The review begins with the established drug classes. Cholinesterase inhibitors such as donepezil, rivastigmine and galantamine, together with the N-methyl-D-aspartate receptor antagonist memantine, continue to deliver small but statistically significant and clinically meaningful improvements in cognition and function. A meta-analysis of 43 randomized clinical trials encompassing more than 16,000 patients, cited in the review, quantifies both the efficacy and the substantial discontinuation rates that complicate real-world use. What is new, however, is the emerging biomarker dimension. Stratified analyses now suggest that individuals with biochemically confirmed Alzheimer pathology, verified through amyloid positron emission tomography or cerebrospinal fluid markers, respond more robustly to these agents than patients whose cognitive impairment arises from other mechanisms. Studies of amyloid PET-negative mild cognitive impairment show markedly attenuated cognitive responses to cholinesterase inhibitors, and positron emission tomography work even hints that these drugs may influence tau pathology within the Alzheimer disease continuum. The implication is profound: the era of prescribing cognitive enhancers on clinical impression alone may be drawing to a close, replaced by biomarker-informed precision symptomatic therapeutics.

Beyond the cholinergic and glutamatergic mainstream, the review charts a strikingly diverse pipeline of next-generation symptomatic agents. Selective muscarinic receptor agonism, a strategy first explored with xanomeline in the 1990s, has returned to prominence with modern M1-selective compounds such as HTL0018318, which showed preliminary pharmacodynamic activity in mild-to-moderate Alzheimer disease, and with xanomeline-based programs now being tested for Alzheimer-related psychosis in the ADEPT-5 trial. Multitarget agents are advancing in parallel: blarcamesine, which modulates the sigma-1 receptor and other pathways, reported phase IIB/III results in early Alzheimer disease, while masupirdine, a selective serotonergic 5-HT6 antagonist, showed exploratory signals on agitation, aggression and psychosis in moderate disease. Neurotrophic modulation represents another frontier, with positive allosteric modulators of neurotrophin receptors under development to support synaptic resilience, and brain-derived neurotrophic factor gene therapy being explored as a longer-term strategy for neurodegeneration.

Drug repurposing has emerged as a particularly pragmatic route to broader symptomatic benefit. The review highlights a Delphi consensus process and stakeholder consultation that prioritized existing medicines with plausible mechanisms and safety profiles for Alzheimer disease, alongside work identifying synergistic combinations of repurposed treatments. The logic is compelling: established drugs with decades of safety data can be recombined rationally to hit multiple neurotransmitter and circuit-level systems simultaneously, potentially achieving additive or synergistic effects that single agents cannot. Combination therapy itself is gaining formal traction, with the EU/US Clinical Trials on Alzheimer’s Disease task force articulating frameworks for testing cholinesterase inhibitor plus memantine regimens and, ultimately, pairing symptomatic agents with disease-modifying antibodies such as lecanemab and donanemab, whose approvals have changed the therapeutic context in which symptomatic care is delivered.

On the non-pharmacological side, the evidence base has matured considerably. Cognitive training, structured physical exercise, cognitive stimulation therapy and multimodal lifestyle programmes all show small-to-moderate benefits, with the strongest and most consistent effects observed in people with mild cognitive impairment. Computerized cognitive training meta-analyses demonstrate measurable gains in memory and general cognition, and comparative trials have even suggested that crossword puzzles may outperform computerized games on some outcomes. Exercise research, synthesized through network meta-analyses, points to benefits for executive function, activities of daily living and potentially the capacity for independent living, with aerobic, resistance and multicomponent regimens each contributing. The landmark FINGER trial, which combined diet, exercise, cognitive training and vascular risk monitoring, and its American counterpart US POINTER, which compared structured against self-guided multidomain lifestyle intervention, have established that comprehensive lifestyle programmes can protect global cognition in at-risk older adults, findings now being translated into public health policy.

Cognitive stimulation therapy deserves particular attention as one of the few non-drug interventions with evidence at the level of established dementia, not merely its prodrome. Systematic reviews and meta-analyses of randomized controlled trials using the original protocol show benefits for cognition and quality of life in mild-to-moderate disease, and emerging work extends the approach to mild cognitive impairment. Yet the review is candid about the implementation gap. Scalability, workforce training, delivery fidelity and real-world adherence remain formidable barriers, particularly in residential aged care settings where systematic reviews document persistent obstacles to embedding evidence-based non-pharmacological therapies. Non-invasive brain stimulation, including repetitive transcranial magnetic stimulation and transcranial direct current stimulation, is profiled as an adjunctive technology with encouraging meta-analytic signals for cognition and daily functioning, though heterogeneity across protocols tempers enthusiasm.

