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. 2024 Mar;20(3):1703-1715.
doi: 10.1002/alz.13537. Epub 2023 Dec 13.

Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum

Natalia Vilor-Tejedor  1   2   3   4 , Patricia Genius  1   2   4 , Blanca Rodríguez-Fernández  1   2   4 , Carolina Minguillón  1   4   5 , Iman Sadeghi  1   2 , Armand González-Escalante  1   4   6 , Marta Crous-Bou  1   7   8 , Marc Suárez-Calvet  1   4   5   9 , Oriol Grau-Rivera  1   4   5   9 , Anna Brugulat-Serrat  1   4   5   10 , Gonzalo Sánchez-Benavides  1   4   5 , Manel Esteller  11   12   13   14   15 , Karine Fauria  1   5 , José Luis Molinuevo  1   16 , Arcadi Navarro  1   2   6   14   17 , Juan Domingo Gispert  1   4   6   18   19 ; Alzheimer's Disease Neuroimaging Initiative; ALFA study
Affiliations

Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum

Natalia Vilor-Tejedor et al. Alzheimers Dement. 2024 Mar.

Abstract

Introduction: In 2013, the ALzheimer's and FAmilies (ALFA) project was established to investigate pathophysiological changes in preclinical Alzheimer's disease (AD), and to foster research on early detection and preventive interventions.

Methods: We conducted a comprehensive genetic characterization of ALFA participants with respect to neurodegenerative/cerebrovascular diseases, AD biomarkers, brain endophenotypes, risk factors and aging biomarkers. We placed particular emphasis on amyloid/tau status and assessed gender differences. Multiple polygenic risk scores were computed to capture different aspects of genetic predisposition. We additionally compared AD risk in ALFA to that across the full disease spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Results: Results show that the ALFA project has been successful at establishing a cohort of cognitively unimpaired individuals at high genetic predisposition of AD.

Discussion: It is, therefore, well-suited to study early pathophysiological changes in the preclinical AD continuum. Highlights Prevalence of ε4 carriers in ALzheimer and FAmilies (ALFA) is higher than in the general European population The ALFA study is highly enriched in Alzheimer's disease (AD) genetic risk factors beyond APOE AD genetic profiles in ALFA are similar to clinical groups along the continuum ALFA has succeeded in establishing a cohort of cognitively unimpaired individuals at high genetic AD risk ALFA is well suited to study pathogenic events/early pathophysiological changes in AD.

Keywords: AD continuum; ALFA study; Alzheimer's disease; neurogenetics; neurological diseases; prevention.

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Conflict of interest statement

J.L.M. is currently a full‐time employee of Lundbeck and has previously served as a consultant or at advisory boards, or has given lectures in symposia sponsored by the following for‐profit companies: Roche Diagnostics, Genentech, Novartis, Lundbeck, Oryzon, Biogen, Lilly, Janssen, Green Valley, MSD, Eisai, Alector, BioCross, GE Healthcare, ProMIS Neurosciences. J.D.G. has received speaker's or consultant's fees from Philips Nederlands, Roche Diagnostics and Biogen and research support from GE Healthcare, Roche Diagnostics and Hoffmann‐La Roche. M.S.C. has served as a consultant and at advisory boards for Roche Diagnostics International Ltd., has given lectures in symposia sponsored by Roche Diagnostics, S.L.U., Roche Farma, S.A. and Roche Sistemas de Diagnósticos, Sociedade Unipessoal, Lda. and research support from Roche Diagnostics International Ltd. G.S.B. has served as a consultant for Roche Farma, S.A. The remaining authors declare that they have no conflict of interest. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Summarized information of the characteristics of project participants.
FIGURE 2
FIGURE 2
Distribution of APOE‐ε4 carriers in the ALFA and ALFA+ samples. ALFA, ALzheimer's and FAmilies; APOE, apolipoprotein E.
FIGURE 3
FIGURE 3
Distribution of genetic scores in the ALFA parent cohort. ALFA, ALzheimer's and FAmilies.
FIGURE 4
FIGURE 4
Distribution of genetic scores of AD along the AD continuum. (A) Subgroups from ALFA and ADNI within the AD continuum. (B) Subgroups within the AD continuum stratifying ALFA participants by amyloid status. Pairwise comparisons are assessed to compare the median PRS‐AD (Wilcoxon test) among groups. Significant results at nominal p‐value are displayed (p‐value < 0.05*; p‐value < 0.01**, p‐value < 0.001***). AD, Alzheimer's disease; ADNI, Alzheimer's Disease Neuroimaging Initiative; ALFA, ALzheimer's and FAmilies; PRS‐AD, polygenic risk scores of AD.
FIGURE 5
FIGURE 5
Distribution of genetic scores of AD along the AD continuum stratified by risk factors.  (A) Distribution stratified by APOE‐ε4 carriership. (B) Distribution stratified by AT group. (C) Distribution stratified by sex. Pairwise comparisons are assessed to compare the median PRS‐AD (Wilcoxon test) among groups. Significant results at nominal p‐value are displayed (p‐value < 0.05*; p‐value < 0.01**, p‐value < 0.001***). AD, Alzheimer's disease; APOE, apolipoprotein E; PRS‐AD, polygenic risk scores of AD.
See this image and copyright information in PMC

References

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