scholarly journals Effect of Polygenic Score on Alzheimer’s Disease Risk Depends on Age and APOE Status

2020 ◽  
Author(s):  
Brian Fulton-Howard ◽  
Alison M. Goate ◽  
Robert P. Adelson ◽  
Jeremy Koppel ◽  
Marc L. Gordon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Disease Risk ◽  
Age Of Onset ◽  
Low Cost ◽  
Screening Method ◽  
Disease Onset ◽  
Risk Scores ◽  
Cross Sectional

AbstractPolygenic risk scores (PRS) have the potential to serve as a low-cost, non-invasive screening method for Alzheimer’s disease (AD). However, to what extent age and the Apolipoprotein E-ε4 (APOE4) risk allele influence the effect of PRS is underexplored. In a cohort of 346 superager controls (age ≥ 90 years), 2,930 controls (age 60-89) and 1,760 AD cases, we computed APOE-independent PRS for AD. When using superager controls, subjects with PRS in the top decile had nearly five times greater odds of having AD than subjects in the lowest decile (OR=4.91, P=2.24×10−6). In our cross-sectional cohort, PRS modifies the age of onset for AD among APOE4 carriers, but not among non-carriers. Among APOE4 carriers, PRS in the top decile was associated with a five years earlier AD onset than the lowest decile (70.0 vs 75.0 years; t-test P=2.4×10−5). These findings suggest that APOE-independent genetic risk disproportionally affects younger APOE4 carriers, leading to earlier disease onset, while older controls carry less genetic risk.

Apolipoprotein E polymorphism and age of onset for Alzheimer's disease in a bi-ethnic sample

2004 ◽  
Vol 16 (3) ◽  
pp. 317-326 ◽  
Author(s):  
Dylan G. Harwood ◽  
Warren W. Barker ◽  
Raymond L. Ownby ◽  
Peter St. George-Hyslop ◽  
Michael Mullan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Age Of Onset ◽  
Disease Onset ◽  
Cross Sectional Study ◽  
Community Dwelling ◽  
Cross Sectional ◽  
Ε4 Allele ◽  
The Impact

Objective: This study examined the association between the Apolipoprotein-E ε4 allele (APOE ε4) and age of disease onset in a bi-ethnic sample of community dwelling Alzheimer's disease (AD) patients.Design: Cross-sectional study of AD patients evaluated at a University-affiliated outpatient memory disorders clinic.Subjects: A clinic-based cohort of white non-Hispanic (WNH; n=601) and white Hispanic (WH; n=359) patients diagnosed with possible or probable AD according to NINCDS-ADRDA diagnostic criteria.Measures: Global cognitive functioning of the subjects was evaluated using the Mini-mental State Exam. The age of onset of AD was calculated from the patient's current age minus the reported duration of disease obtained from a knowledgeable family member.Results: A significant relationship was discovered between APOE ε4 and age of onset for WNH, with lower ages of onset among patients carrying the ε4/ε4 and ε3˜/ε4 genotypes in relation to patients with the ε3/ε3 genotype. The results revealed a more modest effect for APOE genotype in the WH cohort, with a lower age of onset witnessed among ε4 positive patients (ε2/ε4, ε3/ε4 and ε4/ε4 genotypes) in comparison to ε4 negative patients (ε2/ε2, ε2/ε3 and ε3/ε3 genotypes).Conclusion: The association between the ε4 allele and earlier age of onset was more pronounced in WNH compared to WH patients, suggesting the impact of APOE polymorphism on clinical phenotype may be different for distinct ethnic groups in the U.S.

scholarly journals Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer's Disease: a cross-sectional study

BMC Medicine ◽  
2006 ◽  
Vol 4 (1) ◽  
Author(s):  
Mehul A Trivedi ◽  
Taylor W Schmitz ◽  
Michele L Ries ◽  
Britta M Torgerson ◽  
Mark A Sager ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Middle Aged ◽  
Cross Sectional ◽  
Episodic Encoding

CYP46A1 variants influence Alzheimer’s disease risk and brain cholesterol metabolism

2009 ◽  
Vol 24 (3) ◽  
pp. 183-190 ◽  
Author(s):  
Heike Kölsch ◽  
Dieter Lütjohann ◽  
Frank Jessen ◽  
Julius Popp ◽  
Frank Hentschel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Cholesterol Metabolism ◽  
Disease Risk ◽  
Brain Cholesterol ◽  
Increased Risk ◽  
Csf Levels ◽  
Interaction Term ◽  
Gene Variability

AbstractBackgroundCholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer’s disease (AD) and results are contradictory.MethodsWe performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.ResultsTwo of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p = 0.016; rs4900442: p = 0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p = 0.006). Haplotypes including both SNPs were calculated and haplotype G–C was identified to influence the risk of AD (p = 0.005). AD patients and non-demented controls, who were carriers of the G–C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p = 0.001) and cholesterol (p < 0.001).ConclusionOur results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.

scholarly journals A Multiomics Approach to Heterogeneity in Alzheimer’s Disease: Focused Review and Roadmap

2019 ◽  
Author(s):  
AmanPreet Badhwar ◽  
G. Peggy McFall ◽  
Shraddha Sapkota ◽  
Sandra E. Black ◽  
Howard Chertkow ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
New Drugs ◽  
Data Driven ◽  
Risk Scores ◽  
Multiple Levels ◽  
Multimodal Biomarkers ◽  
Design And Testing ◽  
Key Pathways

AbstractEtiological and clinical heterogeneity is increasingly recognized as a common characteristic of Alzheimer’s disease and related dementias. This heterogeneity complicates diagnosis, treatment, and the design and testing of new drugs. An important line of research is discovery of multimodal biomarkers that will facilitate the targeting of subpopulations with homogeneous pathophysiological signatures. High-throughput ‘omics’ are unbiased data driven techniques that probe the complex etiology of Alzheimer’s disease from multiple levels (e.g. network, cellular, and molecular) and thereby account for pathophysiological heterogeneity in clinical populations. This review focuses on data reduction analyses that identify complementary disease-relevant perturbations for three omics techniques: neuroimaging-based subtypes, metabolomics-derived metabolite panels, and genomics-related polygenic risk scores. Neuroimaging can track accrued neurodegeneration and other sources of network impairments, metabolomics provides a global small-molecule snapshot that is sensitive to ongoing pathological processes, and genomics characterizes relatively invariant genetic risk factors representing key pathways associated with Alzheimer’s disease. Following this focused review, we present a roadmap for assembling these multiomics measurements into a diagnostic tool highly predictive of individual clinical trajectories, to further the goal of personalized medicine in Alzheimer’s disease.

scholarly journals Evaluation of APOE Genotype and Vascular Risk Factors As Prognostic and Risk Factors for Alzheimer’s Disease and Their Influence On Age of Symptoms Onset

2019 ◽  
Vol 7 (4) ◽  
pp. 516-520 ◽  
Author(s):  
Gabriela Novotni ◽  
Milena Jakimovska ◽  
Dijana Plaseska-Karanfilska ◽  
Nikolina Tanovska ◽  
Igor Kuzmanovski ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Age Of Onset ◽  
Disease Onset ◽  
Vascular Risk Factors ◽  
Modifiable Risk Factors ◽  
Vascular Risk ◽  
Awareness Campaigns

BACKGROUND: Alzheimer’s disease (AD), the most common cause of dementia, is evolving to become a threatening epidemy of the 21st century. Only 21% of the predicted number of AD patients in Macedonia have been diagnosed and treated, which means that almost 80% are underdiagnosed or misdiagnosed. Apolipoprotein E gene (APOE) is recognised as the strongest genetic risk factor for sporadic AD. Whether and when Alzheimer’s disease develops, depends on the very complex interaction between genetic and modifiable risk factors. It has been known that vascular factors like hypertension, diabetes mellitus, hypercholesterolemia and obesity increase the risk of developing both AD, vascular dementia and mixed AD and vascular pathology AIM: This study aims to evaluate the influence of APOEε4 allele presence and modifiable vascular risk factors (hypertension, diabetes mellitus and dyslipidemia) as prognostic and risk factors for AD and their influence on the age of onset of AD symptoms among 144 AD patients from Macedonia. MATERIAL AND METHODS: Study group of a total of 144 patients diagnosed with AD was evaluated. APOE genotyping was performed using APOE haplotype-specific sequence specific-primer (SSP)-PCR (Polymerase Chain Reaction) methodology. The non-standardized questionnaire was used to obtain information about demographics, lifestyle and modifiable risk factors that could influence disease onset and phenotype. RESULTS: Statistically significant association was found between the presences of APOEε4 allele in AD group versus controls. The presence of APOEε4 allele increases the risk of developing AD in a 3-fold manner. The average age of disease onset in the ε4 carrier group was 67.2 ± 8.3 and in the ε4 non-carrier group 69.7 ± 9.4. This confirms that the presence of APOEε4 allele shifts towards earlier disease onset, though the difference is not statistically significant. Out of the vascular risk factors, only hypertension was significantly associated with earlier AD onset. Out of total 144 patients, in 22.9% the first symptom onset was before the age of 65, that can be considered as early onset Alzheimer’s Disease (EOAD), which is much higher than 5% for EOAD as most of the studies report. CONCLUSIONS: The average age of disease onset of 68.4 years could be considered earlier than the average age of AD onset worldwide. Out of all the vascular risk factors analysed in this study, only hypertension and dyslipidemia were found to significantly increase the risk for developing AD and only the presence of hypertension influences the age of onset, shifting towards earlier disease onset. Public awareness campaigns should be organised to influence general population knowledge about Alzheimer’s disease, early recognition and the influence of modifiable vascular risk factors.

