NeurologyLive® Year in Review 2025: What Trials Could Reshape Alzheimer Care?

In 2025, the NeurologyLive^® staff was a busy bunch, covering clinical news and data readouts from around the world across a number of key neurology subspecialty areas. From major study publications and FDA decisions to societal conference sessions and expert interviews, the team spent all year bringing the latest information to the website's front page.

Among our key focus areas is Alzheimer disease and dementia, a field that experienced massive shifts in the therapeutic paradigm in the past 12 months, among other progress. Although major news items often appear among the top pieces our team produces, sometimes smaller stories reach those heights for other reasons—clinical impact and interest, or concerns about the small- or big-picture parts of care, for example. Whatever the reason for the attention these stories got, their place here helps provide an understanding of the themes in this field over the course of 2025.

With the amount of ongoing research, it's nearly impossible to narrow down just 8 trials that may impact the field of Alzheimer research, but we'll highlight some of the top ongoing trials.

1. Phase 2/3 Dominantly Inherited Alzheimer Network Trial (DIAN-TU)

The phase 2/3 DIAN-TU platform trial (NCT05269394) is designed to evaluate the potential benefits of etalanetug, an antitau therapy, administered with background antiamyloid treatment in patients with an AD–causing mutation. The study incorporates combined amyloid- and tau-targeting therapy to address ethical and recruitment considerations, as participants have expressed a preference for inclusion of an approved amyloid-directed agent when randomized to etalanetug (Eisai).

The primary outcome is whether etalanetug plus lecanemab (Leqembi; Eisai) is superior to placebo plus lecanemab in reducing tau spread, as measured by tau PET, from 24 weeks to 104 and 208 weeks in a symptomatic AD population. Eligible participants included adults aged 18 to 80 years who were known carriers of an AD–causing mutation and were in 10 years before or after their predicted or actual age of cognitive symptom onset. Participants were also required to be cognitively normal or have mild cognitive impairment or mild dementia, defined by a Clinical Dementia Rating (CDR) score of 0 to 1.

2. Phase 1b/2a Brainshuttle AD Study of Trontinemab

The goal of the phase 1b/2a Brainshuttle AD study (NCT04639050) is to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of multiple-ascending intravenous (IV) doses of of trontinemab (Roche) in patients with prodromal or mild to moderate AD, who are amyloid positive based on amyloid PET scan. The primary outcome is the percentage of participants experiencing adverse events during Part 1 and Part 2 (approximately 56 weeks), Part 3 (up to approximately 52 weeks), and Part 4 (up to approximately 129 weeks).

Clinical eligibility included a diagnosis of probable mild to moderate AD dementia, consistent with National Institute on Aging–Alzheimer’s Association criteria, or prodromal AD consistent with criteria for mild cognitive impairment because of AD. Additional inclusion criteria included a screening Mini-Mental State Examination score of 18 to 28 and a global CDR score of 0.5, 1, or 2 in 84 days before baseline, as well as a positive amyloid positron emission tomography scan (more than 50 Centiloid units) obtained in 12 months before baseline.

3. Phase 1/2a Study of ALZN002 in Mild-to-Moderate AD Dementia

This first-in-human, randomized, double-blind, placebo-controlled, parallel-group phase 1/2a study (NCT05834296) is evaluating autologous amyloid β mutant peptide–pulsed dendritic cells (ALZN002; Alzamend Neuro) in patients with mild to moderate AD dementia. The study will assess the safety and tolerability of multiple ascending doses of ALZN002 compared with placebo and to identify an optimal dose that induces antiamyloid β antibody responses while maintaining safety, to inform dose selection for a subsequent phase 2b efficacy study. The primary outcome is the frequency and severity of treatment-emergent adverse events through study completion.

Eligible participants are aged 60 to 85 years with a diagnosis of AD, with confirmation at screening, based either on a positive amyloid PET or on a historical positive amyloid PET obtained in 6 months prior to the screening visit. Additional inclusion criteria include a clinical diagnosis of probable or possible AD according to National Institute on Aging–Alzheimer’s Association criteria, a global CDR score of 0.5 to 2, a Mini-Mental State Examination (MMSE) score of 14 to 26, and an Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog11) score greater than 12 at screening and baseline.

4. Phase 3 TRAILBLAZER-ALZ 3 Study of Donanemab in Preclinical AD

The phase 3 TRAILBLAZER-ALZ 3 study (NCT05026866) aims to evaluate the safety and efficacy of donanemab (Kisulna; Eli Lilly) administered intravenously compared with placebo in patients at risk for cognitive and functional decline of AD. The primary outcome being time to clinical progression as measured by CDR over up to 332 weeks in the study population. Furthermore, approximately 800 additional participants will be enrolled in the 12-month Addendum 7 to evaluate the safety of an alternative titration regimen.

