The genetic landscape of Alzheimer disease

Carmona, Susana; Hardy, John; Guerreiro, Rita

doi:10.1016/b978-0-444-64076-5.00026-0

Cited by 90 publications

(65 citation statements)

References 112 publications

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“…Unexpectedly, the presence of the APOE ε4 allele was not found to contribute significantly to the prediction of the diagnostic status of participants, despite the fact that it is the most important genetic factor of sporadic AD [44]. This finding could be attributed to the inclusion of APOE interaction factors in the models, which has possibly resulted in an attenuation of the impact of APOE as one of the main predictive covariates.…”

Section: Discussionmentioning

confidence: 87%

Cerebrospinal Fluid BACE1 Activity and sAβPPβ as Biomarker Candidates of Alzheimer’s Disease

Alexopoulos

Thierjung

Grimmer

et al. 2018

Dement Geriatr Cogn Disord

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Background/Aims: The utility of β-site amyloid-β precursor protein (AβPP) cleaving enzyme 1 (BACE1) activity and soluble AβPP β (sAβPPβ) levels in cerebrospinal fluid (CSF) in detecting Alzheimer’s disease (AD) is still elusive. Methods: BACE1 activity and sAβPPβ concentration were measured in patients with AD dementia (n = 56) and mild cognitive impairment (MCI) due to AD (n = 76) with abnormal routine AD CSF markers, in patients with MCI with normal CSF markers (n = 39), and in controls without preclinical AD (n = 48). In a subsample with available ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET) data, ordinal regression models were employed to compare the contribution of BACE1 and sAβPPβ to correct diagnostic classification to that of FDG PET. Results: BACE1 activity was significantly higher in patients with MCI due to AD compared to both controls and patients with MCI with normal CSF markers. sAβPPβ did not differ between any of the studied groups. Interestingly, BACE1 activity was not found to be inferior to FDG PET as predictive covariate in differentiating between the diagnostic groups. Conclusions: Further studies using biomarker-underpinned diagnoses are warranted to shed more light on the potential diagnostic utility of BACE1 activity as AD biomarker candidate in MCI.

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Section: Discussionmentioning

confidence: 87%

Cerebrospinal Fluid BACE1 Activity and sAβPPβ as Biomarker Candidates of Alzheimer’s Disease

Alexopoulos

Thierjung

Grimmer

et al. 2018

Dement Geriatr Cogn Disord

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“…The ε4 allele of apolipo-protein E ( APOE ) is the biggest genetic risk factor for AD and encodes a lipid transport protein involved in cholesterol metabolism [29]. Genome-wide association studies (GWAS) in late-onset AD have identified single nucleotide polymorphisms (SNPs) implicated in lipid processes, such as CLU and ABCA7 [24, 37], and enrichment in cholesterol metabolism pathways [9]. Considered together, these findings suggest ‘pleiotropy’, where variations in a single gene can affect multiple, seemingly unrelated phenotypes [42].…”

Section: Introductionmentioning

confidence: 99%

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

et al. 2018

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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.

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“…The ε 4 allele of apolipoprotein E (APOE) is the biggest genetic risk factor for AD and encodes a lipid transport protein involved in cholesterol metabolism [22]. Genome-wide association studies (GWAS) in late-onset AD have identified single nucleotide polymorphisms (SNPs) implicated in lipid processes, such as CLU and ABCA7 [17,31], and enrichment in cholesterol metabolism pathways [7]. Considered together, these findings suggest 'pleiotropy', where variations in a single gene can affect multiple, seemingly unrelated phenotypes [37].…”

Section: Introductionmentioning

confidence: 99%

Lipid associated polygenic enrichment in Alzheimer’s disease

Tan

Fan³

et al. 2018

Preprint

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Cardiovascular (CV) and lifestyle associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε 4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV associated genes also increase risk for AD (genetic pleiotropy). Using large genome-wide association studies (GWASs) (total n > 500,000 cases and controls) and validated tools to quantify genetic pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), lowdensity (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (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 57 SNPs on 19 different chromosomes that were jointly associated with AD and CV outcomes including APOA4, ABCA1, ABCG5, LIPG, and MTCH2/SPI1. We found that common genetic variants influencing AD are associated with multiple CV RFs, at times with a different directionality of effect. Expression of these AD/CV pleiotropic genes was enriched for lipid metabolism processes, over-represented within astrocytes and vascular structures, highly co-expressed, and differentially altered within AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid associated RFs. Rather than a single causal link between genetic loci, RF and the outcome, we found that common genetic variants influencing AD are associated with multiple CV RFs. Our collective findings suggest that a network of genes involved in lipid biology also influence Alzheimer's risk.

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The genetic landscape of Alzheimer disease

Cited by 90 publications

References 112 publications

Cerebrospinal Fluid BACE1 Activity and sAβPPβ as Biomarker Candidates of Alzheimer’s Disease

Cerebrospinal Fluid BACE1 Activity and sAβPPβ as Biomarker Candidates of Alzheimer’s Disease

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer’s disease

Lipid associated polygenic enrichment in Alzheimer’s disease

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