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

dc.contributor.authorLim, Yen Ying
dc.contributor.authorMaruff, Paul
dc.contributor.authorBarthélemy, Nicolas R.
dc.contributor.authorGoate, Alison
dc.contributor.authorHassenstab, Jason
dc.contributor.authorSato, Chihiro
dc.contributor.authorFagan, Anne M.
dc.contributor.authorBenzinger, Tammie L. S.
dc.contributor.authorXiong, Chengjie
dc.contributor.authorCruchaga, Carlos
dc.contributor.authorLevin, Johannes
dc.contributor.authorFarlow, Martin R.
dc.contributor.authorGraff-Radford, Neill R.
dc.contributor.authorLaske, Christoph
dc.contributor.authorMasters, Colin L.
dc.contributor.authorSalloway, Stephen
dc.contributor.authorSchofield, Peter R.
dc.contributor.authorMorris, John C.
dc.contributor.authorBateman, Randall J.
dc.contributor.authorMcDade, Eric
dc.contributor.authorDominantly Inherited Alzheimer Network
dc.contributor.departmentNeurology, School of Medicine
dc.date.accessioned2024-04-30T18:09:40Z
dc.date.available2024-04-30T18:09:40Z
dc.date.issued2022-03-01
dc.description.abstractImportance: 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.
dc.identifier.citationLim YY, Maruff P, Barthélemy NR, et al. Association of BDNF Val66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease [published correction appears in JAMA Neurol. 2022 Mar 1;79(3):313]. JAMA Neurol. 2022;79(3):261-270. doi:10.1001/jamaneurol.2021.5181
dc.identifier.urihttps://hdl.handle.net/1805/40379
dc.language.isoen_US
dc.publisherAmerican Medical Association
dc.relation.isversionof10.1001/jamaneurol.2021.5181
dc.relation.journalJAMA Neurology
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectAlzheimer disease
dc.subjectBrain-derived neurotrophic factor
dc.subjectPositron-emission tomography
dc.subjectMemory disorders
dc.titleAssociation of BDNF Val66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease
dc.typeArticle
ul.alternative.fulltexthttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804973/
Files
Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
Lim2022Association-PP.pdf
Size:
836.66 KB
Format:
Adobe Portable Document Format
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.99 KB
Format:
Item-specific license agreed upon to submission
Description: