Effects of Alzheimer's Disease-Associated Risk Loci on Cerebrospinal Fluid Biomarkers and Disease Progression: A Polygenic Risk Score Approach

Martiskainen, Henna; Helisalmi, Seppo; Viswanathan, Jayashree; Kurki, Mitja; Hall, Anette; Herukka, Sanna‐Kaisa; Sarajärvi, Timo; Natunen, Teemu; Kurkinen, Kaisa M.A.; Huovinen, Jaakko; Mäkinen, Petra; Laitinen, Matti; Koivisto, Anne M.; Mattila, Kari M.; Lehtimäki, Terho; Remes, Anne M.; Leinonen, Ville; Haapasalo, Annakaisa; Soininen, Hilkka; Hiltunen, Mikko

doi:10.3233/jad-140777

Cited by 51 publications

(43 citation statements)

References 18 publications

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“…An AD genetic risk score was calculated by multiplying each individual GWAS allele effect size using the beta coefficients obtained from a previous data set. This type of analysis demonstrated that AD genetic risk score could predict LOAD phenotype (Chouraki et al, 2016; Desikan et al, 2017; Sleegers et al, 2015; Verhaaren et al, 2013; Xiao et al, 2015; Yokoyama et al, 2015), mild cognitive impairment conversion to LOAD (Adams et al, 2015; Rodriguez-Rodriguez et al, 2013), hippocampal cortical thickness (Harrison et al, 2016; Sabuncu et al, 2012), hippocampal volume (Lupton et al, 2016), cerebrospinal fluid biomarkers (Martiskainen et al, 2015), and plasma inflammatory biomarkers (Morgan et al, 2017). This approach has been expanded to include further polymorphisms of smaller but important effect sizes to develop a polygenic risk score (PRS) (Euesden et al, 2015).…”

Section: Introductionmentioning

confidence: 97%

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

Chaudhury

Patel

Barber

et al. 2018

Neurobiology of Aging

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Sporadic early-onset Alzheimer’s disease (sEOAD) exhibits the symptoms of late-onset Alzheimer’s disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer’s disease (AD) identifies APOE ε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer’s Project consortium, with association data from 17,008 late-onset Alzheimer’s disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy.

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Section: Introductionmentioning

confidence: 97%

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

Chaudhury

Patel

Barber

et al. 2018

Neurobiology of Aging

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“…Based on the results from our in vitro cell culture findings relating to SEPT8 and BACE1, we next investigated whether the mRNA profiles of the different SEPT8 transcript variants showed a relationship with β-secretase activity, which was measured previously from the same tissue samples (Laitera et al, 2014;Martiskainen et al, 2015). We observed a significant negative correlation between exon 10b ( probe 807) and β-secretase activity (r=−0.46, P<0.001, Spearman correlation, n=55) in the temporal cortex.…”

Section: Downregulation Of Sept8 Decreases Endogenous Bace1 Protein Lmentioning

confidence: 72%

“…This cohort consists of RNA samples from the post mortem temporal cortex of 60 subjects with varying degrees of Alzheimer's-disease-related neurofibrillary pathology ( phosphorylated tau protein staining with AT8 antibody) ( Table 1). The subjects were grouped based on Braak staging into three subgroups: Braak stages 0-II, Braak stages III or IV, and Braak stages V or VI (Braak et al, 2006;Martiskainen et al, 2015). We found that the expression profile at the 3′ end of SEPT8 was significantly different between the Braak groups in the temporal cortex (Fig.…”

Section: Downregulation Of Sept8 Decreases Endogenous Bace1 Protein Lmentioning

confidence: 84%

“…As further support for the suggested role of SEPT8 in the early stages of Alzheimer's-disease-associated pathophysiology, we identified transcript-variant-specific alterations in the expression profile of SEPT8 mRNA that could be related to the Alzheimer'sdisease-related neurofibrillary pathology in the human temporal cortex. In these assessments, we used a well-established brain tissue sample set, which has been previously used to assess the expression and splicing status of Alzheimer's-disease-associated risk genes as well as α-, β-and γ-secretase activity in the human temporal cortex (Laitera et al, 2014;Martiskainen et al, 2015). The analysis of SEPT8-exon-specific microarray probes revealed that although total SEPT8 mRNA levels were unaltered, the levels of TV1 were significantly reduced and those of TV2-TV4 were increased according to the Alzheimer's-disease-related neurofibrillary pathology.…”

