<i>APOE</i> genotypes modify the obesity paradox in dementia.

Abstract

While 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 (<i>APOE</i>) genotype and obesity in dementia. Clinical 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, <i>APOE</i> genotype and obesity states, were reviewed. Obesity was associated with cognitive decline in early elderly cognitively normal individuals without <i>APOE4</i>, especially those with <i>APOE2</i>. Neuropathological analyses adjusted for dementia status showed that <i>APOE2</i> carriers 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 in <i>APOE4</i> carriers. Obesity was associated with fewer Alzheimer's pathologies in individuals with dementia. Obesity may accelerate cognitive decline in middle to early elderly cognitive normal individuals without <i>APOE4</i> likely 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 with <i>APOE4</i>, through protecting against Alzheimer's pathologies. These results support that <i>APOE</i> genotype modifies the obesity paradox in dementia.