APOEgenotypes modify the obesity paradox in dementia

Abstract

BackgroundWhile obesity in midlife is a risk factor for dementia, several studies suggested that obesity also protected against dementia, hence so-called obesity paradox. The current study aims to address the relationship between apolipoprotein E (APOE) genotype and obesity in dementia.MethodsClinical and neuropathological records of the National Alzheimer’s Coordinating Center (NACC) in the USA, which longitudinally followed approximately 20 000 subjects with different cognitive statues,APOEgenotype and obesity states, were reviewed.ResultsObesity was associated with cognitive decline in early elderly cognitively normal individuals withoutAPOE4, especially those withAPOE2. Neuropathological analyses adjusted for dementia status showed thatAPOE2carriers tended to have more microinfarcts and haemorrhages due to obesity. On the other hand, obesity was associated with a lower frequency of dementia and less cognitive impairment in individuals with mild cognitive impairment or dementia. Such trends were particularly strong inAPOE4carriers. Obesity was associated with fewer Alzheimer’s pathologies in individuals with dementia.ConclusionsObesity may accelerate cognitive decline in middle to early elderly cognitive normal individuals withoutAPOE4likely by provoking vascular impairments. On the other hand, obesity may ease cognitive impairment in both individuals with dementia and individuals at the predementia stage, especially those withAPOE4, through protecting against Alzheimer’s pathologies. These results support thatAPOEgenotype modifies the obesity paradox in dementia.