Midlife adiposity predicts earlier onset of Alzheimer's dementia, neuropathology and presymptomatic cerebral amyloid accumulation.

Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD.

Common genetic variation in the gene encoding interleukin-1-receptor antagonist (IL-1RA) is associated with altered circulating IL-1RA levels.

Interleukin-1-receptor antagonist (IL-1RA) modulates the biological activity of the proinflammatory cytokine interleukin-1 (IL-1) and could play an important role in the pathophysiology of inflammatory and metabolic traits. We genotyped seven single nucleotide polymorphisms (SNPs) that capture a large proportion of common genetic variation in the IL-1RN gene in 1256 participants from the Invecchiare in Chianti study. We identified five SNPs associated with circulating IL-1RA levels with varying degrees of significance (P-value range=0.016-4.9 x 10(-5)). We showed that this association is likely to be driven by one haplotype, most strongly tagged by rs4251961. This variant is only in weak linkage disequilibrium (r(2)=0.25) with a previously reported variable number of tandem repeats polymorphism (VNTR) in intron-2 although a second variant, rs579543, that tags the VNTR (r(2)=0.91), may also be independently associated with IL-1RA levels (P=0.03). We found suggestive evidence that the C allele at rs4251961 that lowers IL-1RA levels is associated with an increased IL-1beta (P=0.03) level and may also be associated with interferon -gamma (P=0.03), alpha-2 macroglobulin (P=0.008) and adiponectin (P=0.007) serum levels. In conclusion, common variation across the IL-1RN gene is strongly associated with IL-1RA levels.