scholarly journals A comprehensive analysis of methods for assessing polygenic burden on Alzheimer’s disease pathology and risk beyond APOE

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Andre Altmann ◽  
Marzia A Scelsi ◽  
Maryam Shoai ◽  
Eric de Silva ◽  
Leon M Aksman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Diagnosis ◽  
Risk Scores ◽  
Imaging Biomarkers ◽  
Cross Sectional ◽  
Polygenic Risk ◽  
Apoe Ε4 ◽  
Polygenic Scores ◽  
Apoe Locus

Abstract Genome-wide association studies have identified dozens of loci that alter the risk to develop Alzheimer’s disease. However, with the exception of the APOE-ε4 allele, most variants bear only little individual effect and have, therefore, limited diagnostic and prognostic value. Polygenic risk scores aim to collate the disease risk distributed across the genome in a single score. Recent works have demonstrated that polygenic risk scores designed for Alzheimer’s disease are predictive of clinical diagnosis, pathology confirmed diagnosis and changes in imaging biomarkers. Methodological innovations in polygenic risk modelling include the polygenic hazard score, which derives effect estimates for individual single nucleotide polymorphisms from survival analysis, and methods that account for linkage disequilibrium between genomic loci. In this work, using data from the Alzheimer’s disease neuroimaging initiative, we compared different approaches to quantify polygenic disease burden for Alzheimer’s disease and their association (beyond the APOE locus) with a broad range of Alzheimer’s disease-related traits: cross-sectional CSF biomarker levels, cross-sectional cortical amyloid burden, clinical diagnosis, clinical progression, longitudinal loss of grey matter and longitudinal decline in cognitive function. We found that polygenic scores were associated beyond APOE with clinical diagnosis, CSF-tau levels and, to a minor degree, with progressive atrophy. However, for many other tested traits such as clinical disease progression, CSF amyloid, cognitive decline and cortical amyloid load, the additional effects of polygenic burden beyond APOE were of minor nature. Overall, polygenic risk scores and the polygenic hazard score performed equally and given the ease with which polygenic risk scores can be derived; they constitute the more practical choice in comparison with polygenic hazard scores. Furthermore, our results demonstrate that incomplete adjustment for the APOE locus, i.e. only adjusting for APOE-ε4 carrier status, can lead to overestimated effects of polygenic scores due to APOE-ε4 homozygous participants. Lastly, on many of the tested traits, the major driving factor remained the APOE locus, with the exception of quantitative CSF-tau and p-tau measures.

scholarly journals Validity and reliability of the Brazilian Portuguese version of the Australian National University - Alzheimer’s Disease Risk Index (ANU-ADRI)

2018 ◽  
Vol 12 (3) ◽  
pp. 235-243 ◽  
Author(s):  
Marcus Kiiti Borges ◽  
Alessandro Ferrari Jacinto ◽  
Vanessa Albuquerque Citero
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Risk ◽  
Risk Index ◽  
Community Dwelling ◽  
Self Report ◽  
Risk Scores ◽  
Validity And Reliability ◽  
Portuguese Version ◽  
Group B

