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Decision tree analysis of genetic risk for clinically heterogeneous Alzheimer's disease.

Yokoyama JS, Bonham LW, Sears RL, Klein E, Karydas A, Kramer JH, Miller BL, Coppola G - BMC Neurol (2015)

Bottom Line: A 17-marker risk panel predicted AD significantly better than APOE genotype alone (P < 0.00001) in the Discovery cohort, but not in the Validation cohort.In decision tree analyses, we found that APOE best differentiated cases from controls only in AmnAD but not AtAD.Our study suggests that APOE ε4 remains the best predictor of broad AD risk when compared to multiple other genetic factors with modest effects, that phenotypic heterogeneity in broad AD can complicate simple polygenic risk modeling, and supports the association between HFE and AD risk in individuals without APOE ε4.

View Article: PubMed Central - PubMed

Affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, 94158, USA. Jennifer.Yokoyama@ucsf.edu.

ABSTRACT

Background: Heritability of Alzheimer's disease (AD) is estimated at 74% and genetic contributors have been widely sought. The ε4 allele of apolipoprotein E (APOE) remains the strongest common risk factor for AD, with numerous other common variants contributing only modest risk for disease. Variability in clinical presentation of AD, which is typically amnestic (AmnAD) but can less commonly involve visuospatial, language and/or dysexecutive syndromes (atypical or AtAD), further complicates genetic analyses. Taking a multi-locus approach may increase the ability to identify individuals at highest risk for any AD syndrome. In this study, we sought to develop and investigate the utility of a multi-variant genetic risk assessment on a cohort of phenotypically heterogeneous patients with sporadic AD clinical diagnoses.

Methods: We genotyped 75 variants in our cohort and, using a two-staged study design, we developed a 17-marker AD risk score in a Discovery cohort (n = 59 cases, n = 133 controls) then assessed its utility in a second Validation cohort (n = 126 cases, n = 150 controls). We also performed a data-driven decision tree analysis to identify genetic and/or demographic criteria that are most useful for accurately differentiating all AD cases from controls.

Results: We confirmed APOE ε4 as a strong risk factor for AD. A 17-marker risk panel predicted AD significantly better than APOE genotype alone (P < 0.00001) in the Discovery cohort, but not in the Validation cohort. In decision tree analyses, we found that APOE best differentiated cases from controls only in AmnAD but not AtAD. In AtAD, HFE SNP rs1799945 was the strongest predictor of disease; variation in HFE has previously been implicated in AD risk in non-ε4 carriers.

Conclusions: Our study suggests that APOE ε4 remains the best predictor of broad AD risk when compared to multiple other genetic factors with modest effects, that phenotypic heterogeneity in broad AD can complicate simple polygenic risk modeling, and supports the association between HFE and AD risk in individuals without APOE ε4.

No MeSH data available.


Related in: MedlinePlus

Area under the curve values for each scoring set. Area under the curve (AUC) values are provided for each scoring method (in black) as well as the difference between the current and previous scoring method (Δ AUC, in gray). Score sets were iteratively assessed until two consecutive resulting AUC values were lower than the preceding AUC value. The resulting scoring method [“Q”] had an AUC of 0.88.
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Fig2: Area under the curve values for each scoring set. Area under the curve (AUC) values are provided for each scoring method (in black) as well as the difference between the current and previous scoring method (Δ AUC, in gray). Score sets were iteratively assessed until two consecutive resulting AUC values were lower than the preceding AUC value. The resulting scoring method [“Q”] had an AUC of 0.88.

Mentions: By iteratively adding genetic variants, we found that a risk score panel comprising 17 variants (“Q”) was the best predictor of AD status (Table 3; Figure 2). When evaluated alone, APOE genotype had modest predictive value for differentiating AD cases from controls. The 17-marker risk score had a significantly better AUC and was better at predicting AD risk than APOE alone (P < 0.00001; Figure 3).Table 3


Decision tree analysis of genetic risk for clinically heterogeneous Alzheimer's disease.

