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Clinical trials landscape

TL;DR — The 2025 pipeline held 138 unique drugs across 182 registered trials: biological disease-targeted therapies 30%, small-molecule disease-targeted therapies 43%, cognitive enhancers 14%, neuropsychiatric agents 11%; repurposed agents made up 33% of the pipeline and biomarkers were a primary outcome in 27% of active trials (Cummings 2025, PMID 40463637). Populating the global subset requires 32,284 participants, 25,628 of them for phase 3, across 5,361 sites of which 50% are in the United States and only 7% in low- and middle-income countries (Cummings 2025, PMID 40555627). The centre of gravity has shifted upstream: the two positive symptomatic-stage antibody programmes have moved into preclinical AD (TRAILBLAZER-ALZ 3, NCT05026866, n≈2,996, active, primary completion Nov 2027; AHEAD 3-45, NCT04468659, n≈1,400, active, primary completion Dec 2028), while next-generation amyloid agents test subcutaneous delivery and brain-shuttle transport (TRAILRUNNER-ALZ 3, NCT06653153; trontinemab phase 3, NCT07169578 and NCT07170150). Tau has target engagement without a clinical result — the MAPT antisense oligonucleotide now named diranersen reduced CSF t-tau by 56% (95% CI 50–62) in phase 1b and is in a 416-participant phase 2 (NCT05399888). The largest repurposing bet has now reported: oral semaglutide did not slow CDR-SB decline at 104 weeks in evoke or evoke+ (differences −0.08, 95% CI −0.35 to 0.20, and +0.10, −0.17 to 0.38) (Cummings 2026, PMID 41865758; NCT04777396; NCT04777409).

All NCT identifiers on this page were retrieved from live ClinicalTrials.gov API queries on 2026-08-31. Statuses and dates are as recorded on that date and must be re-queried before reuse.

Pipeline shape

Category Share of 2025 pipeline
Small-molecule disease-targeted therapies 43%
Biological disease-targeted therapies 30%
Cognitive enhancers 14%
Neuropsychiatric symptom agents 11%
Repurposed agents (across categories) 33%
Active trials with a biomarker primary outcome 27%

Source: Cummings 2025, PMID 40463637 (138 drugs, 182 trials, 15 distinct targeted disease processes; both counts higher than the 2024 pipeline).

Geography is skewed. Of active trials, 33% are global; 73% of phase 3 trials are global versus a lower share at phase 1–2; 46 countries participate, 28% of them low- or middle-income; but only 7% of the 5,361 sites are in low- and middle-income countries even though those countries carry the majority of dementia cases and the largest projected growth (Cummings 2025, PMID 40555627; see epidemiology and burden). Eighty-nine percent of global trials are industry-sponsored.

Amyloid: symptomatic stage

Trial NCT Status (2026-08-31) n Design Key dates
CLARITY AD (lecanemab) NCT03887455 Active, not recruiting 1,906 actual Phase 3; IV and SC lecanemab vs placebo; core primary CDR-SB at 18 months, extension safety Start 2019-03-27; completion 2029-06-30
TRAILBLAZER-ALZ 2 (donanemab) NCT04437511 Active, not recruiting 1,736 actual Phase 3; primary iADRS at week 76 in overall and low/medium-tau populations Start 2020-06-19; primary completion 2023-04-14; completion 2028-11
TRAILBLAZER-ALZ 4 (donanemab vs aducanumab) NCT05108922 Completed 148 actual Phase 3 open-label; primary = complete amyloid clearance on florbetapir PET at 6 months 2021-11-16 to 2023-09-19
TRAILBLAZER-ALZ 6 (donanemab dosing/ARIA) NCT05738486 Active, not recruiting 1,175 actual Phase 3; primary = any ARIA-E occurrence across dosing regimens Start 2023-02-28; primary completion 2024-05-16
Donanemab real-world comparative study NCT06566170 Recruiting 6,250 estimated Donanemab + usual care vs usual care; primary = time to first increase in Dependence Scale level Start 2024-10-07; primary completion 2033-02

Results for CLARITY AD (van Dyck 2023, PMID 36449413), TRAILBLAZER-ALZ 2 (Sims 2023, PMID 37459141) and TRAILBLAZER-ALZ 4 are on anti-amyloid immunotherapy.

