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Randomized Controlled Trial
. 2025 Aug 26;334(8):681-691.
doi: 10.1001/jama.2025.12923.

Structured vs Self-Guided Multidomain Lifestyle Interventions for Global Cognitive Function: The US POINTER Randomized Clinical Trial

Laura D Baker  1 , Mark A Espeland  2 , Rachel A Whitmer  3 , Heather M Snyder  4 , Xiaoyan Leng  2 , Laura Lovato  2 , Kathryn V Papp  5   6   7 , Melissa Yu  8 , Miia Kivipelto  9   10   11 , Ashley S Alexander  12 , Susan Antkowiak  13 , Maryjo Cleveland  1 , Claire Day  14 , Richard Elbein  15 , Sarah Tomaszewski Farias  16 , Deborah Felton  2 , Katelyn R Garcia  2 , Darren R Gitelman  17 , Sarah Graef  18 , Marjorie Howard  2 , Jeffrey Katula  19 , Katherine Lambert  20 , Olivia Matongo  21 , Anne Marie McDonald  15 , Valory Pavlik  8 , Rema Raman  22 , Stephen Salloway  23   24 , Christy Tangney  25 , Jennifer Ventrelle  25 , Sharon Wilmoth  1 , Benjamin J Willliams  26 , Rena Wing  23   27 , Nancy Woolard  1 , Maria C Carrillo  4
Affiliations
Randomized Controlled Trial

Structured vs Self-Guided Multidomain Lifestyle Interventions for Global Cognitive Function: The US POINTER Randomized Clinical Trial

Laura D Baker et al. JAMA. .

Abstract

Importance: Identifying new interventions to slow and prevent cognitive decline associated with dementia is critical. Nonpharmacological interventions targeting modifiable risk factors are promising, relatively low-cost, accessible, and safe approaches.

Objective: To compare the effects of two 2-year lifestyle interventions on cognitive trajectory in older adults at risk of cognitive decline and dementia.

Design, setting, and participants: Single-blind, multicenter randomized clinical trial enrolling 2111 participants from May 2019 to March 2023 (final follow-up, May 14, 2025) at 5 clinical sites in the US. Participant inclusion criteria enriched risk of cognitive decline and included age 60 to 79 years, sedentary lifestyle, and suboptimal diet plus at least 2 additional criteria related to family history of memory impairment, cardiometabolic risk, race and ethnicity, older age, and sex.

Interventions: Participants were randomly assigned with equal probability to structured (n = 1056) or self-guided (n = 1055) interventions. Both interventions encouraged increased physical and cognitive activity, healthy diet, social engagement, and cardiovascular health monitoring, but differed in structure, intensity, and accountability.

Main outcomes and measures: The primary comparison was difference between intervention groups in annual rate of change in global cognitive function, assessed by a composite measure of executive function, episodic memory, and processing speed, over 2 years.

Results: Among the 2111 individuals enrolled (mean age, 68.2 [SD, 5.2] years; 1455 [68.9%] female), 89% completed the year 2 assessment. The mean global cognitive composite z score increased from baseline over time in both groups, with a mean rate of increase per year of 0.243 SD (95% CI, 0.227-0.258) for the structured intervention and 0.213 SD (95% CI, 0.198-0.229) for the self-guided intervention. The mean rate of increase per year was statistically significantly greater for the structured group than the self-guided group by 0.029 SD (95% CI, 0.008-0.050; P = .008). Based on prespecified secondary subgroup comparisons, the structured intervention benefit was consistent for APOE ε4 carriers and noncarriers (P = .95 for interaction) but appeared greater for adults with lower vs higher baseline cognition (P = .02 for interaction). Fewer ascertained adverse events were reported in the structured group (serious: 151; nonserious: 1091) vs the self-guided group (serious: 190; nonserious: 1225), with a positive COVID-19 test result being the most common adverse event overall and more frequent in the structured group.

Conclusions and relevance: Among older adults at risk of cognitive decline and dementia, a structured, higher-intensity intervention had a statistically significant greater benefit on global cognition compared with an unstructured, self-guided intervention. Further investigation of functional outcomes, biomarkers, and ongoing extended follow-up will help address clinical relevance and sustainability of the observed cognitive benefits.

Trial registration: ClinicalTrials.gov Identifier: NCT03688126.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Espeland reported receipt of grants from the National Institutes of Health (NIH) and personal fees from Annovis Bio, Acumen Pharma, and Nestlé. Dr Whitmer reported receipt of grants from the NIH. Dr Leng reported receipt of grants from the Alzheimer’s Association (outside the submitted work) and the NIH. Dr Yu reported receipt of grants from Biogen, Eisai, AriBio, Suven, and Novo Nordisk and nonfinancial support from Cognition Therapeutics. Dr Kivipelto reported serving on scientific advisory boards for Combinostics, Eisai, Eli Lilly, and Nestlé. Ms Alexander reported that her organization, Kelsey Research Foundation, conducts commercially sponsored clinical trials across various medical specialties; collaborates with and serves as a subcontractor on research studies with academic medical centers and other nonprofit research groups; and receives philanthropic funding to support research and organizational operations as well as specific support within the areas of cancer prevention, diagnosis and treatment, and education. Dr Gitelman reported receipt of fees from AbbVie, Eisai, and Lilly for advisory board membership (paid to institution) and receipt of grants from Bristol Myers Squibb, Cassava, Eisai, and Lilly. Dr Raman reported receipt of grants from the National Institute on Aging, the Alzheimer’s Association, Eisai, and the American Heart Association (awarded to institution). Dr Salloway reported receipt of grants from the NIH. Dr Tangney reported receipt of royalties from UpToDate. Dr Snyder, Ms Antkowiak, Ms Day, Mr Elbein, Ms Lambert, Ms Matongo, Ms McDonald, and Dr Carrillo report being employees of the Alzheimer’s Association. No other disclosures were reported.

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