The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease

Abstract

In Alzheimer’s disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.

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Funding

This project was supported by The Dominantly Inherited Alzheimer’s Network (DIAN, UF1 AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), the NIHR Queen Square Dementia Biomedical Research Centre and the MRC Dementias Platform UK (MR/L023784/1 and MR/009076/1), and AMED under grant number JP17dk0207036 and JP17kk0205009. This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. The FACEHBI study is supported by Grifols®, Piramal®, Araclon Biotech®, Laboratorios Echevarne S.A. and Fundació ACE, Institut Català de Neurociències Aplicades. M.E.—Alzheimer Forschung Initiative & LMU excellent; J.C.—K23AG049087; B.A.G.—K01AG053474, Barnes-Jewish Hospital Foundation Willman Scholar Fund; Y.Y.L.—National Health and Medical Research Council (NHMRC) GNT1111603, GNT1147465.

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Correspondence to Michael Ewers.

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A.M.F. has received research funding from Biogen, Fujirebio, and Roche Diagnostics. She is a member of the scientific advisory boards for Roche, Genentech, and AbbVie and also consults for Araclon/Griffols and DiamiR.: Y.Y.L. has served as a scientific consultant to Biogen and Lundbeck; M.B. who has consulted or advisory board for Araclon, Grifols, Lilly, Nutricia, Roche and Servier. She received fees for lectures and funds for research from Araclon, Grifols, Nutricia, Roche and Servier. She has not received personal compensations from these organizations. A. Ruiz has consulted for Grifols and Landsteiner Genmed. He received funds for research and/or reimbursement of expenses for congresses attendance from Araclon, and Grifols. He has not received personal compensations from these organizations: T.B., Investigator, initiated research funding sponsored by Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) and Foundation for the NIH. Clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly, Roche, Jaansen, Biogen, and NIH. Travel sponsored by the American Society for Neuroradiology, Alzheimer’s Association International Convention, NIH. The remaining authors declare that they have no conflict of interest.

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Franzmeier, N., Ren, J., Damm, A. et al. The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease. Mol Psychiatry (2019). https://doi.org/10.1038/s41380-019-0404-6

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