Summary

Alzheimer’s disease (AD), a progressive neurodegenerative disorder affecting millions worldwide, has seen significant advancements in oral medication research between 2023 and 2026. While traditional treatments like cholinesterase inhibitors (e.g., donepezil) provide symptomatic relief, recent studies have focused on disease-modifying pills targeting amyloid-beta (Aβ), tau proteins, inflammation, and metabolic pathways. These efforts aim to slow progression in early-stage AD, with several candidates advancing through Phase 3 trials. However, challenges such as mixed trial outcomes and side effects persist. This report synthesizes key findings from clinical trials, highlighting promising drugs, pipeline trends, and future implications as of January 2026.

Key Recent Studies and Clinical Trials

Recent research emphasizes oral formulations for better patient compliance compared to intravenous therapies like lecanemab (approved 2023) and donanemab (approved 2024). Below are highlights from pivotal studies conducted or completed between 2023 and 2026.

Semaglutide (Rybelsus) – Repurposed GLP-1 Agonist

Semaglutide, an oral glucagon-like peptide-1 (GLP-1) receptor agonist originally for diabetes, was tested in the largest AD trials to date: the EVOKE and EVOKE+ Phase 3 studies (2023–2025). These randomized, double-blind trials enrolled 3,808 adults with early symptomatic AD. Topline results, announced in late 2025, showed no significant slowing of cognitive decline over two years, as measured by primary endpoints like the Clinical Dementia Rating-Sum of Boxes (CDR-SB). However, secondary analyses revealed improvements in biomarkers, including reduced tau protein levels, decreased brain inflammation, and less nerve cell damage. The trials were discontinued early for the extension phase due to lack of efficacy in the overall population, but experts suggest potential for preventive use or combination therapies, building on prior diabetes-AD links. Full results are slated for presentation at the Alzheimer’s and Parkinson’s Diseases Conference in March 2026.

Valiltramiprosate (ALZ-801) – Amyloid Oligomer Inhibitor

Developed by Alzheon, ALZ-801 is an oral prodrug of tramiprosate that inhibits Aβ oligomer formation, particularly in APOE4 carriers (a high-risk genetic group). The Phase 3 APOLLOE4 trial, completed in 2025 with 325 early AD participants, demonstrated slowed cognitive decline and improved biomarkers like plasma p-tau181. Safety data highlighted a favorable profile with minimal amyloid-related imaging abnormalities (ARIA). As the first potential oral disease-modifier, Alzheon plans FDA submission in 2026, potentially marking a shift from infusions to pills.

Buntanetap Tartrate – Multi-Protein Targeting Agent

Annovis Bio’s buntanetap, a once-daily oral pill, targets amyloid, tau, and alpha-synuclein to combat neurodegeneration. The ongoing Phase 3 trial (NCT06709014), initiated in 2025, involves patients with early AD and aims for topline results by mid-2026. Interim data from earlier phases suggest improvements in cognition and daily function, with a unique mechanism differentiating it from amyloid-only therapies. Global sales forecasts predict significant market impact if approved.

AR1001 – Phosphodiesterase-5 Inhibitor

AriBio’s AR1001, repurposed from sildenafil-like compounds, is in the Phase 3 POLARIS-AD trial (NCT05531526) with over 1,150 early AD participants. The study, set to conclude by late 2025, evaluates its role in slowing progression via neuroprotection and anti-inflammation. Observational data link similar drugs to reduced AD risk, and topline results expected in Q2 2026 could position it as a low-cost oral option, with projected global sales of $674 million by 2033.

Other Notable Candidates

• Saracatinib: An oral kinase inhibitor, repurposed for AD, showed memory reversal in animal models. Human Phase 2 trials are underway, focusing on synaptic restoration.
• Remternetug: Eli Lilly’s oral anti-amyloid agent completed initial Phase 3 data collection in 2025, with full results due in 2026.
• Combination approaches, like E2814 (anti-tau) with lecanemab, are in Phase 2, exploring synergistic oral-IV strategies.

Alzheimer’s Drug Pipeline Overview

As of January 1, 2025, the AD pipeline includes 182 clinical trials assessing 138 drugs, a increase from prior years. Key trends:

• Disease-Modifying Therapies (DMTs): 73% of agents (biologicals: 30%, small molecules: 43%) target core pathologies like amyloid and tau.
• Symptomatic Treatments: 25% focus on cognition (14%) and neuropsychiatric symptoms (11%).
• Repurposed Drugs: 33% of the pipeline, including GLP-1 agonists and PDE5 inhibitors, leverage existing safety data for faster development.
• NIA-Funded Trials: Over 400 active studies, including prevention trials like AHEAD 3-45 (BAN2401 for preclinical AD) and caregiver interventions.
  Biomarkers serve as primary outcomes in 27% of trials, emphasizing measurable endpoints like PET scans and CSF analysis.

Category	Number of Trials	Number of Drugs	Phase Breakdown
Phase 3	48	31	Focus: Efficacy in large cohorts
Phase 2	86	75	Focus: Dose optimization, safety
Phase 1	48	45	Focus: Initial human testing
Total	182	138	–

Challenges and Future Directions

Despite progress, high failure rates (up to 95%) and substantial investments ($6 billion annually in the US) underscore challenges. Side effects like ARIA in amyloid-targeters and limited efficacy in advanced stages remain hurdles. Future research may prioritize prevention in at-risk groups (e.g., APOE4 carriers) and multi-target pills. With 12 FDA-approved drugs as of 2024, including recent additions like lecanemab, the field is evolving toward personalized, accessible treatments.

Conclusion

The 2023–2026 era marks a pivotal shift in AD research, with oral pills like ALZ-801 and AR1001 offering hope for convenient, disease-slowing options. While setbacks like semaglutide’s trials highlight the complexity of AD, the robust pipeline suggests breakthroughs ahead. Patients and caregivers should consult healthcare providers for trial participation or updates.

Citations

1. Researching new drugs for Alzheimer’s disease – https://www.alzheimers.org.uk/what-we-do/researchers/news/researching-new-drugs-alzheimers-disease
2. NIA-Funded Active Alzheimer’s and Related Dementias Clinical Trials and Studies – https://www.nia.nih.gov/research/ongoing-AD-trials
3. Trials to watch: Three major catalysts in Alzheimer’s disease – https://www.clinicaltrialsarena.com/features/trials-to-watch-three-major-catalysts-in-alzheimers-disease
4. Long-awaited results of GLP-1 trial in Alzheimer’s disease show disappointing results – https://www.drugdiscoverynews.com/long-awaited-results-of-glp-1-trial-in-alzheimer-s-disease-show-disappointing-results-16865
5. Alzheimer’s disease drug development pipeline: 2025 – https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70098
6. What’s Next for Alzheimer’s Disease Treatments: A 2024 Forecast – https://www.brightfocus.org/resource/whats-next-for-alzheimers-disease-treatments-a-2024-forecast
7. Key Neurology Trial Readouts to Watch in Early 2026 – https://www.neurologylive.com/view/key-neurology-trial-readouts-to-watch-in-early-2026
8. Alzheimer’s treatments: What’s on the horizon? – https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-treatments/art-20047780
9. Recent Advances in Drug Development for Alzheimer’s Disease – https://www.mdpi.com/1422-0067/26/8/3905
10. Clinical Trial Awareness: 5 Alzheimer’s Trials That Could Shape Tomorrow’s Treatment – https://trialx.com/clinical-trial-awareness-5-alzheimers-trials-that-could-shape-tomorrows-treatment