Sustained visceral fat loss is associated with attenuated brain atrophy and improved cognitive function in late midlife

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 Sustained visceral fat loss is associated with attenuated brain atrophy and improved cognitive function in late midlife

Cite this article as: Pachter, D., Klein, H., Kamer, O. et al. Sustained visceral fat loss is associated with attenuated brain atrophy and improved cognitive function in late midlife. Nat Commun (2026). https://doi.org/ 10.1038/s41467-026-71141-4

Dafna Pachter, Hadar Klein, Omer Kamer, Dana Tamar Goldberg Toren, Liav Alufer, Noa Ebstein Karamani, Tomer Atlas, Amit Yaary, Idan Hagbi, Yoash Chassidim, Ilan Shelef, Moti Salti, Frauke Beyer, Veronica Witte, Assaf Rudich, Uri Yoel, Gal Ben-Arie, Anat Yaskolka Meir, Alon Kaplan, Gal Tsaban, Hila Zelicha, Carmi Bartal, Lu Qi, Matthias Blüher, Michael Stumvoll, Uta Ceglarek, Berend Isermann, Dong D. Wang, Meir J. Stampfer, Frank B. Hu, Galia Avidan & Iris Shai 

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Abstract 

 We examined whether long-term exposure to visceral-adipose-tissue (VAT) influences brain atrophy and cognitive performance years after lifestyle intervention. In the Follow-Interventions-Trial (FIT) project, 533 adults (age=61.4y, 86% men) from four prior 18-24-month lifestyle randomized-clinical-trials underwent abdominal/brain magnetic-resonance-imaging (MRI)s and Montreal-Cognitive-Assessment (MoCA) testing 5-16y after interventions. Lower VAT exposure, calculated by area-under-the-curve, from baseline, post-intervention, and follow-up, independently resulted in higher MoCA scores. VAT loss during intervention predicted higher brain volumes at follow-up, independent of weight loss. Among participants with three brain and VAT MRI scans, lower long-term VAT was associated with a slower rate of brain atrophy. These patterns were not observed for deep/superficial subcutaneous adipose-tissues. Improved glycemic control parameters, rather than lipid or inflammatory markers, were mostly related to the favorable longitudinal brain outcomes. This long-term, large-scale intervention and follow-up MRI study suggests that sustained visceral fat loss, rather than weight loss, is linked to better cognition and attenuation of brain atrophy years later, mainly via improved glycemic control. Trial registration: DIRECT (Clinical-trials-identifier: NCT00160108); CASCADE (Clinical-trials identifier: NCT00784433); CENTRAL (Clinical-trials-identifier: NCT01530724); DIRECT-PLUS (Clinical-trials-identifier: NCT03020186). 

Introduction 

 Visceral adipose tissue (VAT) has emerged as a critical factor in brain aging. Large studies and systematic reviews consistently find strong associations between VAT and adverse brain outcomes.1-7 Specifically, higher VAT levels predict greater brain atrophy, including lower hippocampal,2,8 gray matter,2,3 and white matter volumes,2 larger ventricular volume,8 and cognitive decline.1,4,6-8 Despite robust observational evidence, there is a limited understanding of whether long-term exposure to lower visceral adiposity, independent of weight loss, can attenuate brain atrophy and protect cognitive function over time. The Magnetic Resonance Imaging (MRI) Follow-up Intervention Trials (FIT) project addresses this gap by leveraging multiple abdominal adipose depot measurements obtained via MRI in two completed randomized controlled trials (RCTs): CENTRAL9 and DIRECT-PLUS.10-12 In addition, we conducted cross-sectional analyses of VAT, brain atrophy, and cognitive function using follow-up data from all four RCTs (DIRECT,13 CASCADE,14,15 CENTRAL,9 and DIRECT-PLUS10-12). By combining repeated VAT measurements, brain MRI, and cognitive testing, we investigated how visceral adiposity influences brain atrophy and cognitive performance, and whether reductions in VAT preserved brain structure and function years after intervention. 

 Results 

 Participant Retention and Follow-Up Of the 881 eligible RCT participants from the DIRECT, CASCADE, CENTRAL, and DIRECT-PLUS trials, 647 participants (73.4%) were successfully identified for the FIT project (The study timeline and data acquisition are illustrated in Figure 1. Figure 1A created with BioRender.com. The study flow diagram is provided in Figure 1B). Of these, 599 (92.6% of 647) completed assessments, and 48 were deceased cases. Among the 599 participants with 5-16 years of follow-up data, brain MRI structural ARTICLE IN PRESS analyses were performed for 533 (89% of 599) participants (Table 1).

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