Disentangling the biological pathways involved in early features of Alzheimer's disease in the Rotterdam Study

Ahmad, Shahzad; Bannister, Christian; Lee, Sven J. van der; Vojinović, Dina; Adams, Hieab H.H.; Ramı́rez, Alfredo; Escott‐Price, Valentina; Sims, Rebecca; Baker, Emily; Williams, Julie; Holmans, Peter; Vernooij, Meike W.; Ikram, M. Arfan; Amin, Najaf; Duijn, Cornelia M. van

doi:10.1016/j.jalz.2018.01.005

Cited by 40 publications

(49 citation statements)

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“…Ephrin type‐A receptor 1 (EPHA1) belongs to the eph receptor subfamily that is the largest family of receptor tyrosine kinases, mediating axonal guidance, synaptic plasticity, and cell‐to‐cell communication in the central nervous system (CNS) . Moreover, EPHA1 can modulate leukocyte extravasation, chemotaxis, and inflammatory cell migration . Indeed, ample evidence has implicated the involvement of EPHA 1, as well as MS4A4A and TREM2 listed below, in the immune module of AD .…”

Section: Discussionmentioning

confidence: 99%

“…30,31 Moreover, EPHA1 can modulate leukocyte extravasation, chemotaxis, and inflammatory cell migration. [32][33][34] Indeed, ample evidence has implicated the involvement of EPHA1, as well as MS4A4A and TREM2 listed below, in the immune module of AD. 22,35,36 As previously described, 37 we observed no aberrant EPHA1 expression in the PFC region of AD patients, neither in the hippocampus.…”

Section: Zyx and Epha1 Gene At 7q34-7q35mentioning

confidence: 99%

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Shared genes between Alzheimer’s disease and ischemic stroke

Wei

Cui

et al. 2019

CNS Neurosci Ther

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Summary Aims Although converging evidence from experimental and epidemiological studies indicates Alzheimer's disease (AD) and ischemic stroke (IS) are related, the genetic basis underlying their links is less well characterized. Traditional SNP‐based genome‐wide association studies (GWAS) have failed to uncover shared susceptibility variants of AD and IS. Therefore, this study was designed to investigate whether pleiotropic genes existed between AD and IS to account for their phenotypic association, although this was not reported in previous studies. Methods Taking advantage of large‐scale GWAS summary statistics of AD (17,008 AD cases and 37,154 controls) and IS (10,307 IS cases and 19,326 controls), we performed gene‐based analysis implemented in VEGAS2 and Fisher's meta‐analysis of the set of overlapped genes of nominal significance in both diseases. Subsequently, gene expression analysis in AD‐ or IS‐associated expression datasets was conducted to explore the transcriptional alterations of pleiotropic genes identified. Results 16 AD‐IS pleiotropic genes surpassed the cutoff for Bonferroni‐corrected significance. Notably, MS4A4A and TREM2 , two established AD‐susceptibility genes showed remarkable alterations in the spleens and brains afflicted by IS, respectively. Among the prioritized genes identified by virtue of literature‐based knowledge, most are immune‐relevant genes ( EPHA1 , MS4A4A , UBE2L3 and TREM2 ), implicating crucial roles of the immune system in the pathogenesis of AD and IS. Conclusions The observation that AD and IS had shared disease‐associated genes offered mechanistic insights into their common pathogenesis, predominantly involving the immune system. More importantly, our findings have important implications for future research directions, which are encouraged to verify the involvement of these candidates in AD and IS and interpret the exact molecular mechanisms of action.

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Section: Discussionmentioning

confidence: 99%

Section: Zyx and Epha1 Gene At 7q34-7q35mentioning

confidence: 99%

Shared genes between Alzheimer’s disease and ischemic stroke

Wei

Cui

et al. 2019

CNS Neurosci Ther

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“…Previous studies showed that polygenic risk score of AD not only associated with increased risk of AD, but also with neuropathological hallmarks of AD, lifetime risk and the age at onset in both APOE ε4 carriers and non-carriers. [28,29,[48][49][50][51][52] We now add that the PRS for AD also associates with escaping AD at extremely old ages. This adds further importance to the potentiality of using PRS and APOE genotype in a clinical setting.…”

Section: Discussionmentioning

confidence: 99%

“…However, the degree to which pathways functionality may contribute to the individual risk can be studied with pathway-specific polygenic risk scores (PRS). [28,29] In a typical polygenic risk score, the effect-sizes of all genetic variants that significantly associate with a trait are combined. [30] In a pathway-specific PRS, however, additional information is necessary, namely: (i) the association of genetic variants to genes, and (ii) the association of genes to pathways.…”

Section: Introductionmentioning

confidence: 99%

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Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s Disease

Tesi

Lee

Hulsman

et al. 2019

Preprint

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Developing Alzheimer's disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (I) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N=1,895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N=1,654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N=293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p<0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p<0.05), while specifically immune response (p=0.003) and endocytosis (p=0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.

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Immunity and amyloid beta, total tau and neurofilament light chain: Findings from a community‐based cohort study

Fani

Ahmad

Ikram

et al. 2020

Alzheimer's & Dementia

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Introduction We investigated how components of immunity relate to biomarkers of Alzheimer's disease (AD) in plasma and explored the influence of AD genetic risk factors in the population‐based Rotterdam Study. Methods In 7397 persons, we calculated the granulocyte‐to‐lymphocyte ratio (GLR), platelet‐to‐lymphocyte ratio (PLR), and systemic immune‐inflammation index (SII). In 3615 of these persons, plasma amyloid‐beta (Aβ)42 and Aβ40 were measured. Next, we constructed an overall genetic risk score (GRS) based on genome‐wide significant variants, both including and excluding APOE ε4. Results All innate immunity phenotypes were related to higher Aβ, most strongly with a doubling in GLR leading to a 1.9% higher Aβ42 (95% confidence interval [95% CI] 0.4 to 3.3%) and 3.2% higher Aβ40 (95% CI 2.0 to 4.3%). Higher AD GRS including APOE ε4 was associated with higher immunity markers. Discussion Higher levels of immunity markers were associated with higher Aβ in plasma. Participants with a higher genetic predisposition to AD had higher immunity markers, where these effects were mainly driven by APOE ε4.

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Disentangling the biological pathways involved in early features of Alzheimer's disease in the Rotterdam Study

Abstract: Our study suggests that the clinical spectrum of early AD pathology is explained by different biological pathways, in particular, the endocytosis, clathrin/AP2 adaptor complex, and immune response pathways, that are independent of apolipoprotein E (APOE).

Cited by 40 publications

References 77 publications

Shared genes between Alzheimer’s disease and ischemic stroke

Shared genes between Alzheimer’s disease and ischemic stroke

Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s Disease

Immunity and amyloid beta, total tau and neurofilament light chain: Findings from a community‐based cohort study

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