Eligible participants were required to have a Telephone Interview for Cognitive Status–modified score indicative of intact cognitive function and a phosphorylated tau (P-tau) result consistent with the presence of amyloid pathology. Participants also must have a reliable study partner and a backup partner familiar with the participant’s daily functioning and cognitive abilities. In addition, participants must have adequate literacy, vision, and hearing to complete neuropsychological testing at screening.

5. Phase 3 TRAILRUNNER-ALZ 3 Study of Remternetug in Early AD

The phase 3 TRAILRUNNER-ALZ 3 study (NCT06653153) aims to assess the difference in time to developing or worsening memory, thinking, or functional problems because of AD occurring in patients treated with remternetug (Eli Lilly) compared with placebo. The primary outcome is the time to clinically meaningful progression as measured by CDR from baseline to time to event up to 255 weeks. In addition, eligible participants who receive placebo during the double-blind treatment period may choose to extend their study participation to receive open-label remternetug in an extension period.

Eligible participants were required to have a P-tau result indicative of amyloid pathology and a reliable study partner, with a backup, who is familiar with the participant’s overall function and daily cognitive abilities. Participants must also have adequate literacy, vision, and hearing to complete neuropsychological testing at screening. Cognitive and functional assessments must indicate no to minimal impairment, as measured by the MMSE and the Functional Activities Questionnaire. Participants receiving symptomatic treatments for AD must have maintained a stable dose for at least 30 days prior to screening.

6. Phase 3 AHEAD 3-45 Study of Lecanemab in Preclinical AD

The AHEAD 3-45 trial (NCT04468659) is a phase 3 study assessing the efficacy and safety of lecanemab in patients with preclinical AD and elevated amyloid and also in patients with early preclinical AD and intermediate amyloid. The aim of the study is to determine whether treatment with lecanemab is superior to placebo on change from baseline of the Preclinical Alzheimer Cognitive Composite 5 (PACC5) at 216 weeks of treatment and to determine whether treatment with lecanemab is superior to placebo in reducing brain amyloid accumulation as measured by amyloid PET at 216 weeks of treatment.

This study will also evaluate the long-term safety and tolerability of lecanemab in participants enrolled in the extension phase. Eligible participants were adults aged 55 to 80 years, with plasma biomarker results predictive of intermediate or elevated brain amyloid at screening or previously confirmed elevated or intermediate amyloid by PET, cerebrospinal fluid (CSF), or plasma testing. At screening, participants were required to have a global CDR score of 0, a MMSE score at least 27, and a Wechsler Memory Scale–Revised Logical Memory subscale II score at least 6.

7. Phase 3 Clarity AD to Confirm Safety and Efficacy of Lecanemab in Early AD

The phase 3 Clarity AD study (NCT03887455) aims to evaluate the efficacy of lecanemab in patients with early AD by determining the superiority of lecanemab compared with placebo, as measured by the change from baseline in the CDR-SB at 18 months of treatment in the core study. The study will also evaluate the long-term safety and tolerability of lecanemab in patients with early AD in the extension phase and whether the long-term effects of lecanemab as measured by the CDR-SB at the end of the core study is maintained over time in the extension phase.

The extension phase Part B will continue dosing with lecanemab in countries where lecanemab may not be commercially available. Eligible participants were adults aged 50 to 90 years with objective impairment in episodic memory, defined as at least 1 standard deviation below the age-adjusted mean on the Wechsler Memory Scale IV–Logical Memory II subscale. Participants were also required to have a positive biomarker for brain amyloid pathology, a Mini-Mental State Examination score between 22 and 30 at screening and baseline, and a body mass index between 17 and 35.

8. Phase 2 SToMP-AD Study of Senolytics to Modulate the Progression of AD

This phase 2 multisite, randomized, double-blind placebo controlled trial (NCT04685590) aims to assess the safety, feasibility, and efficacy of senolytics in older adults with amnestic mild cognitive impairment (MCI) or early-stage AD who are tau PET positive. The primary outcome measure is the incidence of serious and nonserious adverse events in the treatment group compared with placebo from baseline to 48 weeks. Participants eligible were adults aged 60 years and older with a diagnosis of amnestic mild cognitive impairment or early AD.

Inclusion required evidence of elevated tau protein, either from cerebrospinal fluid obtained during screening or from previously available CSF samples. Use of FDA-approved Alzheimer medications is permitted if participants have been on a stable dose for at least 3 months prior to study entry. Laboratory eligibility criteria include normal blood cell counts, normal liver and renal function without clinically significant abnormalities as determined by the coordinating center Medical Monitor, total cholesterol less than 240 mg/dL, and HbA1c no more than 7%.

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