Abstract The ANU-ADRI is a self-report tool that assesses risk for Alzheimer’s Disease (AD). Objective: To validate an adapted Portuguese version of this instrument and to carry out the reliability Test-Retest of the ANU-ADRI in Brazil. Methods: In this longitudinal study, the sample was formed (n=100) by two groups (A and B): each comprising 50 patients assisted by GPs (general practitioners) or specialists in dementia. All participants were cognitively healthy upon screening using the MMSE. The ANU-ADRI was applied at baseline (Test) and again within 1 week of the test (Retest). Results: There was a correlation between the mean scores of the ANU-ADRI Test and Retest (r=0.918, P<0.001). Group A had higher ANU-ADRI scores than those of group B (P<0.05). There was a moderate negative linear relation between the ANU-ADRI and MMSE scores (r= -0.353, P<0.001). Conclusion: The ANU-ADRI is a valid and reliable instrument to assess whether community-dwelling Brazilians are at greater risk for AD. Low levels of education were associated with higher risk scores on the ANU-ADRI.

scholarly journals Environmental factors influencing the link between APOE ε4 and Alzheimer's disease (AD) risk

2018 ◽  
Vol 31 (2) ◽  
pp. 305-306 ◽  
Author(s):  
Keith Fluegge
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Temporal Relationship ◽  
Disease Risk ◽  
Apoe Ε4 ◽  
Factors Influencing ◽  
Increased Risk ◽  
Ε4 Allele

While APOE ε4 allele is considered a genetic risk factor for Alzheimer's disease (AD), no relation existed between APOE ε4 and AD in the Yoruba in Nigeria among cohorts included in early prevalence waves. The authors’ explanation that other disease susceptibilities may provoke earlier mortality is inconsistent with the Yoruba having a lower incidence of disease risk factors. Cohort enrichment in 2001 has altered the authors’ conclusions; Yorba participants homozygous, and not heterozygous, for the ε4 allele had significantly increased risk for AD (HR = 2.95, p = 0.0002) (Hendrie et al., 2014). This is a critical revelation, yet it is not clear why such a temporal relationship exists between risk genotypes and AD among the Yoruba. This letter proposes an explanation.

scholarly journals The genetic risk of Alzheimer’s disease beyond APOE ε4: systematic review of Alzheimer’s genetic risk scores

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Hannah Stocker ◽  
Tobias Möllers ◽  
Laura Perna ◽  
Hermann Brenner
Keyword(s):  
Systematic Review ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Risk Scores ◽  
Genetic Risk Scores ◽  
Apoe Ε4

scholarly journals Association between the APOE ε4 Allele and Late-Onset Alzheimer’s Disease in an Ecuadorian Mestizo Population

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Stefany Montufar ◽  
Cristian Calero ◽  
Rodrigo Vinueza ◽  
Patricio Correa ◽  
Andrea Carrera-Gonzalez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Genetic Risk ◽  
Disease Risk ◽  
Late Onset ◽  
Genetic Risk Factor ◽  
Genotype Frequencies ◽  
Healthy Control ◽  
Genetic Contributions

Alzheimer’s disease (AD) is the most common neurodegenerative disease. It has two main pathological hallmarks: amyloid plaques and neurofibrillary tangles. The APOE ε4 allele has been recognized as the strongest genetic risk factor for late-onset Alzheimer’s disease (LOAD) in several populations worldwide, yet the risk varies by region and ethnicity. The aims of this study were to describe APOE allele and genotype frequencies and examine the relationship between the APOE ε4 allele and LOAD risk in an Ecuadorian Mestizo population. We carried out a case-control study comprising 56 individuals clinically diagnosed with probable AD (≥65 years of age) and 58 unrelated healthy control subjects (≥65 years of age). Genotyping was performed using the real-time PCR method. Our data showed that allelic and genotypic frequencies follow the trends observed in most worldwide populations. We also found a high-risk association between APOE ε4 allele carriers and LOAD (OR = 7.286; 95% CI = 2.824–18.799; p<0.001). Therefore, we concluded that APOE ε4 must be considered an important genetic risk factor for LOAD in the Ecuadorian Mestizo population. Additionally, we suggest that in mixed populations the effects of admixture and ethnic identity should be differentiated when evaluating genetic contributions to Alzheimer’s disease risk.

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