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Review
. 2025 Dec;12(10):100328.
doi: 10.1016/j.tjpad.2025.100328. Epub 2025 Oct 27.

Alzheimer Combination Therapies: Overview and Scenarios

Jeffrey L Cummings  1 , Aaron H Burstein  2 , Howard Fillit  2
Affiliations
Review

Alzheimer Combination Therapies: Overview and Scenarios

Jeffrey L Cummings et al. J Prev Alzheimers Dis. 2025 Dec.

Abstract

Progress in understanding the complexity of Alzheimer's disease informs the search for combination therapies that can successfully prevent or substantially slow the progression of the disease. Anti-amyloid monoclonal antibodies are the first approved disease targeted therapies; they slow disease progression by approximately 30 %. Building on these agents in add-on therapies is one avenue to designing combination treatments. Development of combination drugs consisting of two or more novel interventions is an alternate pathway for combination treatment development. Combination therapies can involve small molecule drugs, biological agents, devices, stem cells, gene therapies, lifestyle interventions, or cognitive training. Nonclinical assessment of drug combinations may involve animal models or new approach methodologies such as induced pluripotent stem cells or organoids. Phase 1 trials are required to characterize each member of a novel combination. Phase 2 trials may use a 2-by-2 factorial design comparing each drug to placebo and the drug combination. In Phase 3, comparison of the novel combination to standard of care may be sufficient or more complex designs may be required. Targets for combination therapies beyond amyloid-related processes include tau abnormalities, inflammation, neurodegeneration, and co-pathologies such as alpha-synuclein and TDP-43. The choice of combination therapies will depend on the strength of the information regarding the target, biomarkers to guide clinical trials, and a candidate agent with the appropriate mechanism of action. Computational strategies based on network analysis of disease and drugs, validation in non-clinical models, and use of real-world data may facilitate prioritization of candidates for combination treatments.

Keywords: Alzheimer's disease; Co-pathology; Combination therapy; Inflammation; Monoclonal antibodies; Synaptic plasticity.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeffrey L Cummings reports a relationship with Acadia Pharmaceuticals Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Acumen Pharmaceuticals Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with ALZpath Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Annovis Bio Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Artery Therapeutics Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Axsome Therapeutics Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Biogen Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Biohaven Ltd that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Bristol-Myers Squibb Company that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Eisai Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Fosun Pharma USA Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Global Alzheimer’s Platform Foundation that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Hummingbird Diagnostics GmbH that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with IGC Pharma that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Julius Clinical BV that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Kinoxis Therapeutics that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Lighthouse Pharma that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Eli Lilly and Company that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Lundbeck LLC that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Merck & Co Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with MoCA Cognition that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Novo Nordisk Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with NSC Therapeutics GmbH that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with OptoCeutics that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Praxis Bio Research that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with reMYND Nv that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Roche that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Scottish Brain Sciences that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Signant Health that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Jiangsu Simcere Pharmaceutical Co Ltd that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Sinaptica Therapeutics that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with T-Neuro Dx that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with TrueBinding Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with Vaxxinity Inc that includes: consulting or advisory. Jeffrey L Cummings reports a relationship with CNS Innovations that includes: equity or stocks. Jeffrey L Cummings reports a relationship with Mangrove Therapeutics that includes: equity or stocks. Jeffrey L Cummings reports a relationship with Journal of Prevention of Alzheimer’s Disease that includes: board membership. Jeffrey L Cummings reports a relationship with Journal of Prevention of Translational Neurodegeneration that includes: board membership. Jeffrey L Cummings has ownership of copy right for Neuropsychiatric Inventory. Howard Fillit reports a relationship with Therini Bio Inc that includes: board of directors membership. Howard Fillit reports a relationship with Alector Inc that includes: chairman, Independent Data Management Committee membership. Howard Fillit reports a relationship with ProMIS Neurosciences Inc that includes: clinical advisory board membership. Howard Fillit reports a relationship with LifeWorx that includes: consulting or advisory and board membership. Howard Fillit reports a relationship with TheKey that includes: consulting or advisory and board membership. Howard Fillit reports a relationship with ADmit Therapeutics SL that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig 1
Fig. 1
“Fast fail” approach for novel combination with advancing of the novel agents only the novel combination performs better than placebo.
Fig 2
Fig. 2
“Fast fail” approach for add-on combination with advancing of the novel agent only if it succeeds in performing better than approved agent without the novel agent.
Fig 3
Fig. 3
Factorial 2 × 2 combination platform design with Bayesian analysis and progression to 2nd round agents and combinations if the first candidates and candidate combinations do not show efficacy.
Fig 4
Fig. 4
Three arm combination therapy platform design comparing each drug to the comparison to determine if the comparison is superior to each drug alone and progression to substitute agents if the original candidates do not show efficacy.
See this image and copyright information in PMC

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