Cognitive gene risk profile for the prediction of cognitive decline in presymptomatic Alzheimer’s disease

Porter, Tenielle; Villemagne, Victor L.; Savage, Greg; Milicic, Lidija; Lim, Yen Ying; Maruff, Paul; Masters, Colin L.; Ames, David; Bush, Ashley I.; Martins, Ralph N.; Rainey‐Smith, Stephanie R.; Rowe, Christopher C.; Taddei, Kevin; Groth, David; Verdile, Giuseppe; Burnham, Samantha; Laws, Simon M.

doi:10.1016/j.pmip.2018.03.001

Cited by 22 publications

(30 citation statements)

References 49 publications

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“…In a recent study, decision trees were used to report a genetic risk profile derived from a set of candidate genes related to cognitive performance selected a priori in order to explore the combined effect of these genes on cognitive impairment rates during the preclinical stage of AD. The results support the hypothesis that the combination of genes associated with cognitive performance makes it possible to identify groups with accelerated rates of cognitive impairment [23].…”

Section: State Of Artsupporting

confidence: 80%

Towards a Proposal of Personalized Medical Decision Support Systems: Analysis of Gene Expression Levels of Diabetes Mellitus, Inflammation and Oxidative Stress in Alzheimer’s Disease

Gutiérrez¹,

Cruz-Ramírez²,

Emiliano³

et al. 2019

RCS

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The increased incidence of Alzheimer's disease (AD) and diabetes mellitus (DM) are emerging as major public health problems worldwide. Both sufferings share pathophysiological characteristics and have no cure. Inflammation of the central and peripheral nervous system has been shown to be the link between DM and AD. Oxidative stress is also associated with AD and DM. The increasing complexity of the problems and the continuous growth of information creates the need for the use of Decision Suport System (DSS) driven by the use of new technologies such as big data and machine learning. In this context, the objective of this work is to use decision trees and Bayesian networks as mechanisms of classification of AD gene expression levels, DM, inflammation and oxidative stress, MMSE (Mini-Mental State Examination) score and the number of neurofibrillary tangles to classify 31 individuals (9 healthy controls and 22 AD patients in three different stages of disease) that could be key in the development of AD. Our results allowed us to generate classification models of different states of AD severity, according to the MMSE and we found that the level of expression of the ADIPOQ gene could play an important role in the onset of AD. Our predictive model can contribute knowledge that could be incorporated into a personalized medical DSS in the future.

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Section: State Of Artsupporting

confidence: 80%

Towards a Proposal of Personalized Medical Decision Support Systems: Analysis of Gene Expression Levels of Diabetes Mellitus, Inflammation and Oxidative Stress in Alzheimer’s Disease

Gutiérrez¹,

Cruz-Ramírez²,

Emiliano³

et al. 2019

RCS

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“…In addition, abnormally high neocortical Aβ in cognitively normal (CN) older adults is associated with an increased risk for cognitive decline and development of AD (Villemagne et al, 2011). Despite this, levels of Aβ alone do not track well with progressive cognitive decline and there is strong convergent evidence that variable rates of decline in the preclinical stages of AD may be influenced by genetic factors (Lim et al, 2015a,b; Porter et al, 2018a,c). Identification of genetic factors that contribute to accelerated rates of cognitive decline in at risk individuals will be of significant importance, through an increased understanding of potential mechanisms of preclinical decline and the identification of individuals most suitable for intervention trials.…”

Section: Introductionmentioning

confidence: 99%

“…The genes containing these variants have roles in promotion of neuronal survival ( BDNF ; Brain Derived Neurotropic Factor; (Lim et al, 2015a), synaptic plasticity ( KIBRA ; Kidney and Brain expressed protein; (Tracy et al, 2016; Porter et al, 2018a), regulation of dopamine availability ( COMT ; Catechol- O -methyltranferase; Sheldrick et al, 2008), longevity ( KL ; Klotho; Arking et al, 2002), inflammation ( CSMD1 ; CUB and Sushi Multiple Domain 1; Kraus et al, 2006) and amyloid precursor protein (APP) processing ( SPON1 ; Spondin 1; Ho and Sudhof, 2004). In addition to the independent association of these genes with cognitive performance, we have also recently reported on the utility of combining these cognition-associated genetic variants for assessing longitudinal cognition (Porter et al, 2018c). As identified above there is also a significant body of literature combining GWAS derived AD risk associated genetic variants, typically within a core set of 21 genes, into PRSs that have previously been associated with the clinical classification of AD and disease phenotypes, albeit with inconsistency of association with cognition.…”

Section: Introductionmentioning

confidence: 99%

A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer’s Disease

Porter

Burnham

Savage

et al. 2018

Front. Aging Neurosci.

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Studies of Alzheimer’s disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRStruec¯APOE) or excluding APOE (emPRStrues¯APOE). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer’s cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRStruec¯APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRStrues¯APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development.

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“…Methods for DNA extraction and genotyping have been previously described (Brown et al, 2014; Porter et al, 2018a, b). Briefly, QIAamp DNA Blood Maxi Kits (Qiagen, Hilden, Germany) were used for DNA extraction from whole blood as per manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

COMT val158met is not associated with Aβ-amyloid and APOE ε4 related cognitive decline in cognitively normal older adults

et al. 2019

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Highlights Effect of COMT Val158Met on cognitive decline in preclinical AD investigated. Impact on Aβ-amyloid and APOE ε4 mediated decline assessed. COMT does not influence Aβ-amyloid or APOE ε4 driven cognitive decline.

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Cognitive gene risk profile for the prediction of cognitive decline in presymptomatic Alzheimer’s disease

Cited by 22 publications

References 49 publications

Towards a Proposal of Personalized Medical Decision Support Systems: Analysis of Gene Expression Levels of Diabetes Mellitus, Inflammation and Oxidative Stress in Alzheimer’s Disease

Towards a Proposal of Personalized Medical Decision Support Systems: Analysis of Gene Expression Levels of Diabetes Mellitus, Inflammation and Oxidative Stress in Alzheimer’s Disease

A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer’s Disease

COMT val158met is not associated with Aβ-amyloid and APOE ε4 related cognitive decline in cognitively normal older adults

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