Section: Discussionmentioning

confidence: 99%

“…4A): SEPT8 TV1 [483 amino acids (aa), referred to as the 'canonical' sequence, 56 kDa], SEPT8 TV2 (429 aa, differs from the canonical sequence as follows: aa 430-483 missing, 50 kDa), SEPT8 TV3 (442 aa, differs from the canonical sequence as follows: 429-442, NRSDIGAHQPGMSL→KASGWSSIYSVTIP, aa 443-483 missing, 52 kDa), and SEPT8 TV4 (369 aa, differs from the canonical sequence as follows: aa 1-60 missing, aa 430-483 missing, 44 kDa). To determine the expression status of SEPT8 transcript variants in our well-established human brain sample cohort (Martiskainen et al, 2015), we applied a microarray-based approach in which probes were designed to capture all the exons in the SEPT8 mRNA (Fig. 4B).…”

Section: Downregulation Of Sept8 Decreases Endogenous Bace1 Protein Lmentioning

confidence: 99%

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SEPT8 modulates β-amyloidogenic processing of APP via affecting the sorting and accumulation of BACE1

Kurkinen

Marttinen

Turner

et al. 2016

Journal of Cell Science

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Dysfunction and loss of synapses are early pathogenic events in Alzheimer's disease. A central step in the generation of toxic amyloid-β (Aβ) peptides is the cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Here, we have elucidated whether downregulation of septin (SEPT) protein family members, which are implicated in synaptic plasticity and vesicular trafficking, affects APP processing and Aβ generation. SEPT8 was found to reduce soluble APPβ and Aβ levels in neuronal cells through a posttranslational mechanism leading to decreased levels of BACE1 protein. In the human temporal cortex, we identified alterations in the expression of specific SEPT8 transcript variants in a manner that correlated with Alzheimer's-disease-related neurofibrillary pathology. These changes were associated with altered β-secretase activity. We also discovered that the overexpression of a specific Alzheimer'sdisease-associated SEPT8 transcript variant increased the levels of BACE1 and Aβ peptides in neuronal cells. These changes were related to an increased half-life of BACE1 and the localization of BACE1 in recycling endosomes. These data suggest that SEPT8 modulates β-amyloidogenic processing of APP through a mechanism affecting the intracellular sorting and accumulation of BACE1.

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Genetics of A lzheimer's Disease

Brookes¹,

Morgan²

2017

Encyclopedia of Life Sciences

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Knowledge on the genetic aetiology of Alzheimer's disease has greatly increased over the past 20 years. We are now finding that more genetic variants than previously thought play a role in disease susceptibility. Key Concepts Advances in genetic research into a complex disorder. Alzheimer's disease (AD) is the most common form of dementia and is genetically heterogeneous. The APOE gene has the largest effect size on risk for AD, and is the most replicated finding. Understanding of the genetic risk factors for AD has been greatly increased by advancements in technology. Multiple gene have now been identified as being involved in the aetiology of AD, and have highlight biological pathways that may be affected. Still, these genes do not account for all of the estimated genetic aetiology and therefore variants with even smaller effect size are being investigated through polygenic risk score analysis.

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Effects of Alzheimer's Disease-Associated Risk Loci on Cerebrospinal Fluid Biomarkers and Disease Progression: A Polygenic Risk Score Approach

Abstract: AD risk loci polygenically contribute to Aβ pathology in the CSF and temporal cortex, and this effect is potentially associated with increased γ-secretase activity.

Cited by 51 publications

References 18 publications

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

SEPT8 modulates β-amyloidogenic processing of APP via affecting the sorting and accumulation of BACE1

Genetics of A lzheimer's Disease

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