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Interactions between inflammation, sex steroids, and Alzheimer's disease risk factors.

ABSTRACT: Alzheimer's disease (AD) is an age-related neurodegenerative disorder for which there are no effective strategies to prevent or slow its progression. Because AD is multifactorial, recent research has focused on understanding interactions among the numerous risk factors and mechanisms underlying the disease. One mechanism through which several risk factors may be acting is inflammation. AD is characterized by chronic inflammation that is observed before clinical onset of dementia. Several genetic and environmental risk factors for AD increase inflammation, including apolipoprotein E4, obesity, and air pollution. Additionally, sex steroid hormones appear to contribute to AD risk, with age-related losses of estrogens in women and androgens in men associated with increased risk. Importantly, sex steroid hormones have anti-inflammatory actions and can interact with several other AD risk factors. This review examines the individual and interactive roles of inflammation and sex steroid hormones in AD, as well as their relationships with the AD risk factors apolipoprotein E4, obesity, and air pollution.

SUBMITTER: Uchoa MF

PROVIDER: S-EPMC5123957 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

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Interactions between inflammation, sex steroids, and Alzheimer's disease risk factors.

Uchoa Mariana F MF Moser V Alexandra VA Pike Christian J CJ

Frontiers in neuroendocrinology 20160917

Alzheimer's disease (AD) is an age-related neurodegenerative disorder for which there are no effective strategies to prevent or slow its progression. Because AD is multifactorial, recent research has focused on understanding interactions among the numerous risk factors and mechanisms underlying the disease. One mechanism through which several risk factors may be acting is inflammation. AD is characterized by chronic inflammation that is observed before clinical onset of dementia. Several genetic ...[more]

PMID: 27651175

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Project description:Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

Dataset Information

Interactions between inflammation, sex steroids, and Alzheimer's disease risk factors.

Publications

Interactions between inflammation, sex steroids, and Alzheimer's disease risk factors.

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