How is the brain affected by metabolically healthy or unhealthy obesity in adulthood and elderly? A narrative review of neuroimaging and neurocognitive findings

The global aging of the population, coupled with an increasing prevalence of sedentary lifestyle and overnutrition, is fueling an alarming rise in the worldwide obesity rates. Besides its well-known bodily consequences, obesity is increasingly recognized as a risk factor for cognitive impairment, dementia, mood disorders, and emotional distress, suggesting a possible role of adiposity in the pathogenesis of both neurodegeneration and neuropsychiatric diseases. Despite the growing research interest, the pathophysiological mechanisms linking obesity to brain health remain poorly understood. Specifically, it is unclear whether the neuroanatomical, neurofunctional, and neurocognitive correlates of late-life obesity are directly imputable to either the excessive body fat accumulation or physiological age-related neurodegeneration, or if they are mediated by possible cardio-metabolic comorbidities which are common chronic conditions among the elderly. This narrative review synthesizes evidence on neuroimaging (MRI) and neurocognitive findings across adulthood and late life, with a focus on the metabolically healthy obese individuals, a sub-group of the obese population maintaining a favorable cardio-metabolic health profile. Direct studies on metabolically healthy obesity often report inconclusive evidence for the effect of obesity on neuroanatomical impairments or cognitive functions, and when the effects are present, they are much less pronounced compared to those observed in metabolically unhealthy individuals. Yet, many indirect studies reporting the effects of obesity after controlling for cardio-metabolic conditions suggest that obesity <i>per se</i> is associated with brain atrophy, reduced white matter integrity, and alterations in rewards-homeostatic-control networks. In conclusion, current evidence indicates that metabolically healthy obesity might not be entirely benign for brain health. More longitudinal multimodal imaging studies, with better characterization of both obesity and metabolic phenotypes, are therefore warranted to clarify trajectories and causal pathways.