Amyloid: preclinical and secondary prevention

Trial NCT Status n Population and primary outcome
TRAILBLAZER-ALZ 3 (donanemab) NCT05026866 Active, not recruiting 2,996 estimated Preclinical AD; primary = time to clinical progression on a CDR-based composite; primary completion 2027-11
AHEAD 3-45 (lecanemab) NCT04468659 Active, not recruiting 1,400 estimated Two sub-trials: A45 primary = PACC5 change at week 216; A3 primary = amyloid PET SUVr change at week 216; primary completion 2028-12-21, completion 2031-01-16
A4 (solanezumab) NCT02008357 Completed 1,169 actual Preclinical AD; PACC at ~240 weeks. Reported: no effect (difference −0.30, 95% CI −0.82 to 0.22, P=0.26) (Sperling 2023, PMID 37458272)
Trontinemab, cognitively unimpaired at risk NCT07717411 Not yet recruiting 1,600 estimated Primary = time to progression, confirmed CDR global score >0; start planned 2026-11-30

A4 is the completed control case for this design: an antibody that did not lower plaque (amyloid rose in both arms, +11.6 vs +19.3 Centiloids) produced no clinical effect over 240 weeks. TRAILBLAZER-ALZ 3 and AHEAD 3-45 test the opposite condition — deep clearance started before symptoms.

Amyloid: next generation

Agent NCT Status n Distinguishing feature
Remternetug (TRAILRUNNER-ALZ 3) NCT06653153 Active, not recruiting 1,400 estimated Subcutaneous; primary = time to clinically meaningful CDR progression; completion 2030-10
Remternetug (DIAN-TU) NCT06647498, NCT05552157 Recruiting 280 estimated each Dominantly inherited AD; stage 1 primary = change in amyloid load (Centiloids, ¹¹C-PiB PET); primary completion 2034
Trontinemab (brain-shuttle) NCT07169578, NCT07170150 Recruiting 800 estimated each Transferrin-receptor shuttle for enhanced brain penetration; primary = CDR-SB change at week 72
Trontinemab phase 1b/2 (Brainshuttle AD) NCT04639050 Active, not recruiting 241 actual Multiple ascending dose; primary = adverse events
Lecanemab in dominantly inherited AD (DIAN-TU ART) NCT06384573 Active, not recruiting 40 actual Amyloid Removal Trial; primary = time to recurrent CDR-SB progression; completion 2030-06
Donanemab + RG6289 in PSEN1 carriers NCT06996730 Not yet recruiting 240 estimated Combination amyloid + gamma-secretase modulator; primary = Centiloid change

Tau

Programme NCT Status n Result or endpoint
IONIS-MAPTRx / BIIB080 phase 1b NCT03186989 Completed 46 actual Dose-dependent CSF t-tau reduction 56% (95% CI 50–62) and p-tau181 51% (38–63); tau-PET reduction, largest in the temporal composite (−0.71 SUVR, 95% CI −1.40 to −0.02) at week 100 (Edwards 2023, PMID 37902726)
Diranersen (BIIB080) phase 2 NCT05399888 Active, not recruiting 416 actual Primary = dose response in CDR-SB change to week 76; primary completion 2026-03-11
E2814 with concurrent lecanemab NCT06602258 Active, not recruiting 105 actual Primary = CSF MTBR-tau-243 change at 6 months — a target-engagement endpoint for combination therapy
Alzheimer's Tau Platform master protocol NCT06957418, NCT07167966 Recruiting / enrolling by invitation 900 / 450 estimated Primary = tau-PET reduction; regimen A pairs AADvac1 with donanemab
AV-1980R tau vaccine (TAURUS-1980) NCT07158905 Recruiting 48 estimated Phase 1 in preclinical AD; primary = treatment-emergent adverse events
Anti-tau monoclonal antibodies (gosuranemab, semorinemab, tilavonemab, zagotenemab) — Reported 2,193 across 6 RCTs Network meta-analysis: placebo ranked best on CDR-SB and ADCS-ADL (SUCRA 75.7% and 79.5%) (Cai 2024, PMID 39945003)
Gosuranemab (TANGO) NCT03352557 Terminated 654 actual Phase 2, 78 weeks. High-dose CDR-SB change 1.85 vs 1.85 placebo; CSF unbound N-terminal tau reduced at all doses (P<0.0001) (Shulman 2023, PMID 38012285)
Semorinemab (Tauriel) NCT03289143 Terminated 457 actual Phase 2, 73 weeks, n=422 mITT. CDR-SB Δ 2.19 placebo vs 2.36–2.41 across doses (Teng 2022, PMID 35696185)

The strategic question the tau field is answering is whether extracellular antibody clearance failed because the target is intracellular. Diranersen (production reduction) and E2814 (targeting the microtubule-binding region, with a CSF MTBR-tau-243 endpoint) are the two live tests. See tau biology and spread.

