POINTER Imaging Study Links Brain Biomarkers, Cognitive Benefit

Key Takeaways

• No overall intervention-group differences were observed in longitudinal cognitive or imaging outcomes.
• Aβ status and Aβ accumulation were not associated with intervention-group differences and did not moderate them.
• In the structured group, the tau-cognition association was attenuated, and lower baseline hippocampal volume was linked with greater cognitive benefit vs the self-guided group.

Among 983 participants who underwent at least 1 MRI or PET scanning session, the POINTER Imaging ancillary study found no overall longitudinal differences in prespecified imaging biomarkers or global cognition between structured and self-guided multidomain programs. Across the 2-year trial, the groups remained similar on prespecified brain measures and the global cognitive composite. Some imaging-defined characteristics were associated with larger between-group cognitive differences, even as group-level findings stayed neutral overall.

POINTER Imaging was an ancillary study of the 2-year, single-blind, multicenter US POINTER randomized clinical trial. Neuroimaging data were collected from eligible enrolled participants at five clinical sites in the United States during the parent trial. Eligible adults were 60 to 79 years old, had a sedentary lifestyle and suboptimal diet, met at least 2 additional cognitive risk criteria, and had no contraindications to neuroimaging. Both programs emphasized physical and cognitive activity, healthy nutrition, social engagement, and cardiovascular health monitoring, but differed in intensity and accountability. Of 1943 parent-trial participants assessed for eligibility, 983 underwent scanning, including 516 in the structured group and 467 in the self-guided group; the imaged subset had a mean age of 68.4 years, and 61.5% were female.

The prespecified primary imaging outcomes were global β-amyloid burden, entorhinal cortex tau burden, hippocampal volume, and white matter hyperintensity volume, and the primary cognitive measure was the global cognitive composite. Investigators found no between-group differences over time for cognition or any primary imaging endpoint, and Aβ status or accumulation were not associated with those differences and did not moderate them. The structured program was likewise not associated with overall biomarker trajectories across the measured imaging domains.

Greater entorhinal cortex tau increase was associated with worse cognitive change in the self-guided group, but that relationship was weaker in the structured group. The difference in association was 0.289, with a 95% CI of 0.029 to 0.550 and an interaction P value of .03. Lower baseline hippocampal volume was also associated with greater cognitive benefit for participants in the structured group vs the self-guided group, measuring 0.077 SD compared with 0.002 SD at higher volume. The respective 95% CIs were 0.022 to 0.132 and -0.037 to 0.041, with interaction P = .03.

Enrollment occurred from May 2019 to March 2023, and final follow-up was reported on May 14, 2025. The findings apply to older adults at risk for cognitive decline who were eligible for neuroimaging. In that population, the structured intervention was not associated with overall brain biomarker trajectories or with Aβ pathology. At the same time, the report in JAMA Neurology linked lower baseline hippocampal volume and other at-risk imaging features with greater cognitive benefit for the structured group vs the self-guided group.