Shared Biological Pathways Between Alzheimer’s Disease and Ischemic Stroke

So have your doctor analyze this and come up with concrete protocols to prevent Alzheimers post stroke. 

Shared Biological Pathways Between Alzheimer’s Disease and Ischemic Stroke 

Pan Cui^1,2, Xiaofeng Ma^1,2, He Li^1,2, Wenjing Lang^1,2 and Junwei Hao^1,2*

• ¹Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
• ²Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System, Tianjin Neurological Institute, Ministry of Education and Tianjin City, Tianjin, China

Alzheimer’s disease (AD) and ischemic stroke (IS) are an immense socioeconomic burden worldwide. There is a possibility that shared genetic factors lead to their links at epidemiological and pathophysiological levels. Although recent genome-wide association studies (GWAS) have provided profound insights into the genetics of AD and IS, no shared genetic variants have been identified to date. This prompted us to initiate this study, which sought to identify shared pathways linking AD and IS. We took advantage of large-scale GWAS summary data of AD (17,008 AD cases and 37,154 controls) and IS (10,307 cases and 19,326 controls) to conduct pathway analyses using genetic pathways from multiple well-studied databases, including GO, KEGG, PANTHER, Reactome, and Wikipathways. Collectively, we discovered that AD and IS shared 179 GO categories (56 biological processes, 95 cellular components, and 28 molecular functions); and the following pathways: six KEGG pathways; two PANTHER pathways; four Reactome pathways; and one in Wikipathways pathway. The more fine-grained GO terms were mainly summarized into different functional categories: transcriptional and post-transcriptional regulation, synapse, endocytic membrane traffic through the endosomal system, signaling transduction, immune process, multi-organism process, protein catabolic metabolism, and cell adhesion. The shared pathways were roughly classified into three categories: immune system; cancer (NSCLC and glioma); and signal transduction pathways involving the cadherin signaling pathway, Wnt signaling pathway, G-protein signaling and downstream signaling mediated by phosphoinositides (PIPs). The majority of these common pathways linked to both AD and IS were supported by convincing evidence from the literature. In conclusion, our findings contribute to a better understanding of common biological mechanisms underlying AD and IS and serve as a guide to direct future research.

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. It is characterized pathologically by extracellular deposits of amyloid-β peptide (Aβ) and intracellular neurofibrillary tangles (NFTs) containing tau protein (Cuyvers and Sleegers, 2016). Ischemic stroke (IS) is a major health-threatening cerebrovascular disease with severe complications, such as post-stroke infection, physical disability, and cognitive deficits (Donnan et al., 2008). These two neurological diseases have immense socioeconomic impact worldwide (Norrving and Kissela, 2013; Alzheimer’sAssociation, 2016).

Mounting evidence suggests that there is a potential correspondence between AD and IS. Firstly, epidemiological studies have revealed that AD is a contributing factor to the development of IS (Chi et al., 2013; Tolppanen et al., 2013), and vice versa (Gamaldo et al., 2006). Secondly, AD and IS have common risk factors (e.g., hypertension, diabetes, obesity, and hyperlipidemia) (de Bruijn and Ikram, 2014; Boehme et al., 2017). Thirdly, recent evidence has indicated that brain ischemia can promote the development of AD by inducing β-/γ-secretase-mediated Aβ accumulation and tau protein gene alterations (Salminen et al., 2017; Pluta et al., 2018). Fourth, neuroinflammation elicited by the immune system is thought to play essential roles in the development and progression of both AD and IS (Liu Y.H. et al., 2013; Anrather and Iadecola, 2016). Lastly, research shows that abnormal tau protein also plays crucial roles in IS (Tuo et al., 2017). Together, these findings support the hypothesis that shared genetic risk factors link AD and IS at the epidemiological and pathophysiological levels.

Recent genome-wide association studies (GWASs) have provided profound insights into the complex genetic architecture of AD (Shen et al., 2015; Li et al., 2016; Liu et al., 2016; Zhang et al., 2016; Jun et al., 2017; Sims et al., 2017) and IS (Traylor et al., 2012; Williams et al., 2013; Kilarski et al., 2014; Malik et al., 2016; Network et al., 2016; Crawford et al., 2018). Most recently, 29 risk loci for AD (Jansen et al., 2018) and 28 loci associated with IS and its subtypes [i.e., large vessel disease (LVD), cardioembolic stroke (CE), and small vessel disease (SVD)] (Malik et al., 2018) have been identified. Despite these findings, no significant genetic variants shared by AD and IS or its subtypes were discovered. From the perspective of pathways, however, four gene ontology (GO) categories jointly associated with AD and SVD were identified (Traylor et al., 2016). Moreover, single-disease pathway analysis demonstrates that AD and IS share common pathways that involve natural killer (NK) cells, i.e., NK cell mediated cytotoxicity in AD (Lambert et al., 2010; Liu et al., 2014; Chen et al., 2016; Jiang et al., 2017) and NK cell signaling in IS (Malik et al., 2016). These findings imply that the link between AD and IS may have to do with shared genetic signals at the pathway level.

Complex diseases like AD and IS are mostly driven by the joint interactions of associated genes affected by large proportions of SNPs well below genome-wide significance, and the crosstalk of regulatory pathways (Furlong, 2013). Based on this concept, pathway-based analysis has been an effective strategy to investigate the potential mechanisms of complex disease (Luo et al., 2010; Jin et al., 2014), thus is widely used to unravel either single disease etiology or pleiotropism of clinically distinct diseases (Lesnick et al., 2007; Liu G. et al., 2012; Liu Y. et al., 2013; Liu et al., 2014; Bao et al., 2015; Xiang et al., 2015). Taken together, these considerations prompted us to perform pathway analyses using AD and IS GWAS data to further dissect their common molecular mechanisms.

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