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

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• 作者：Kristel Sleegers^a ; ^b ; ¹ ; ^{kristel.sleegers@molgen.vib-ua.be" class="auth_mail" title="E-mail the corresponding author} ; Karolien Bettens^a ; ^b ; ¹ ; Arne De Roeck^a ; ^b ; Caroline Van Cauwenberghe^a ; ^b ; Elise Cuyvers^a ; ^b ; Jan Verheijen^a ; ^b ; Hanne Struyfs^b ; Jasper Van Dongen^a ; ^b ; Steven Vermeulen^a ; ^b ; Sebastiaan Engelborghs^b ; ^c ; Mathieu Vandenbulcke^d ; Rik Vandenberghe^e ; Peter Paul De Deyn^b ; ^c ; ^f ; Christine Van Broeckhoven^a ; ^b ; ^{christine.vanbroeckhoven@molgen.vib-ua.be" class="auth_mail" title="E-mail the corresponding author} ; on behalf of the BELNEU consortium
• 关键词：Alzheimer's disease ; Genetic risk profile ; Genotype-phenotype correlation ; CSF Aβ1&ndash ; 42 ; Onset age ; Family history
• 刊名：Alzheimer's & Dementia
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：11
• 期：12
• 页码：1452-1460
• 全文大小：1200 K

文摘

The ability to identify individuals at increased genetic risk for Alzheimer's disease (AD) may streamline biomarker and drug trials and aid clinical and personal decision making.

Methods

We evaluated the discriminative ability of a genetic risk score (GRS) covering 22 published genetic risk loci for AD in 1162 Flanders-Belgian AD patients and 1019 controls and assessed correlations with family history, onset age, and cerebrospinal fluid (CSF) biomarkers (Aβ_1–42, T-Tau, P-Tau_181P).

Results

A GRS including all single nucleotide polymorphisms (SNPs) and age-specific APOE ε4 weights reached area under the curve (AUC) 0.70, which increased to AUC 0.78 for patients with familial predisposition. Risk of AD increased with GRS (odds ratio, 2.32 (95% confidence interval 2.08–2.58 per unit; P < 1.0e⁻¹⁵). Onset age and CSF Aβ_1–42 decreased with increasing GRS (P_{onset_age} = 9.0e⁻¹¹; P_Aβ = 8.9e⁻⁷).

Discussion

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.