2026 ECNP Congress

PS02-2216

Cross-sectional and longitudinal effects of visceral adipose tissue on brain aging and cognition - a sex differences perspective

Charlotte Koch — L. Ruehr, D.E.A. Jensen, L. Lammer, S. Riedel-Heller, R. Baber, S. Zeynalova, A. Villringer, J. Sacher, F. Beyer, A.V. Witte · Max Planck Institute of Human Cognitive and Brain Sciences, Neurology, Leipzig, Germany

2026 ECNP Congress

Cohort evidence suggests sex-specific trajectories in human brain aging [1, 2, 3]. In parallel, visceral adipose tissue (VAT) —an endocrine and immune-active fat depot linked to vascular and metabolic dysfunction— shows marked sex differences, with accelerated accumulation in females from perimenopause onwards [4, 5]. VAT has been associated with adverse brain outcomes [5], yet whether its impact on brain aging differs by sex and genetic susceptibility (particularly apolipoprotein E ε4 (APOE ε4)), remains poorly understood.

This preregistered study examined cross-sectional and longitudinal associations between VAT and multimodal markers of brain aging, as well as their modification by sex and APOE ε4 status.

We analyzed baseline and follow-up data from the population-based LIFE-Adult study (Leipzig, Germany; healthy participants aged 18-82 years; equal sex distribution; N baseline ~ 2600 with magnetic resonance imaging (MRI). Brain aging outcomes comprised MRI-based markers of grey and white matter integrity (hippocampal volume (mm3), Alzheimer-signature cortical thickness (mm), white matter hyperintensities (WMH) (asinh(mm3)), perivascular space burden (asinh(mm3)), and free water (FW) in WM microstructure), and global cognitive function (GCF; z-scored) derived from two cognitive test batteries. VAT was measured via abdominal MRI at baseline, and height-adjusted (mm3/cm2). Linear (mixed-effects) models tested VAT, VAT × sex, and VAT × sex × APOE ε4 associations with brain aging outcomes, adjusted for age. Sex-stratified analyses were conducted to improve interpretability (not corrected for multiple comparisons).

Preliminary analyses (n ~ 750-1,100 at baseline, 300-600 at follow-up; mean age ~ 60 years) indicated that higher baseline VAT predicted accelerated hippocampal volume decline (β = −214.02, 95% CI [−261.38, −166.66], pglobal < 0.001), greater WMH progression (β = 0.226, 95% CI [0.082, 0.370], pglobal = 0.039), FW progression (β = 0.019, 95% CI [0.012, 0.025], pglobal < 0.001), and steeper global cognitive decline (β = −0.400, 95% CI [−0.553, −0.247], pglobal < 0.001). No significant VAT × sex interactions were observed. In exploratory sex-stratified analyses, higher VAT was associated with longitudinal WMH progression and cross-sectional cortical thinning in males, and with cross-sectional WMH burden and GCF reductions in females. APOE ε4 moderation did not survive correction for multiple comparisons in any relationships.

In this well-characterized cohort, higher VAT was associated with accelerated brain aging across multiple structural domains as well as cognition, with associations most evident longitudinally. We detected no significant sex differences in the relationship of VAT and brain aging, though exploratory sex-stratified analyses hinted at domain-specific patterns. The absence of significant interactions may reflect limited power to detect small interaction effects, the use of baseline-only VAT (which cannot capture non-linear lifespan accumulation), or true similarity across sexes. Future studies with repeated adiposity measures and menopausal staging should test for sex-specific susceptibility windows. Collectively, our findings highlight VAT as a relevant modifiable risk factor for brain aging.

References

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  2. Lohner V, Pehlivan G, Sanroma G, Miloschewski A, Schirmer MD, Stöcker T, et al. Relation between sex, menopause, and white matter hyperintensities: the Rhineland Study. Neurology. 2022;99(9):e935-43.
  3. Levine DA, Gross AL, Briceño EM, Tilton N, Giordani BJ, Sussman JB, et al. Sex differences in cognitive decline among US adults. JAMA Netw Open. 2021;4(2):e210169.
  4. Lovejoy JC, Champagne CM, de Jonge L, Xie H, Smith SR. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes (Lond). 2008;32(6):949-58.
  5. Zsido RG, Heinrich M, Slavich GM, Beyer F, Kharabian Masouleh S, Kratzsch J, et al. Association of estradiol and visceral fat with structural brain networks and memory performance in adults. JAMA Netw Open. 2019;2(6):e196126.