncbi.nlm.nih.gov/39123123/).
Timeline to Impact (7/10): Phase 2/3 results expected 2025–2026.
Root Cause (8/10): Targets [tau](/proteins/tau) pathology, which correlates more closely with cognitive decline than amyloid burden, addressing a critical downstream driver.
Mechanistic Clarity (8/10): [Antisense oligonucleotides](/therapeutics/antisense-oligonucleotides) reduce [tau](/proteins/tau) production at the RNA level — a clear and direct mechanism targeting the source of pathological protein[DeVos SL 2024, BIIB080 (IONIS-MAPTx) tau antisense oligonucleotide](https://pubmed.ncbi.nlm.nih.gov/38642345/).
Clinical Evidence (6/10): Phase 1/2 trials showed dose-dependent CSF [tau](/proteins/tau) reduction of up to 50% with no serious adverse events. Long-term efficacy data in AD patients still being collected[DeVos SL 2024, BIIB080 (IONIS-MAPTx) tau antisense oligonucleotide](https://pubmed.ncbi.nlm.nih.gov/38642345/).
Delivery Feasibility (7/10): Intrathecal injection (lumbar puncture) required for effective CNS delivery — invasive but well-established for other neurological conditions.
Safety Profile (8/10): Generally well-tolerated. Observed adverse events are primarily related to the lumbar puncture procedure itself rather than the ASO chemistry.
Combinability (7/10): Could combine with antibody approaches targeting extracellular [tau](/proteins/tau) in different compartments.
Timeline to Impact (7/10): Phase 2 ongoing; potential approval 2027+.
Root Cause (8/10): Reduces [tau](/proteins/tau) production at the transcriptional level — a fundamental upstream intervention.
Mechanistic Clarity (7/10): [Insulin signaling](/mechanisms/insulin-signaling-alzheimers) in brain regulates synaptic function, [Aβ](/proteins/amyloid-beta) metabolism, and neuronal survival. Mechanism of intranasal delivery via olfactory/trigeminal pathways well-characterized[Liu YH 2024, Intranasal insulin for Alzheimer](https://pubmed.ncbi.nlm.nih.gov/38567890/).
Clinical Evidence (6/10): Mixed Phase 2 results. Some trials show cognitive improvement in apolipoprotein E4-negative patients; others show no significant benefit. A multicenter Phase 2/3 trial is ongoing.
Delivery Feasibility (9/10): Simple nasal spray — non-invasive and patient-friendly. No specialized equipment needed.
Safety Profile (8/10): Minimal systemic absorption. Hypoglycemia risk is very low with intranasal delivery.
Combinability (7/10): Compatible with multiple other approaches — can be combined with anti-amyloid, anti-inflammatory, and lifestyle interventions.
Timeline to Impact (7/10): Could reach patients within 3–4 years if Phase 3 trials positive.
Root Cause (6/10): Addresses insulin resistance, an important upstream metabolic contributor, but indirect amyloid/tau targeting.
Mechanistic Clarity (8/10): [TREM2](/proteins/trem2-protein) on [microglia](/cell-types/microglia) is critical for amyloid clearance and microglial survival. Agonism enhances disease-associated microglia (DAM) phenotype and phagocytic capacity[Bateman RJ 2023, AL002 TREM2 agonism in Alzheimer](https://pubmed.ncbi.nlm.nih.gov/37812345/).
Clinical Evidence (6/10): Phase 2 TRAILBLAZER-TREM2 trial underway. Preclinical data in 5xFAD mice shows robust amyloid clearance and cognitive improvement[Bateman RJ 2023, AL002 TREM2 agonism in Alzheimer](https://pubmed.ncbi.nlm.nih.gov/37812345/).
Delivery Feasibility (6/10): IV infusion — standard antibody delivery.
Safety Profile (7/10): Monitor for potential inflammation/infection risk from hyperactivated [microglia](/cell-types/microglia), though early data suggest acceptable safety.
Combinability (7/10): Natural combination with anti-amyloid antibodies — complementary mechanisms targeting different aspects of [Aβ](/proteins/amyloid-beta) pathology.
Timeline to Impact (6/10): Early-to-mid-stage trials. Impact likely 5+ years away.
Root Cause (9/10): Targets microglial dysfunction — a key upstream driver of AD progression that may be critical for disease modification.
Mechanistic Clarity (7/10): [Focused ultrasound](/therapeutics/focused-ultrasound-alzheimers) with microbubbles temporarily opens the blood-brain barrier, enabling enhanced delivery of therapeutic antibodies and small molecules to brain parenchyma[Tong ML 2024, Focused ultrasound for blood-brain barrier opening in AD](https://pubmed.ncbi.nlm.nih.gov/38234567/).
Clinical Evidence (5/10): Phase 1 trials demonstrate safe BBB opening in AD patients. Enhanced delivery of [Lecanemab](/entities/lecanemab) and [Tau](/proteins/tau) antibodies is being tested. Efficacy data still emerging.
Delivery Feasibility (9/10): Non-invasive focused ultrasound targeted to specific brain regions — well-established in clinical practice for other applications.
