Journal Article

DZNE-2026-00827

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png GWAS meta-analysis of cerebrospinal fluid Alzheimer's biomarkers reveals loci regulating lipids, brain volume and autophagy.

Timsina, J. ; Jiang, C. ; McCartney, D. L. ; Tao, F. ; Dalmasso, M. C. ; Najar, J. ; Anastasi, F. ; Ohlei, O. ; Puerta Fuentes, R. ; Yang, C. ; Bradley, J. ; Western, D. ; Ali, M. ; Wang, C. ; Yang, C. ; Wu, Y. ; Liu, M. ; Budde, J. ; Williams, J. ; Mahoney, R. ; Castillo Morales, A. ; Hohman, T. J. ; Dumitrescu, L. ; Wang, T.-C. ; Tesi, N. ; Kern, S. ; Waern, M. ; Skoog, I. ; van Harten, A. ; Pijnenburg, Y. A. L. ; van der Flier, W. M. ; Sánchez-Juan, P. ; Rodriguez-Rodriguez, E. ; Kleineidam, L.DZNE* ; Peters, O.DZNE* ; Schneider, A.DZNE* ; Küçükali, F. ; Bellenguez, C. ; Grenier-Boley, B. ; Heikkinen, S. ; de Rojas, I. ; Rujescu, D. ; Scherbaum, N. ; Hausner, L. ; Düzel, E.DZNE* ; Grimmer, T. ; Wiltfang, J.DZNE* ; Vandenberghe, R. ; Engelborghs, S. ; Heilmann-Heimbach, S. ; Schmid, M.DZNE* ; Tegos, T. ; Scarmeas, N. ; Dols-Icardo, O. ; Moreno, F. ; Pérez-Tur, J. ; Bullido, M. J. ; Sánchez-Valle, R. ; Álvarez, V. ; García-González, P. ; Mir, P. ; Real, L. M. ; Piñol-Ripoll, G. ; García-Alberca, J. M. ; Seelaar, H. ; Ramakers, I. ; Papma, J. ; Hulsman, M. ; Laske, C.DZNE* ; Teipel, S.DZNE* ; Priller, J.DZNE* ; Perneczky, R.DZNE* ; Buerger, K.DZNE* ; Nöthen, M. M. ; Lewczuk, P. ; Kornhuber, J. ; Hampel, H. ; Giegling, I. ; Goldhardt, O. ; Diehl-Schmid, J. ; Andrade, V. ; Heneka, M.DZNE* ; Frölich, L. ; Vogelgsang, J. ; Graff, C. ; Thonberg, H. ; Ullgren, A. ; Papenberg, G. ; Deleuze, J.-F. ; Dufouil, C. ; Wagner, M.DZNE* ; Jessen, F.DZNE* ; Holstege, H. ; van Duijn, C. ; Lebouvier, T. ; Hannon, O. ; Leinonen, V. ; Soininen, H. ; Herukka, S.-K. ; Giedraitis, V. ; Löwenmark, M. ; Kilander, L. ; Genius, P. ; Rodríguez, B. ; Luckett, E. S. ; Navarro, A. ; Cano, A. ; Marquié, M. ; Blennow, K. ; Zetterberg, H. ; Lleo, A. ; Boada, M. ; Ruiz, A. ; Lee, V. M. ; Van Deerlin, V. M. ; Deming, Y. ; Johnson, S. C. ; Engelman, C. D. ; Pastor, P. ; Alvarez, I. ; Peskind, E. R. ; Heslegrave, A. J. ; Saykin, A. J. ; Nho, K. ; Schindler, S. E. ; Morris, J. C. ; Holtzman, D. M. ; McDade, E. ; Renton, A. E. ; Goate, A. ; Ibanez, L. ; Riemenschneider, M. ; Albert, M. S. ; Laws, S. M. ; Porter, T. ; O'Brien, E. K. ; Shaw, L. M. ; Tijms, B. M. ; Ingelsson, M. ; Visser, P. J. ; Hiltunen, M. ; Sleegers, K. ; Ritchie, C. W. ; Sims, R. ; Belloy, M. ; Lambert, J.-C. ; Vilor-Tejedor, N. ; Fernández, M. V. ; Li, Q. S. ; Nagle, M. W. ; Marioni, R. E. ; Ramirez, A.DZNE* ; Bertram, L. ; van der Lee, S. J. ; Cruchaga, C.

2026
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-026-71682-8

Abstract: Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation.

Keyword(s): Humans (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: cerebrospinal fluid (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Genome-Wide Association Study (MeSH) ; Brain: pathology (MeSH) ; Brain: metabolism (MeSH) ; Biomarkers: cerebrospinal fluid (MeSH) ; Autophagy: genetics (MeSH) ; tau Proteins: cerebrospinal fluid (MeSH) ; tau Proteins: genetics (MeSH) ; Lipid Metabolism: genetics (MeSH) ; Amyloid beta-Peptides: cerebrospinal fluid (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Apolipoproteins E: genetics (MeSH) ; Female (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Male (MeSH) ; Biomarkers ; tau Proteins ; Amyloid beta-Peptides ; Apolipoproteins E

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Contributing Institute(s):

1. Neuropsychology (AG Wagner)
2. Biomarker-Assisted Early Detection of Dementias (AG Peters)
3. Translational Dementia Research (Bonn) (AG Schneider)
4. Clinical Neurophysiology and Memory (AG Düzel)
5. Molecular biomarkers for predictive diagnostics of neurodegenerative diseases (AG Wiltfang)
6. Mathematics, statistics and informatics methods for support of population studies and clinical research (AG Schmid Bonn)
7. Parkinson Genetics (AG Gasser)
8. Clinical Dementia Research (Rostock /Greifswald) (AG Teipel)
9. Translational Neuropsychiatry (AG Priller)
10. Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)
11. Clinical Research (Munich) (Clinical Research (Munich))
12. Clinical Alzheimer’s Disease Research (AG Jessen)
13. Patient Studies (Bonn) (Patient Studies (Bonn))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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