Non-amyloid, non-tau

Programme NCT Status n Note
Semaglutide (evoke, evoke+) NCT04777396, NCT04777409 Completed Registry: 1,840 each; publication: 1,855 / 1,953 randomised Oral semaglutide up to 14 mg vs placebo. At week 104, CDR-SB differences were −0.08 (95% CI −0.35 to 0.20; P=0.57) and +0.10 (−0.17 to 0.38; P=0.46): neither trial was efficacious. Treatment-emergent adverse events occurred in 91.2% vs 84.8%; 5 deaths were considered treatment-related by investigators (1 semaglutide, 4 placebo) (Cummings 2026, PMID 41865758)
Liraglutide (ELAD) NCT01843075 Unknown (registry); publication 2026 204 actual Phase 2b, 52 weeks, non-diabetic mild-to-moderate AD. Primary cerebral glucose metabolic rate difference −0.17 (−0.39 to 0.06, P=0.14); unadjusted ADAS-Exec 0.15 (0.03–0.28, P=0.01); no ADCS-ADL or CDR-SB difference (Edison 2026, PMID 41326666)
AL002 (TREM2 agonist, INVOKE-2) NCT04592874 Completed 356 actual Phase 2, 381 randomised. Target engaged (CSF sTREM2 down, osteopontin up); CDR-SB at week 96 missed at all doses (LS differences −0.31 to +0.13, all P>0.05); ARIA-like MRI the most frequent TEAE (Mummery 2026, PMID 41787076)
Minocycline (MAD) ISRCTN16105064 Published 544 200 or 400 mg vs placebo, 24 months, mild AD. sMMSE decline 4.1 vs 4.3 points (difference 0.1, −1.1 to 1.2, P=0.90); 400 mg poorly tolerated (Howard 2020, PMID 31738372)
Verubecestat EPOCH / APECS NCT01739348 / NCT01953601 Terminated 2,211 / 1,454 actual BACE1 inhibition. EPOCH: no ADAS-cog or ADCS-ADL benefit at 78 weeks (Egan 2018, PMID 29719179). APECS: 40 mg worse than placebo on CDR-SB (2.02 vs 1.58, P=0.01) and faster progression to dementia (HR 1.38) (Egan 2019, PMID 30970186)
ALZ-801 (valiltramiprosate), APOE4/4 early AD NCT04770220 Completed 325 actual Phase 3 in APOE ε4 homozygotes; primary = ADAS-Cog13; primary completion 2024-05-29
Hydromethylthionine (TRx0237, LUCIDITY) NCT03446001 Completed 598 actual Phase 3, 16 vs 8 mg/day vs control; primary = ADAS-cog11
Blarcamesine (ANAVEX2-73) open-label extension NCT04314934 Completed 300 actual Primary = treatment-related adverse events
IL-2 plus semaglutide NCT07651319 Recruiting 30 estimated Phase 1/2 immunomodulation
Semaglutide + intranasal insulin (COMMETS) NCT06072963 Recruiting 80 estimated Phase 2, metabolic combination

Repurposed agents are a third of the pipeline (PMID 40463637), and the GLP-1 class was the largest single repurposing bet. Its two null phase 3 results now join the null 12-month intranasal-insulin phase 2/3 precedent (Craft 2020, PMID 32568367), discussed on vascular and metabolic contributions.

Prevention and non-drug trials

Trial NCT Status n Result
FINGER NCT01041989 Unknown (registry status) 1,200 estimated Between-group NTB difference 0.022 z/year (95% CI 0.002–0.042, P=0.030) (Ngandu 2015, PMID 25771249)
US POINTER NCT03688126 Completed 2,000 actual Structured vs self-guided difference 0.029 SD/year (95% CI 0.008–0.050, P=0.008); both arms improved (Baker 2025, PMID 40720610)
ACHIEVE (hearing) NCT03243422 Completed 977 actual Primary null: difference 0.002 (95% CI −0.077 to 0.081, P=0.96); prespecified cohort interaction p=0.010 (Lin 2023, PMID 37478886)
SPRINT (MIND substudy) NCT01206062 Completed 9,361 actual Probable dementia HR 0.83 (0.67–1.04); MCI HR 0.81 (0.69–0.95) (PMID 30688979)
D-CARE (care models) NCT03786471 Completed 2,176 actual No difference between health-system, community-based and usual dementia care on behavioural symptoms or caregiver strain (Reuben 2025, PMID 39878968)

