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1 Alzheimer's Disease 1 Alzheimer’s disease (AD) genes: Enrichment in cancer genes and those related to comorbid conditions, risk factors (pollution and pathogens) or beneficial agents (NSAIDs and statins). Endogenous compounds related to AD genes target immune and antimicrobial defence. C.J.Carter 41C Marina, Saint Leonard’s on Sea, East Sussex, TN38 0BU, UK Email [email protected] Tel: 0044 (0)7854659602 Abstract Alzheimer’s disease (AD) GWASdb genes (N=1591) were analysed for enrichment versus other disease genes or the host genes of 18 host/pathogen interactomes (viral, bacterial, fungal and protozoan). AD gene/Chemical enrichment was analysed using the Comparative Toxicogenomics Database. AD incidence inversely associates with cancer and AD genes are enriched in cancer genes and in genes affected by carcinogenic or antineoplastic agents. Host/pathogen interactomes were enriched in AD genes, which were also targeted by mycotoxins. Many cancers are pathogen-related. AD genes may convey resistance to pathogens and the Cancer/AD inversion may pivot around this effect. AD genes were enriched in genes for type 2 diabetes, cardiovascular diseases, lipid metabolism disorders, arteriosclerosis, obesity, mood disorders and immune system or infectious diseases. Genes affected by NSAID’s and statins or antidiabetic drugs (PPAR ligands) and dietary polyphenols (all with antimicrobial activity) were also enriched in AD genes. Other drugs targeting AD genes affect sex steroids, retinoid and thyroid hormones and include immunosuppressants and anticonvulsants. AD genes were enriched in genes related to 28 endogenous compounds (retinoids, estrogens, progesterone, corticosterone, calcitriol, vitamins C and D3, folate, methionine and choline, an endogenous aryl hydrocarbon receptor ligand (ITE) and compounds related to oxidative stress. Most could be linked to immune regulation and many, like beta-amyloid, have antimicrobial properties (N-acetyl cysteine, Glutathione, Lithocholic acid, melatonin, Nitric oxide, iron/ascorbic acid, iron/O2 , H2O2, arachidonic and hypochlorous acids) These compounds selectively target immune and pathogen pathways. AD genes were also enriched in genes affected by AD risk factors (dietary fats/sucrose, pesticides, metals, vehicle emissions or smoking and other pollutants. The analysis highlights AD gene subsets related to AD comorbidities, risk factors or beneficial agents. Endogenous chemicals targeted by the AD genes are dedicated to the immune system and 2 specifically to antimicrobial defence. Antimicrobial drugs may aid these endogenous agents and could also be of benefit in AD. Key words: Alzheimer’s disease; gene/environment; pathogens; microbes; pesticides; pollution; heavy metals, anti-inflammatory agents; cancer; type 2 diabetes; cardiovascular disease; antimicrobial Introduction Alzheimer’s disease (AD) has been associated with multiple pathogens (Itzhaki et al. 2016) and bacteria including chlamydia pneumoniae (Gerard et al. 2006) , Treponema’s and spirochetes (Miklossy 2011) the oral pathogen Porphyromonas gingivalis (Dominy et al. 2019) and many other bacteria (Emery et al. 2017) have been detected in the AD brain. Diverse fungi (Pisa et al. 2017;Pisa et al. 2015) or viruses (herpes viruses HSV-1, HSV-6, HSV-7 ) (Readhead et al. 2018;Itzhaki 2017) and hepatitis (MastroeniB et al. 2018) have also been detected in post-mortem AD brains. Many of these pathogens promote beta-amyloid (Aβ) deposition as well as tau phosphorylation (Carter 2017). Aβ is a potent antimicrobial agent with broad-spectrum activity against bacteria, fungi and viruses (Soscia et al. 2010;Bourgade et al. 2016) and its deposition in AD is likely to be a response to cerebral pathogen invasion. Previous studies have shown that AD genes, as well as the proteins found in AD plaques and tangles are enriched in genes used by multiple bacterial, fungal and viral pathogens. They are also enriched in genes related to global pathogen diversity. Other AD risk factors (age, alcohol, aluminium, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption, smoking) promote blood-brain barrier disruption) while the BBB benefits from statins, non-steroidal anti-inflammatory agents (NSAIDs), estrogen, melatonin, memantine, and the Mediterranean diet, each of which have been reported to be of benefit or to reduce the incidence of AD. Many AD genes are localised in immune cells and tissues and converge on processes related to Aβ production. It has been suggested that the AD genes convey resistance to pathogens, as supported by the old age of AD patients, but the benefit they afford becomes detrimental if pathogens are allowed to reach the brain. Essentially, a combination of immunosenescence, which