The most clinically burdensome domain, the review argues, is neuropsychiatric symptomatology. Agitation, depression, apathy, psychosis and sleep disturbance affect the substantial majority of people with Alzheimer disease over the course of illness, driving caregiver distress, institutionalization and reduced quality of life more powerfully than cognitive decline itself. Here the evidence favours personalized psychosocial interventions. The WHELD programme, a factorial cluster-randomized trial combining person-centred care training, tailored social interaction and exercise, and antipsychotic review, reduced agitation and antipsychotic prescribing in nursing homes, and its digital adaptation has since been tested in a randomized controlled trial. Brief operationalized psychosocial interventions for agitation and psychosis, systematic individualized approaches that identify the unmet needs driving behavioural symptoms, and structured strategies such as the DICE framework for caregiver training all demonstrate meaningful reductions in agitation and depression without pharmacological risk. Even treating pain, as a cluster-randomized trial showed, substantially reduces behavioural disturbance in nursing home residents with dementia.

Where drugs are required, the safety calculus is unfavourable for older agents. Atypical antipsychotics offer only modest efficacy against agitation and psychosis while carrying elevated risks of stroke, mortality, cognitive worsening and sedation, findings documented across the CATIE-AD trial, Cochrane reviews and the long-term DART-AD follow-up, which showed sustained excess mortality associated with continued antipsychotic exposure. Against this backdrop, newer agents represent genuine, if incremental, progress. Brexpiprazole, now approved for agitation associated with dementia due to Alzheimer disease, demonstrated significant benefit in two 12-week phase trials and in post hoc analyses of clinically relevant subgroups, with a more favourable metabolic and motor safety profile than predecessors. The dextromethorphan-quinidine combination AXS-05 showed relapse-prevention efficacy in the phase 3 ACCORD trial and became the first non-antipsychotic approved in the United States for dementia-related agitation. Pimavanserin, an inverse agonist at serotonin 5-HT2A receptors, showed significant benefit for dementia-related psychosis in a pivotal trial and phase 2 data in Alzheimer disease psychosis, while escitalopram achieved a positive phase 3 result for agitation, contrasting with the negative mirtazapine findings from the SYMBAD trial. Methylphenidate, meanwhile, offers a modestly effective option for apathy in the ADMET 2 trial.

The review’s forward-looking synthesis is unambiguous about what must change. Future progress will depend on biomarker-informed patient selection, increasingly enabled by blood-based biomarkers now moving into clinical implementation; on the integration of circuit-level measures that connect molecular mechanisms to network dysfunction; on rational combination strategies that span pharmacological and non-pharmacological modalities rather than testing interventions in isolation; and on the adoption of patient-centred outcomes such as goal attainment, quality of life and independence rather than narrow rating-scale endpoints. Symptomatic therapies, the authors conclude, will remain essential for improving quality of life in people with Alzheimer disease even as disease-targeted therapies gradually reshape disease trajectories. In an era captivated by amyloid clearance, the humble work of relieving symptoms, sharpening cognition, preserving function and calming distress is being reimagined with a precision and ambition that may ultimately matter just as much to patients and the families who love them.

Subject of Research: Current evidence and future directions for pharmacological and non-pharmacological symptomatic treatment of Alzheimer disease

Article Title: Symptomatic treatment for Alzheimer disease: current evidence and future directions

Article References: Ballard, C., Doherty, P., Ismail, Z., Corbett, A., & Cummings, J. L. (2026). Symptomatic treatment for Alzheimer disease: current evidence and future directions. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01260-5

Image Credits: AI Generated

DOI: 10.1038/s41582-026-01260-5

Keywords: Alzheimer disease, symptomatic treatment, cholinesterase inhibitors, memantine, neuropsychiatric symptoms, cognitive stimulation therapy, physical exercise, brexpiprazole, pimavanserin, biomarkers, drug repurposing, combination therapy