Symptom-directed trials

Trial NCT Status n Result
Brexpiprazole for agitation NCT03548584 Completed 345 actual CMAI difference −5.32 (95% CI −8.77 to −1.87), P=0.003, Cohen d 0.35 (Lee 2023, PMID 37930669)
CitAD (citalopram for agitation) NCT00898807 Completed 186 actual NBRS-A −0.93 (95% CI −1.80 to −0.06); MMSE −1.05; QTc +18.1 ms (Porsteinsson 2014, PMID 24549548)
HARMONY (pimavanserin, dementia-related psychosis) NCT03325556 Completed 392 actual Discontinuation design: among 217 responders, relapse 13% vs 28% on placebo (HR 0.35, 0.17–0.73, P=0.005); stopped early for efficacy (Tariot 2021, PMID 34289275)
AVP-923 (dextromethorphan–quinidine for agitation) NCT01584440 Completed 220 actual Phase 2 sequential parallel comparison: NPI Agitation/Aggression LS mean −1.5 and −1.6 across stages (Cummings 2015, PMID 26393847)
S-CitAD (escitalopram) NCT03108846 Active, not recruiting 187 actual in registry; 173 randomised in publication Primary endpoint not significantly improved; drug-related QT prolongation observed. PubMed's abstract reports an internally inconsistent point estimate and CI, so no numeric effect is reproduced (Rajji 2025, PMID 40133524)
ADMET 2 (methylphenidate for apathy) NCT02346201 Completed 200 actual NPI apathy difference −1.25 (95% CI −2.03 to −0.47), P=0.002 (Mintzer 2021, PMID 34570180)

Observational and registry infrastructure

Study NCT Status n Purpose
DIAN NCT00869817 Recruiting 700 estimated Dominantly inherited AD natural history; primary = predictive power of biomarkers; source of the pre-symptomatic biomarker timeline (Bateman 2012, PMID 22784036)
Georgia Memory Net anti-amyloid mAb registry NCT05999084 Enrolling by invitation 735 estimated Real-world anti-amyloid outcomes; primary = QDRS change
Korean JOY-ALZ registry NCT06889818 Recruiting 4,000 estimated National treatment and diagnostics registry to 2034
Epidemiology and biomarker study (p-tau217) NCT07142954 Recruiting 3,400 estimated Primary = time to cognitive worsening; a plasma-biomarker-defined cohort

Registries are becoming the main source of post-approval effectiveness and safety data, because the pivotal trials were 18 months long and excluded anticoagulated and high-microbleed patients — see anti-amyloid immunotherapy.

The graveyard, and what it teaches

Failed approach Evidence Lesson
Active Aβ42 immunisation (AN1792) Plaque cleared (2.1% vs 5.1% mean Aβ load) yet 7 of 8 autopsied immunised participants reached severe dementia; no survival or time-to-severe-dementia benefit (Holmes 2008, PMID 18640458) Late plaque removal alone does not stop neurodegeneration
γ-secretase inhibition (semagacestat) Worse function at 140 mg (ADCS-ADL −12.6 vs −9.0, P<0.001), more skin cancers and infections (Doody 2013, PMID 23883379) The enzyme has essential substrates
BACE inhibition (verubecestat, lanabecestat) EPOCH null at 78 weeks (Egan 2018, PMID 29719179); APECS 40 mg worse than placebo on CDR-SB and faster dementia conversion (Egan 2019, PMID 30970186); pooled cognitive worsening (Wessels 2020, PMID 33049114) Profound chronic BACE1 inhibition is not tolerated, including before dementia
TREM2 agonism (AL002) Target engaged; CDR-SB missed at all doses; ARIA-like MRI (Mummery 2026, PMID 41787076) Microglial engagement is not the same as clinical benefit
Monomer-targeting antibody in preclinical AD (solanezumab) No PACC effect over 240 weeks; amyloid rose in both arms (Sperling 2023, PMID 37458272) Engaging the wrong species produces no benefit even with an ideal population
Partial clearance (gantenerumab) 56–66 Centiloid reduction, only ~27% rendered amyloid-negative, CDR-SB differences −0.31 and −0.19, both non-significant (Bateman 2023, PMID 37966285) Depth of clearance may be threshold-dependent
Discordant identical trials (aducanumab) EMERGE −0.39 (P=0.012) vs ENGAGE +0.03 (P=0.833) (Budd Haeberlein 2022, PMID 35542991) Two identical protocols can disagree; single positive trials warrant caution
Extracellular anti-tau antibodies Placebo ranked best on CDR-SB and ADCS-ADL across 6 RCTs (Cai 2024, PMID 39945003) Compartment may matter more than target

