Alzheimer’s Genetics in the GWAS Era: A Continuing Story of ‘Replications and Refutations’

Bertram, Lars

doi:10.1007/s11910-011-0193-z

Cited by 36 publications

(27 citation statements)

References 47 publications

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“…The genetics of AD is being disentangled using agnostic genome-wide research methods (Bertram, 2011). However, genetic research using identified SNPs on AD prognosis or pharmacogenetics is still pending.…”

Section: Discussionmentioning

confidence: 99%

Exploratory analysis of seven Alzheimer's disease genes: disease progression

Ruiz

Hernández

Ronsende-Roca

et al. 2013

Neurobiology of Aging

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The relationships between GWAS-identified and replicated genetic variants associated to Alzheimer’s disease (AD) risk and disease progression or therapeutic responses in AD patients are almost unexplored. 701 AD patients with at least three different cognitive evaluations and genotypic information for APOE and six GWAS-significant SNPs were selected for this study. Mean differences in GDS and MMSE were evaluated using non-parametric tests, GLM and mixed models for repeated measurements. Each chart was also reviewed for evidence of treatment with any cholinesterase inhibitor (AChEI), memantine or both. Relationships between therapeutic protocols, genetic markers and progression were explored using stratified analysis looking for specific effects on progression in each therapeutic category separately. Neither calculation rendered a Bonferroni-corrected statistically significant difference in any genetic marker. Mixed model results suggested differences in the average point in MMSE test for patients carrying PICALM GA or AA genotype compared to GG carriers at the end of the follow up (MMSE mean difference= −0.57 C.I.95%[−1.145−0.009], p=0.047). This observations remained unaltered after covariate adjustments although did not achieve predefined multiple testing significance threshold. PICALM SNP also displayed a significant effect protecting against rapid progression during pharmacogenetics assays although it observed effect displayed heterogeneity among AD therapeutic protocols (p=0.039). None of studied genetic markers was convincingly linked to AD progression or drug response. However, by using different statistical approaches, PICALM rs3851179 marker displayed consistent but weak effects on disease progression phenotypes.

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Section: Discussionmentioning

confidence: 99%

Exploratory analysis of seven Alzheimer's disease genes: disease progression

Ruiz

Hernández

Ronsende-Roca

et al. 2013

Neurobiology of Aging

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“…These studies allow simultaneously investigating literally millions of genetic markers (mostly socalled single-nucleotide polymorphisms, SNPs) in one experiment to assess their effect on disease risk, or quantitative phenotypes. Not unexpectedly, these GWAS have led to more reproducible and more consistent findings than three decades of candidate-genedriven research before [35].…”

Section: The Genetics Of Alzheimer's Diseasementioning

confidence: 96%

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Hampel

Lista

Teipel

et al. 2014

Biochemical Pharmacology

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105

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Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD

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“…Previous genome-wide association studies (GWAS) have identified low-risk variants associated with LOAD [5][6][7][8][9][10], which account for a small proportion of risk. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance [11], indicating that additional undiscovered genetic factors may contribute to AD susceptibility.…”

Section: Introductionmentioning

confidence: 99%

A Common Variant in the MC1R Gene (p.V92M) is associated with Alzheimer’s Disease Risk

Tell‐Martí

Puig-Butillé

Potrony

et al. 2017

JAD

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Abstract. Despite the recent identification of some novel risk genes for Alzheimer's disease (AD), the genetic etiology of late-onset Alzheimer's disease (LOAD) remains largely unknown. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance in LOAD. The evidence indicates that undiscovered genetic factors may contribute to AD susceptibility. In the present study, we sequenced the MC1R gene in 525 Spanish LOAD patients and in 160 controls. We observed that a common MC1R variant p.V92M (rs2228479), not related to pigmentation traits, was present in 72 (14%) patients and 15 (9%) controls and confers increased risk of developing LOAD (OR: 1.99, 95% CI: 1.08-3.64, p = 0.026), especially in those patients whose genetic risk could not be explained by APOE genotype. This association remains and even increased in the subset of 69 patients with typical AD cerebrospinal fluid profile (OR: 3.40 95% CI: 1.40-8.27, p = 0.007). We did not find an association between p.V92M and age of onset of AD. Further studies are necessary to elucidate the role of MC1R in brain cells through the different MC1R pathways.

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Alzheimer’s Genetics in the GWAS Era: A Continuing Story of ‘Replications and Refutations’

Cited by 36 publications

References 47 publications

Exploratory analysis of seven Alzheimer's disease genes: disease progression

Exploratory analysis of seven Alzheimer's disease genes: disease progression

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

A Common Variant in the MC1R Gene (p.V92M) is associated with Alzheimer’s Disease Risk

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