Global Trial to Test Lifestyle Plus Metabolic Tx in Dementia

LONDON — A global trial will evaluate whether adding a metabolism-targeting therapy to intensive lifestyle intervention can enhance the cognitive benefits of lifestyle changes in older adults at risk for dementia.The Alzheimer's Association has announced the Prevention of Risk fOr cogniTive dEcline through Combined Therapy (PROTECT-Cog) study and will provide $100 million in funding. The study will evaluate a metabolism-targeting therapy, such as a GLP-1 receptor agonist, in combination with lifestyle intervention, although the specific agent and other trial details have yet to be finalized.The study builds on evidence that multidomain lifestyle interventions can slow cognitive decline and will assess whether combining them with pharmacologic therapy yields greater benefit than lifestyle intervention alone. “This trial is going to allow us to ask whether adding a booster” further adds to the already documented cognitive benefits of lifestyle interventions, Heather M. Snyder, PhD, senior vice president, Medical & Scientific Relations, Alzheimer’s Association, told Medscape Medical News.The PROTECT-Cog trial launch was announced July 13 at the Alzheimer's Association International Conference (AAIC) 2026.A New StrategyDementia is the leading cause of disability and dependency among older adults worldwide, affecting an estimated 50 million people. That number is projected to nearly triple over the next three decades.PROTECT-Cog builds on growing evidence that multidomain lifestyle interventions can slow cognitive decline in people at increased risk for dementia. Landmark studies, including the 2015 Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) and the US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (US POINTER), have shown that comprehensive lifestyle programs improve cognition in at-risk older adults.In POINTER, the improvements were equivalent to approximately 1-2 years of cognitive advantage for those following a structured multidomain lifestyle intervention compared to those using a self-guided approach, with additional benefits in reducing frailty and sleep apnea and improving blood pressure regulation.Collectively, these studies suggest that the cognitive benefits of lifestyle intervention depend on a multidomain approach rather than any single component. “One big important message is that the sum of the parts is greater than any individual part,” Snyder said.PROTECT-Cog will test whether adding a metabolism-targeting therapy to this multidomain approach provides additional protection against cognitive decline.The idea now is to see whether these benefits can be enhanced with the addition of a drug targeting metabolism.Exploring Metabolic PathwaysSnyder said a growing body of evidence supports targeting metabolic pathways, including large real-world claims analyses in which GLP-1 receptor agonists were associated with a 40% to 70% lower risk of dementia than other diabetes medications.She also cited a pooled analysis of clinical trial data suggesting that dementia occurred more often over time among participants receiving placebo than among those treated with an active agent.She added that growing evidence that targeting metabolic pathways may benefit brain health by reducing neuroinflammation and affecting other biological processes implicated in AD.The study will also assess the impact of adding a drug that supports healthier metabolism and immune function to identify which intervention combination is most effective in delaying mild cognitive impairment while evaluating effects on frailty, quality of life, and overall health.PROTECT-Cog will enroll older adults at increased risk for cognitive decline and compare two multidomain lifestyle intervention programs: one featuring intensive coaching and support and another with the same core components but fewer participant touchpoints.Participants will be followed for 3 years and undergo comprehensive cognitive and health assessments every 6 months.Combination prevention strategies are already being explored in dementia. The MET-FINGER trial, which combines the FINGER multidomain lifestyle intervention with the diabetes drug metformin, is evaluating whether the combination reduces dementia risk while improving health and functional independence in older adults. Similar multidomain prevention strategies have also been adopted in oncology and cardiovascular disease, Snyder noted. She added that it is expected that PROTECT-Cog will begin enrolling participants within about a year.Snyder noted that the phase 3 EVOKE and EVOKE+ trials enrolled participants with biomarker-confirmed Alzheimer's disease — mild cognitive impairment due to AD or mild AD dementia — whereas PROTECT-Cog is designed to evaluate dementia prevention in older adults at risk, regardless of the underlying cause. A ‘Bold Effort’The PROTECT-Cog study is "indeed a bold effort," David S. Knopman, MD, a clinical neurologist at the Mayo Clinic in Rochester, Minnesota, whose research focuses on late-life cognitive disorders, told Medscape Medical News.However, he said the initiative faces major challenges, including the cost of recruiting a large number of participants and the lengthy follow-up required, but added that he is confident the Alzheimer's Association is well aware of those hurdles.The proposed trial "could be justified" only if it enrolls participants with a high burden of vascular risk factors, Knopman said. He believes the EVOKE and EVOKE+ trials failed because participants were at relatively low vascular risk. Although they had biomarker-confirmed AD, few had vascular risk factors or active vascular disease; for example, only 13.6% had diabetes.Snyder and Knopman report no relevant disclosures.