High‐fat diet is associated with accelerated gray matter atrophy in cognitively unimpaired older adults but slower atrophy in individuals with existing mild cognitive impairment

INTRODUCTION: Prior studies showed inconsistent links between dietary fat and Alzheimer's disease (AD) risk. We examined whether dietary fat affected brain atrophy markers differentially based on risk factors like female sex, apolipoprotein ε4 (APOE ε4) status, and cognitive status. METHODS: Participants from the Vanderbilt Memory and Aging Project, classified as cognitively unimpaired (CU) or with mild cognitive impairment (MCI), were included (n = 758). Linear mixed-effects regression models examined associations between total fat intake (Tfat, times/day) and percentage of energy from fat (Pfat, %) and longitudinal gray matter volumes, as well as interactions. RESULTS: Over 4.6 ± 3.1 years, Pfat interacted with cognitive status on longitudinal temporal lobe (p = 0.009) and inferior lateral ventricle volume (p = 0.002). Higher Pfat was associated with faster reduction in temporal lobe volume in CU participants (β = 47.2, p = 0.007) but slower enlargement of the inferior lateral ventricle among participants with MCI (β = -22.5, p = 0.006). DISCUSSION: Different mechanisms may underlie the fat-neurodegeneration relationship across cognitive statuses.