leads to diminished immune capacity and to heightened innate immune/inflammatory mechanisms (Martorana et al. 2012) and a hyperefficient antimicrobial effect of the AD genes promotes excessive Aβ production and associated collateral inflammatory damage (Carter 2017). Alzheimer’s disease has been associated with Type 2 diabetes mellitus (Shinohara and Sato 2017), periodontal disease (Pritchard et al. 2017;Carter et al. 2017) and with atherosclerosis of the carotid or circle of Willis and other cerebral arteries (Xiang 2017;Xu et al. 2015;Beach et al. 2007;Kalback et 3 al. 2004) and with other cardiovascular disorders and their associated conditions (Love and Miners 2016;Attems and Jellinger 2014). In contrast, the incidences of cancer and Alzheimer’s disease are inversely related (Shafi 2016;Snyder et al. 2017). Rheumatoid arthritis has also been inversely associated with Alzheimer’s disease incidence (Policicchio et al. 2017) . Several studies have shown that anti-rheumatic agents and non-steroidal anti-inflammatory drugs (NSAIDS) can delay the progression or reduce the incidence of Alzheimer’s disease (McGeer et al. 2018;McGeer et al. 2016;White et al. 2017;Heneka et al. 2015;Hoozemans et al. 2011). Two meta- analyses have supported these effects in observational studies but not in randomly controlled trials (Zhang et al. 2018a;Wang et al. 2015b) There is some evidence that statins (HMG Co a reductase inhibitors and cholesterol lowering agents) may reduce the incidence or slow the progression of Alzheimer’s disease (Haag et al. 2009;Williams 2015;Wong et al. 2013), although large meta-analyses have cast some doubt on their effectiveness and their benefit may be slight (McGuinness et al. 2016;Mejias-Trueba et al. 2018). These effects may be gene-dependent and simvastatin was more effective in APOE4 carriers (Geifman et al. 2017). A number of studies have linked metals to AD. Arsenic levels in topsoil have been related to the prevalence and mortality of Alzheimer's disease and other dementias in Europe (Dani 2010). A recent meta-analysis has reported that blood levels of aluminium, mercury, and cadmium are significantly higher while levels of lead were reduced in AD patients (Xu et al. 2018b). High levels of cerebral iron, particularly in myelin areas and disrupted iron homoeostasis have also been reported in AD (Liu et al. 2018;Bulk et al. 2018). Air pollution has also been linked to a higher risk of dementia (Carey et al. 2018) A meta-analysis has also supported an association of pesticides with the incidence of Alzheimer’s disease (Yan et al. 2016). In this study, the relationship between AD genes and these various comorbid conditions, pathogens or environmental risk factors was examined using AD susceptibility genes and three extensive databases. The genome-wide association database (GWASdb) contains over ten thousand significant trait/disease associated SNP’s from 435 diseases as classified by disease ontology (P-values < 1.0 × 10-3 ) (Li et al. 2012) http://jjwanglab.org/ gwasdb . The comparative toxicogenomics database currently contains over 40 million chemical/gene interactions (Davis et al. 2017) (CTD; http://ctdbase.org/ ). The manually curated host/pathogen interactomes (HPI) for 18 diverse bacterial (Chlamydia pneumoniae (C.Pneumoniae), Helicobacter pylori (H.Pylori), Borrelia burgdorferi, (Borrelia), Porphyromonas gingivalis (P.Ging), viral (Bornavirus , Dengue virus; Ebola 4 virus, herpes simplex (HSV-1); Human cytomegalovirus (HCMV) ,Epstein barr (EBV), influenza A (INF), hepatitis C (HepC) viruses , HERV-W and human immunodeficiency (HIV-1) retro viruses, fungi (Cryptococcus Neoformans (C.neo), Candida albicans (C.Alb), and others (Toxoplasma Gondii (T.Gondii) and Trypanosoma Cruzi (T.cruzi) are available at http://www.polygenicpathways.co.uk/hpi.htm. GWASdb contains 1591 AD genes and these were cross-referenced with genes associated with other diseases (GWASdb), chemicals and drugs (CTD) and host/pathogen interactomes (HPI). Any over-representation of other disease genes, chemicals of pathogen interactomes with the AD gene dataset was subjected to statistical analysis. Methods The GWASdb database contains curated data for multiple diseases, with a P value cut-off of P < 1.0 x 10-3 (Li et al. 2012) and this was downloaded for analysis. GWASdb contains 1591 Alzheimer’s disease (AD) genes, and AD gene overlaps with other disease gene sets were identified. GWASdb can be downloaded from http://jjwanglab.org/gwasdb or from the Harmonizome database http://amp.pharm.mssm.edu/Harmonizome/ (Rouillard et al. 2016) . This list of 1591 Alzheimer’s disease genes was uploaded to the comparative toxicogenomics database (Davis et al. 2017) (CTD; http://ctdbase.org/
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