Long exposure before symptoms: signal, design warning, not proof

The DIAN-TU gantenerumab open-label extension is the clearest current illustration. Seventy-three mutation carriers received doses up to 1,500 mg every two weeks; only 13 completed three years because the sponsor stopped the study early. PiB-PET fell by an adjusted 0.71 SUVR (95% CI 0.53–0.88), while estimated hazard ratios for clinical decline in asymptomatic carriers were 0.79 (95% CI 0.47–1.32; n=53) for any gantenerumab exposure and 0.53 (0.27–1.03; n=22) for the longest exposure. ARIA occurred in 53%, including microhaemorrhage in 47% and oedema in 30% (Bateman 2025, PMID 40120616; NCT01760005; NCT06424236). The clinical intervals include no effect, and external controls plus selective long exposure prevent causal interpretation; the result is a rationale for a definitive prevention trial, not one.

CLARITY-AD’s open-label extension presents the same inferential problem at larger scale: early-start and delayed-start curves remained separated through 36 months and ARIA became uncommon after six months, but the extension lacks a concurrent placebo group and its abstract supplies no new placebo-adjusted CDR-SB estimate (van Dyck 2025, PMID 41355080; NCT03887455). In trial-landscape terms, extension studies are essential for uncommon harms and durability, but cannot replace long randomised exposure.

Structural problems the pipeline has not solved

  1. Biomarker-pure populations. Trials enrol amyloid-confirmed, low-microbleed, largely non-anticoagulated participants, whereas mixed pathology is the community norm — see vascular and metabolic contributions.
  2. Outcome measures. Effect sizes are reported on composites (CDR-SB, iADRS, PACC5) whose minimal clinically important differences exceed the observed treatment effects (see clinical presentation and staging). Newer designs use time-to-progression endpoints (NCT05026866, NCT06653153, NCT07717411) rather than continuous change, which changes the interpretive frame but not the effect size.
  3. Duration. Prevention trials need 4–8 years (AHEAD 3-45's PACC5 endpoint is at week 216; DIAN-TU remternetug runs to 2034), which makes them expensive, attrition-prone and vulnerable to standard-of-care change mid-trial.
  4. Geography. 7% of sites in low- and middle-income countries against the majority of the disease burden (PMID 40555627).
  5. Combination therapy is barely tested. E2814 + lecanemab (NCT06602258) and donanemab + RG6289 (NCT06996730) are among the few registered combinations, both with biomarker primaries.

Open questions

  • Will deep amyloid clearance before symptom onset prevent or delay clinical AD? TRAILBLAZER-ALZ 3 (NCT05026866) and AHEAD 3-45 (NCT04468659) are the definitive tests and report in 2027–2028.
  • Why did semaglutide fail despite convergent preclinical and observational signals, and can a responder subgroup be identified without converting a null trial into a post-hoc positive claim (Cummings 2026, PMID 41865758; NCT04777396; NCT04777409)?
  • Does lowering tau production, as opposed to binding extracellular tau, produce clinical benefit (NCT05399888; Edwards 2023, PMID 37902726)?
  • Can combination amyloid + tau therapy be evaluated on biomarker endpoints and then confirmed clinically, or does each combination need its own outcome trial (NCT06602258; NCT06996730)?
  • Do brain-shuttle constructs achieve the same clearance with less ARIA, and is that testable before phase 3 completes (NCT07169578, NCT07170150)?
  • What would make trial sites in low- and middle-income countries viable, given that 28% of participating countries are LMICs but only 7% of sites are (Cummings 2025, PMID 40555627)?
  • Should time-to-progression endpoints replace continuous composites as the primary outcome standard, and how would that change the interpretation of already-completed trials?

References

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