Yokoyama JS, Bonham LW, Sears RL, Klein E, Karydas A, Kramer JH, Miller BL, Coppola G - BMC Neurol (2015)

Area under the curve values for each scoring set. Area under the curve (AUC) values are provided for each scoring method (in black) as well as the difference between the current and previous scoring method (Δ AUC, in gray). Score sets were iteratively assessed until two consecutive resulting AUC values were lower than the preceding AUC value. The resulting scoring method [“Q”] had an AUC of 0.88.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4459447&req=5

Fig2: Area under the curve values for each scoring set. Area under the curve (AUC) values are provided for each scoring method (in black) as well as the difference between the current and previous scoring method (Δ AUC, in gray). Score sets were iteratively assessed until two consecutive resulting AUC values were lower than the preceding AUC value. The resulting scoring method [“Q”] had an AUC of 0.88.
Mentions: By iteratively adding genetic variants, we found that a risk score panel comprising 17 variants (“Q”) was the best predictor of AD status (Table 3; Figure 2). When evaluated alone, APOE genotype had modest predictive value for differentiating AD cases from controls. The 17-marker risk score had a significantly better AUC and was better at predicting AD risk than APOE alone (P < 0.00001; Figure 3).Table 3

Bottom Line: A 17-marker risk panel predicted AD significantly better than APOE genotype alone (P < 0.00001) in the Discovery cohort, but not in the Validation cohort.In decision tree analyses, we found that APOE best differentiated cases from controls only in AmnAD but not AtAD.Our study suggests that APOE ε4 remains the best predictor of broad AD risk when compared to multiple other genetic factors with modest effects, that phenotypic heterogeneity in broad AD can complicate simple polygenic risk modeling, and supports the association between HFE and AD risk in individuals without APOE ε4.

View Article: PubMed Central - PubMed

Affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, 94158, USA. Jennifer.Yokoyama@ucsf.edu.

ABSTRACT

Background: Heritability of Alzheimer's disease (AD) is estimated at 74% and genetic contributors have been widely sought. The ε4 allele of apolipoprotein E (APOE) remains the strongest common risk factor for AD, with numerous other common variants contributing only modest risk for disease. Variability in clinical presentation of AD, which is typically amnestic (AmnAD) but can less commonly involve visuospatial, language and/or dysexecutive syndromes (atypical or AtAD), further complicates genetic analyses. Taking a multi-locus approach may increase the ability to identify individuals at highest risk for any AD syndrome. In this study, we sought to develop and investigate the utility of a multi-variant genetic risk assessment on a cohort of phenotypically heterogeneous patients with sporadic AD clinical diagnoses.

Methods: We genotyped 75 variants in our cohort and, using a two-staged study design, we developed a 17-marker AD risk score in a Discovery cohort (n = 59 cases, n = 133 controls) then assessed its utility in a second Validation cohort (n = 126 cases, n = 150 controls). We also performed a data-driven decision tree analysis to identify genetic and/or demographic criteria that are most useful for accurately differentiating all AD cases from controls.

Results: We confirmed APOE ε4 as a strong risk factor for AD. A 17-marker risk panel predicted AD significantly better than APOE genotype alone (P < 0.00001) in the Discovery cohort, but not in the Validation cohort. In decision tree analyses, we found that APOE best differentiated cases from controls only in AmnAD but not AtAD. In AtAD, HFE SNP rs1799945 was the strongest predictor of disease; variation in HFE has previously been implicated in AD risk in non-ε4 carriers.

Conclusions: Our study suggests that APOE ε4 remains the best predictor of broad AD risk when compared to multiple other genetic factors with modest effects, that phenotypic heterogeneity in broad AD can complicate simple polygenic risk modeling, and supports the association between HFE and AD risk in individuals without APOE ε4.

No MeSH data available.


Related in: MedlinePlus