A 22‐single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid Aβ<sub>42</sub>

Sleegers, Kristel; Bettens, Karolien; Roeck, Arne De; Cauwenberghe, Caroline Van; Cuyvers, Elise; Verheijen, Jan; Struyfs, Hanne; Dongen, Jasper Van; Vermeulen, Steven; Engelborghs, Sebastiaan; Vandenbulcke, Mathieu; Vandenberghe, Rik; Deyn, Peter Paul De; Broeckhoven, Christine Van

doi:10.1016/j.jalz.2015.02.013

Cited by 96 publications

(113 citation statements)

References 27 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…47 48 This 75-year-old limit has been used by us and other studies that combine multiple susceptibility loci into a global genetic risk score to improve the prediction of individuals at risk of suffering AD. 49 There is still an open debate regarding the disclosure of IF to participants participating in imaging studies, since there is still a lack of evidence on which to base practice on the balance of harm versus benefit in telling research participants about findings. 5 The existing literature has evaluated the will of participants in medical and non-medical settings to be informed.…”

Section: Discussionmentioning

confidence: 99%

Incidental findings on brain MRI of cognitively normal first-degree descendants of patients with Alzheimer's disease: a cross-sectional analysis from the ALFA (Alzheimer and Families) project

et al. 2017

View full text Add to dashboard Cite

ObjectivesTo describe the prevalence of brain MRI incidental findings (IF) in a cohort of cognitively normal first-degree descendants of patients with Alzheimer's disease (AD).DesignCross-sectional observational study.SettingAll scans were obtained with a 3.0 T scanner. Scans were evaluated by a single neuroradiologist and IF recorded and categorised. The presence of white matter hyperintensities (WMH) was determined with the Fazekas scale and reported as relevant if ≥2.Participants575 participants (45–75 years) underwent high-resolution structural brain MRI. Participants were cognitively normal and scored over the respective cut-off values in all the following neuropsychological tests: Mini-Mental State Examination (≥26), Memory Impairment Screen (≥6), Time Orientation Subtest of the Barcelona Test II (≥68), verbal semantic fluency (naming animals ≥12). Clinical Dementia Rating (CDR) had to be 0.Results155 participants (27.0%) presented with at least one IF. Relevant WMH were present in 7.8% of the participants, and vascular abnormalities, cyst and brain volume loss in 10.7%, 3.1% and 6.9% of the study volunteers, respectively. Neoplastic brain findings were found in 2.4% of participants and within these, meningiomas were the most common (1.7%) and more frequently found in women. A positive correlation between increasing age and the presence of IF was found. Additionally, brain atrophy greater than that expected by age was significantly more prevalent in participants without a parental history of AD.ConclusionsBrain MRIs of healthy middle-aged participants show a relatively high prevalence of IF even when study participants have been screened for subtle cognitive alterations. Most of our participants are first-degree descendants of patients with AD, and therefore these results are of special relevance for novel imaging studies in the context of AD prevention in cognitively healthy middle-aged participants.Trial registration numberNCT02198586.

show abstract

Section: Discussionmentioning

confidence: 99%

Incidental findings on brain MRI of cognitively normal first-degree descendants of patients with Alzheimer's disease: a cross-sectional analysis from the ALFA (Alzheimer and Families) project

et al. 2017

View full text Add to dashboard Cite

show abstract

“…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: 96%

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

Chaudhury

Patel

Barber

et al. 2018

Neurobiology of Aging

View full text Add to dashboard Cite

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.

show abstract

“…AD genetic risk scores have been associated with increased risk of late life cognitive impairment [55], AD risk [56], greater risk of conversion from MCI to AD [54,57,58], and discriminating an AD group from controls [59]. Research on genetic risk approaches have used several procedures for calculating risk scores.…”

Section: Introductionmentioning

confidence: 99%

A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer’s Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOE ɛ4 Carriers

Sapkota

Dixon

2018

JAD

View full text Add to dashboard Cite

Background Trajectories of complex neurocognitive phenotypes in preclinical aging may be produced differentially through selective and interactive combinations of genetic risk. Objective We organize three possible combinations into a “network” of genetic risk indices derived from polymorphisms associated with normal and impaired cognitive aging, as well as Alzheimer’s disease (AD). Specifically, we assemble and examine three genetic clusters relevant to non-demented cognitive trajectories: (1) Apolipoprotein E (APOE), (2) a Cognitive Aging Genetic Risk Score (CA-GRS; Catechol-O-methyltransferase + Brain-derived neurotrophic factor), and (3) an AD-Genetic Risk Score (AD-GRS; Clusterin + Complement receptor 1 + Phosphatidylinositol-binding clathrin assembly protein). Method We use an accelerated longitudinal design (n = 634; age range = 55–95 years) to test whether AD-GRS (low versus high) moderates the effect of increasing CA-GRS risk on executive function (EF) performance and change as stratified by APOE status (ε4+ versus ε4-). Results APOE ε4 carriers with high AD-GRS had poorer EF performance at the centering age (75 years) and steeper 9-year decline with increasing CA-GRS but this association was not present in APOE ε4 carriers with low AD-GRS. Conclusions APOE ε4 carriers with high AD-GRS are at elevated risk of cognitive decline when they also possess higher CA-GRS risk. Genetic risk from both common cognitive aging and AD-related indices may interact in intensification networks to differential predict (1) level and trajectories of EF decline and (2) potential selective vulnerability for transitions into impairment and dementia.

show abstract

A 22‐single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid Aβ₄₂

Abstract: The discriminative ability of this 22-SNP GRS is still limited, but these data illustrate that incorporation of age-specific weights improves discriminative ability. GRS-phenotype correlations highlight the feasibility of identifying individuals at highest susceptibility.

Cited by 96 publications

References 27 publications

Incidental findings on brain MRI of cognitively normal first-degree descendants of patients with Alzheimer's disease: a cross-sectional analysis from the ALFA (Alzheimer and Families) project

Incidental findings on brain MRI of cognitively normal first-degree descendants of patients with Alzheimer's disease: a cross-sectional analysis from the ALFA (Alzheimer and Families) project

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

A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer’s Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOE ɛ4 Carriers

Contact Info

Product

Resources

About

A 22‐single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid Aβ42

Abstract: The discriminative ability of this 22-SNP GRS is still limited, but these data illustrate that incorporation of age-specific weights improves discriminative ability. GRS-phenotype correlations highlight the feasibility of identifying individuals at highest susceptibility.

Cited by 96 publications

References 27 publications

Incidental findings on brain MRI of cognitively normal first-degree descendants of patients with Alzheimer's disease: a cross-sectional analysis from the ALFA (Alzheimer and Families) project

Incidental findings on brain MRI of cognitively normal first-degree descendants of patients with Alzheimer's disease: a cross-sectional analysis from the ALFA (Alzheimer and Families) project

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

A Network of Genetic Effects on Non-Demented Cognitive Aging: Alzheimer’s Genetic Risk (CLU + CR1 + PICALM) Intensifies Cognitive Aging Genetic Risk (COMT + BDNF) Selectively for APOE ɛ4 Carriers

Contact Info

Product

Resources

About

A 22‐single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid Aβ₄₂