A structured multidomain lifestyle intervention may help preserve white matter integrity in older adults at risk for cognitive decline, particularly when initiated before age 70.
In a secondary analysis of the US POINTER randomized clinical trial of over 900 adults, a multidomain lifestyle intervention that combined supervised aerobic, resistance, and flexibility exercise; individualized MIND diet counseling; cognitive training; social engagement; and behavioral coaching slowed increases in free water (FW) — a diffusion MRI-derived marker of early white matter changes — in participants aged 60 to younger than 70 years but not in those aged 70 years or older.
Higher baseline FW was associated with faster white matter hyperintensity (WMH) progression and the development of new cerebral microbleeds (CMBs) over time.
“Multidomain lifestyle interventions may have a greater effect on white matter health when initiated earlier in older adulthood, before vascular and structural brain changes become more advanced,” lead investigator Pauline Maillard, PhD, Department of Neurology, UC Davis, told Medscape Medical News.
“However, the age interaction was a secondary finding, and it should not be interpreted as evidence that individuals aged 70 years or older cannot benefit from lifestyle modification.”
The findings were presented on July 13 at the Alzheimer’s Association International Conference (AAIC) 2026 and simultaneously published online in JAMA Network Open.
Early Brain Aging
Multidomain lifestyle interventions that combine physical activity, dietary modification, cognitive training, and management of vascular risk factors have been associated with reduced dementia risk and slower cognitive decline in older adults at risk.
However, their effects on underlying cerebrovascular changes remain unclear. Cerebral small vessel disease contributes to cognitive decline, and diffusion MRI measures such as FW may help identify early white matter changes better than conventional MRI markers, including WMHs and CMBs.
Previously, the US POINTER, a randomized clinical trial conducted across five US sites, found that a structured multidomain lifestyle intervention led to greater improvements in global cognition than a self-guided program.
For the current analysis, the POINTER Imaging study, a prespecified secondary analysis of the US POINTER trial, investigators assessed whether improvements in cognition were accompanied by changes in MRI markers of cerebrovascular injury and whether these effects varied by age.
The cohort included 959 cognitively unimpaired adults (mean age, 68 years; 61.9% women) who were at increased risk for cognitive decline. Overall, 533 participants were younger than 70 years and 426 were aged 70 years or older. Of the participants, 64.5% had hypertension at baseline.
A total of 503 participants were randomly assigned to the structured intervention and 456 to the self-guided program for 2 years. The self-guided group received educational materials covering the same lifestyle domains but without individualized coaching or goal-directed support.
MRI was performed at baseline and repeated at 12 and 24 months. The investigators assessed several imaging markers of cerebrovascular health, including FW, fractional anisotropy, peak width of skeletonized mean diffusivity (PSMD), analysis along the perivascular space (ALPS) index, WMH volume, and incident CMBs.
Analyses comparing participants younger than 70 years with those aged 70 years or older were prespecified.
Impact on White Matter
The investigators observed a significant three-way interaction among time, intervention group, and age for FW (beta-coefficient, 0.050; P = .006).
Among participants younger than 70 years, those assigned to the structured intervention had a significantly smaller increase in FW over 2 years than those assigned to the self-guided program (beta-coefficient, -0.031; P = .009). No significant between-group difference was observed among participants aged 70 years or older (beta-coefficient, 0.019; P = .18).
The intervention was not associated with significant changes in other MRI measures, including WMH progression, fractional anisotropy, PSMD, the ALPS index, or incident CMBs.
In secondary analyses, the investigators also evaluated whether baseline diffusion MRI markers were associated with later cerebrovascular injury.
Higher baseline FW was associated with a higher likelihood of developing incident CMBs (odds ratio [OR], 1.63; 95% CI, 1.24-2.14; P < .001) and with faster WMH progression over follow-up (beta-coefficient, 0.014; P = .02).
Higher baseline PSMD was also associated with incident CMBs (OR, 1.40; 95% CI, 1.08-1.81; P = .01), whereas lower baseline fractional anisotropy was associated with greater WMH progression (beta-coefficient, -0.018; P = .004).
Beyond Conventional MRI
FW may have been the most sensitive marker for detecting intervention-related changes, said Maillard, because it reflects earlier and potentially reversible biological alterations that occur before more established structural damage develops.
“Free water may capture relatively early and potentially dynamic changes in the extracellular tissue environment, including processes related to vascular dysfunction, inflammation, or blood-brain barrier alterations,” she said.
By contrast, Maillard highlighted that more established MRI markers such as WMHs and CMBs may require longer follow-up before intervention-related changes become apparent.
The link between baseline FW and WMH progression and incident CMBs suggests that elevated FW may identify white matter that is vulnerable to future cerebrovascular injury, Maillard noted.
“These findings support its potential as an early imaging marker of risk, although additional studies are needed to establish its prognostic value, reproducibility, and usefulness at the individual-patient level.”
Maillard cautioned that longer follow-up is needed to determine whether these MRI changes ultimately translate into durable cognitive benefit and to clarify which intervention components and patients are most likely to benefit.
Early Lifestyle Change
The findings add to growing evidence that lifestyle interventions may be most effective when implemented earlier in the course of brain aging, said Zaldy S. Tan, MD, MPH, Carmen and Louis Warschaw Endowed Chair in Neurology, director of the Maxine & Bernard Platzer Lynn Family Memory & Healthy Aging Program, and medical director of the Jona Goldrich Center for Alzheimer’s and Memory Disorders at Cedars-Sinai Medical Center in Los Angeles, who was not involved in the study.
“The age range of participants in this study was 60-79 years, so starting interventions in one’s early sixties — if not earlier — will likely be more beneficial than starting them later in life,” Tan told Medscape Medical News.
FW is an emerging marker of early white matter injury that may be detectable before other changes, such as WMHs and CMBs, become apparent on MRI, Tan noted.
“An increasing white matter free water may indicate several underlying processes, including disruption of the blood-brain barrier and impairment of clearance mechanisms,” he said.
“The attenuation of white matter free water increase over time in the structured multidomain lifestyle intervention group may indicate a lessening of the age-related changes that lead to more permanent signs of white matter injury,” Tan added.
The findings reinforce recommendations for early multidomain lifestyle intervention in older adults at increased risk for cognitive decline, Tan said.
“The earlier people start these interventions, the greater the likelihood of benefit as processes that lead to white matter damage may still be reversible in their early stages.”
Disclosure information for study authors is available in the original study publication. Tan reported no relevant financial disclosures. The study was supported by the Alzheimer’s Association, the National Institute on Aging, and additional public and private partners supporting the US POINTER trial.
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