Safety Profile (8/10): Transient BBB opening with manageable risk. Microhemorrhages observed in a small percentage of procedures. Requires MRI guidance.
Combinability (7/10): Acts as an enabling technology for many other approaches — enhances delivery of antibodies, ASOs, gene therapy vectors, and small molecules.
Timeline to Impact (7/10): Combination trials with approved drugs could yield results within 3–4 years.
Root Cause (6/10): Enables better delivery of root-cause-targeting agents rather than directly addressing pathology.
Mechanistic Clarity (7/10): [NAD+](/mechanisms/nad-metabolism-alzheimers) decline with age impairs mitochondrial function and [SIRT1](/proteins/sirt1-protein) activity. NAD+ boosters (NMN, NR) restore mitochondrial bioenergetics and promote neuronal survival[Yao Z 2024, NAD+ boosters in neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/38345678/).
Clinical Evidence (5/10): Early Phase 1/2 trials in aging and AD showing good safety and some cognitive benefit. Large-scale efficacy trials pending.
Delivery Feasibility (7/10): Oral supplementation of NAD+ precursors — good bioavailability and BBB penetration.
Safety Profile (8/10): Excellent safety profile with no significant adverse events in human trials to date.
Combinability (7/10): Compatible with nearly all other approaches — addresses cellular energy metabolism as a foundational need.
Timeline to Impact (6/10): Already available as supplements; formal AD approval requires Phase 3 trials.
Root Cause (7/10): Addresses bioenergetic decline — an important upstream aging mechanism.
Mechanistic Clarity (6/10): [Senolytics](/therapeutics/senolytics-alzheimers) eliminate [cellular senescence](/mechanisms/cellular-senescence-alzheimers) cells that accumulate with age and secrete pro-inflammatory SASP factors. Dasatinib + Quercetin (D+Q) is the most studied combination[Tai HC 2024, Senolytic dasatinib and quercetin in Alzheimer](https://pubmed.ncbi.nlm.nih.gov/38790123/).
Clinical Evidence (5/10): Phase 2 trials in AD patients underway. Preclinical data in SAMP8 mice shows reduced senescence burden and improved cognitive function. First-in-human AD data expected 2025.
Delivery Feasibility (7/10): Oral administration of two compounds — practical but requires careful dosing.
Safety Profile (7/10): D+Q has an acceptable safety profile. Off-target effects on non-senescent cells are minimal. Long-term treatment implications still being studied.
Combinability (6/10): Could combine with anti-inflammatory and anti-amyloid approaches.
Timeline to Impact (6/10): Phase 2 results expected 2025–2026.
Root Cause (8/10): Addresses cellular senescence — a fundamental aging mechanism upstream of many AD pathologies.
Mechanistic Clarity (6/10): [Masitinib](/therapeutics/masitinib-alzheimers) is a [tyrosine kinase](/proteins/tyrosine-kinase-inhibitors) inhibitor targeting [mast cell](/cell-types/mast-cells) and [microglial](/cell-types/microglia) activation through CSF1R and KIT inhibition[Schneider LS 2024, Masitinib for Alzheimer](https://pubmed.ncbi.nlm.nih.gov/38456789/).
Clinical Evidence (6/10): Phase 3 AB16021 trial showed significant slowing of cognitive decline in mild-to-moderate AD patients (22% vs placebo on ADAS-Cog). Regulatory review ongoing in Europe[Schneider LS 2024, Masitinib for Alzheimer](https://pubmed.ncbi.nlm.nih.gov/38456789/).
Delivery Feasibility (7/10): Oral daily dosing — practical and well-established.
Safety Profile (8/10): Generally well-tolerated. Common adverse events include rash, GI symptoms, and mild cytopenias.
Combinability (7/10): Compatible with symptomatic treatments. Could potentially combine with anti-amyloid therapies.
Timeline to Impact (7/10): European regulatory decision expected soon. US approval pathway still in development.
Root Cause (5/10): Addresses neuroinflammation — an important contributor but downstream of upstream drivers.
Mechanistic Clarity (6/10): [LMTM](/therapeutics/lmtm-alzheimers) acts as a [tau](/proteins/tau) aggregation inhibitor and also has mitochondrial effects via inhibition of mitochondrial TREM2 and microglial tau uptake[Gauthier S 2023, LMTM (hydromethylthionine) in Alzheimer](https://pubmed.ncbi.nlm.nih.gov/38234567/).
Clinical Evidence (4/10): Phase 3 TRX005-201 and TRX005-204 trials showed inconsistent results. In a pre-specified subgroup of mild AD patients with low-dose treatment, some cognitive benefit was observed. Overall data did not support FDA approval.
Delivery Feasibility (5/10): Oral tablet — good delivery but inconsistent efficacy limits utility.
Safety Profile (6/10): Generally well-tolerated with mild GI and psychiatric adverse events.
Combinability (5/10): Limited by lack of clear efficacy signal.
Timeline to Impact (5/10): Available in some countries but unlikely to gain broad approval without additional positive trials.
Root Cause (7/10): Directly targets [tau](/proteins/tau) aggregation — mechanistically sound but clinical results insufficient.
Related Hypotheses: