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Multicenter Study
. 2022 Mar 1;79(3):261-270.
doi: 10.1001/jamaneurol.2021.5181.

Association of BDNF Val66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease

Yen Ying Lim  1 , Paul Maruff  1   2 , Nicolas R Barthélemy  3 , Alison Goate  4 , Jason Hassenstab  3 , Chihiro Sato  3 , Anne M Fagan  3 , Tammie L S Benzinger  5 , Chengjie Xiong  6 , Carlos Cruchaga  7 , Johannes Levin  8   9   10 , Martin R Farlow  11 , Neill R Graff-Radford  12 , Christoph Laske  9   13 , Colin L Masters  14 , Stephen Salloway  15   16 , Peter R Schofield  17   18 , John C Morris  3 , Randall J Bateman  3 , Eric McDade  3 ; Dominantly Inherited Alzheimer Network
Collaborators, Affiliations
Multicenter Study

Association of BDNF Val66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease

Yen Ying Lim et al. JAMA Neurol. .

Erratum in

  • Error in Figure Legends.
    [No authors listed] [No authors listed] JAMA Neurol. 2022 Mar 1;79(3):313. doi: 10.1001/jamaneurol.2022.0335. JAMA Neurol. 2022. PMID: 35285879 Free PMC article. No abstract available.

Abstract

Importance: Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism moderates increases in cerebrospinal fluid (CSF) levels of tau and phosphorylated tau 181 (p-tau181), measured using immunoassay, and cognitive decline in presymptomatic dominantly inherited Alzheimer disease (DIAD). Advances in mass spectrometry show that CSF tau phosphorylation occupancy at threonine 181 and 217 (p-tau181/tau181, p-tau217/tau217) increases with initial β-amyloid (Aβ) aggregation, while phosphorylation occupancy at threonine 205 (p-tau205/tau205) and level of total tau increase when brain atrophy and clinical symptoms become evident.

Objective: To determine whether site-specific tau phosphorylation occupancy (ratio of phosphorylated to unphosphorylated tau) is associated with BDNF Val66Met in presymptomatic and symptomatic DIAD.

Design, setting, and participants: This cross-sectional cohort study included participants from the Dominantly Inherited Alzheimer Network (DIAN) and Aβ-positive cognitively normal older adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data were collected from 2009 through 2018 at multicenter clinical sites in the United States, United Kingdom, and Australia, with no follow-up. DIAN participants provided a CSF sample and completed clinical and cognitive assessments. Data analysis was conducted between March 2020 and March 2021.

Main outcomes and measures: Mass spectrometry analysis was used to determine site-specific tau phosphorylation level; tau levels were also measured using immunoassay. Episodic memory and global cognitive composites were computed.

Results: Of 374 study participants, 144 were mutation noncarriers, 156 were presymptomatic mutation carriers, and 74 were symptomatic carriers. Of the 527 participants in the network, 153 were excluded because their CSF sample, BDNF status, or both were unavailable. Also included were 125 Aβ-positive cognitively normal older adults in the ADNI. The mean (SD) age of DIAD participants was 38.7 (10.9) years; 43% were women. The mean (SD) age of participants with preclinical sporadic AD was 74.8 (5.6) years; 52% were women. In presymptomatic mutation carriers, compared with Val66 homozygotes, Met66 carriers showed significantly poorer episodic memory (d = 0.62; 95% CI, 0.28-0.95), lower hippocampal volume (d = 0.40; 95% CI, 0.09-0.71), and higher p-tau217/tau217 (d = 0.64; 95% CI, 0.30-0.97), p-tau181/tau181 (d = 0.65; 95% CI, 0.32-0.99), and mass spectrometry total tau (d = 0.43; 95% CI, 0.10-0.76). In symptomatic mutation carriers, Met66 carriers showed significantly poorer global cognition (d = 1.17; 95% CI, 0.65-1.66) and higher p-tau217/tau217 (d = 0.53; 95% CI, 0.05-1.01), mass spectrometry total tau (d = 0.78; 95% CI, 0.28-1.25), and p-tau205/tau205 (d = 0.97; 95% CI, 0.46-1.45), when compared with Val66 homozygotes. In preclinical sporadic AD, Met66 carriers showed poorer episodic memory (d = 0.39; 95% CI, 0.00-0.77) and higher total tau (d = 0.45; 95% CI, 0.07-0.84) and p-tau181 (d = 0.46; 95% CI, 0.07-0.85).

Conclusions and relevance: In DIAD, clinical disease stage and BDNF Met66 were associated with cognitive impairment and levels of site-specific tau phosphorylation. This suggests that pharmacological strategies designed to increase neurotrophic support in the presymptomatic stages of AD may be beneficial.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Barthélemy reported a patent pending for cerebrospinal fluid (CSF) tau rate of phosphorylation measurement to define stages of Alzheimer disease and monitor brain kinases/phosphatases activity and a patent pending for novel tau isoforms to predict onset of symptoms and dementia in Alzheimer disease. Dr Goate reported grants from NIH DIAN during conduct of the study and personal fees from consulting or scientific advisory board work for Genentech, AbbVie, UK DRI, Vlaams Instituut voor Biotechnologie (VIB), and Queensland Brain Institute outside the submitted work. Dr Hassenstab reported personal fees from Roche, Eisai, and Parabon Nanolabs outside the submitted work. Dr Fagan reported grants from NIH during the conduct of the study, grants from Centene outside the submitted work, personal fees as a board member for Roche Diagnostics and Diadem outside the submitted work, and consultant fees from DiamiR and Siemens Healthcare Diagnostics, Inc, outside the submitted work. Dr Benzinger reported radiopharmaceutical support from Avid Radiopharmaceuticals, Cerveau, and Life Molecular Imaging; serving on consulting, speakers bureau, and advisory boards for Siemens, Eisai, and Biogen; and serving as an investigator in clinical trials sponsored by Lilly, Roche, Johnson & Johnson, Biogen, and Eisai. Dr Cruchaga reported research support from Biogen, Eisai, Alector, and Parabon and being a member of the advisory boards of Vivid Genetics, Halia Therapeutics, and ADx Healthcare. Dr Levin reported grants from the German Center for Neurodegenerative Diseases (DZNE) during the conduct of the study and the following fees outside the submitted work: compensation from MODAG as part-time chief medical officer; speaker fees from Bayer Vital, Biogen, and Roche; consulting fees from Axon Neuroscience; author fees from Thieme Medical Publishers and W. Kohlhammer; and nonfinancial support from AbbVie. Dr Graff-Radford reported grants from NIH DIAN during the conduct of the study and having taken part in multicenter studies funded by Lilly, Biogen, and AbbVie. Dr Salloway reported grants, personal fees, and nonfinancial support from Biogen; grants and personal fees from Eisai; personal fees and nonfinancial support from Avid; personal fees and nonfinancial support from Novartis; personal fees from Genentech; grants from Lilly; and personal fees and nonfinancial support from Roche, all outside the submitted work. Dr Schofield reported grants from NIH and an anonymous foundation paid through Washington University and grants from Roth Charitable Foundation during the conduct of the study. Dr Morris reported grants from NIH during the conduct of the study. Dr Bateman reported receiving income from C2N Diagnostics for serving on the scientific advisory board and grants from National Institute on Aging (NIA, UFAG032438) during the conduct of the study; funding and nonfinancial support for the DIAN-TU-001 Trial and royalties, funding, and nonfinancial support from members of the DIAN-TU Pharma Consortium, NfL Consortium, and Tau SILK Consortium, which include Avid Radiopharmaceuticals, Janssen, Hoffman La-Roche/Genentech Consulting, Lilly, Eisai Consulting, Biogen, AbbVie, and Bristol Myers Squibb; and personal fees from Amgen Consulting outside the submitted work. Dr McDade reported grants from NIA during the conduct of the study. Drs Barthélemy, Bateman, and McDade are co-inventors of the technology “Methods of diagnosing AD with phosphorylation changes,” licensed by Washington University to C2N Diagnostics. Washington University holds 5% equity in C2N. Through these relationships, Washington University and Drs Barthélemy, Bateman, and McDade are entitled to receive royalties from the license agreement with C2N. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Magnitude of Difference on Each Cognitive and Tau Outcome and Hippocampal Volume Between Mutation Noncarriers and Presymptomatic and Symptomatic Mutation Carriers
A, Magnitude of difference from noncarriers (at 0) with 95% CI for mutation carriers who were presymptomatic, as defined by Clinical Dementia Rating (CDR) global score of 0. B, Magnitude of difference from noncarriers (at 0) with 95% CI for mutation carriers who were symptomatic (CDR global score ≥0.5). DIAN indicates Dominantly Inherited Alzheimer Network; MS, mass spectrometry; p-tau, phosphorylated tau.
Figure 2.
Figure 2.. Associations Between Estimated Year of Expected Symptom Onset (EYO) and Cognitive Outcome and Tau Phosphorylation Occupancy
The cognitive outcomes shown are episodic memory (A) and global cognition (B). Tau phosphorylation occupancy (C and D) is shown at threonine 217 (p-tau181/tau181) and threonine 205 (p-tau205/tau205). Shading represents 95% CI. CDR indicates Clinical Dementia Rating; MC, mutation carrier; p-tau, phosphorylated tau.
See this image and copyright information in PMC

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