BDNF Val66Met, Aβ amyloid, and cognitive decline in preclinical Alzheimer's disease

Lim, Yen Ying; Villemagne, Victor L.; Laws, Simon M.; Ames, David; Pietrzak, Robert H.; Ellis, Kathryn A.; Harrington, Karra; Bourgeat, Pierrick; Salvado, Olivier; Darby, David; Snyder, Peter J.; Bush, Ashley I.; Martins, Ralph N.; Masters, Colin L.; Rowe, Christopher C.; Nathan, Pradeep J.; Maruff, Paul

doi:10.1016/j.neurobiolaging.2013.05.006

Cited by 109 publications

(112 citation statements)

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“…This effect is clinically important as the magnitude of memory impairment related to Met 66 mutation carriers was approximately double that observed in Val 66 homozygote mutation carriers. These findings in the DIAN cohort are consistent with the greater memory decline and hippocampal volume loss observed in older adults with preclinical or prodromal sporadic Alzheimer's disease from the AIBL and ADNI studies (Feng et al, 2013;Lim et al, 2013Lim et al, , 2014b. The results confirm therefore, in an independent sample, that BDNF is important to the preclinical presentation of Alzheimer's disease.…”

Section: Discussionsupporting

confidence: 84%

“…The absence of any effect of Met 66 carriage on amyloid-b burden in preclinical ADAD is also consistent with observations that Met carriage was unrelated to rates of cortical amyloid-b accumulation over 3 years in preclinical and prodromal sporadic Alzheimer's disease (Feng et al, 2013;Lim et al, 2013Lim et al, , 2014b. Together, these findings suggest that the effect of the BDNF Met 66 allele is independent of the effect of amyloid-b on risk for, and progression of, Alzheimer's disease.…”

Section: Discussionsupporting

confidence: 82%

“…One possible explanation for this is that GWAS typically use a clinical classification of dementia as the target phenotype. Consequently, they may overlook the contribution of BDNF because the effects of this gene manifest only in the earliest stages of the disease (Feng et al, 2013;Lim et al, 2013Lim et al, , 2014b. This hypothesis is supported by GWAS of cognitive ageing in non-demented older adults, where BDNF Val66Met has been associated with memory impairment and decline (Harris and Deary, 2011;Papenberg et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…In healthy young adults, memory-dependent hippocampal activity is reduced in Met 66 carriers (Hariri et al, 2003). In the preclinical and prodromal stages of sporadic Alzheimer's disease, prospective studies show Met 66 carriers to have increased rates of decline in episodic memory and hippocampal atrophy relative to Val 66 homozygotes (Feng et al, 2013;Lim et al, 2013Lim et al, , 2014b. These same studies observe rates of cortical amyloid-b accumulation to be unaffected by the Met 66 allele (Lim et al, , 2014b, suggesting that BDNF Met 66 may accelerate neuronal dysfunction and memory decline by moderating pathological processes downstream of cortical amyloid-b accumulation, such as tau aggregation.…”

Section: Introductionmentioning

confidence: 99%

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BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

Lim

Hassenstab

Cruchaga

et al. 2016

Brain

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) for a scientific commentary on this article. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-b-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-b in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) "4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation noncarriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-b and cerebrospinal fluid amyloidb 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-b levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-b on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-b in autosomal dominant Alzheimer's disease.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

Lim

Hassenstab

Cruchaga

et al. 2016

Brain

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“…It would have been interesting to know whether particular cerebral regions, especially the hippocampus, were, on the average, smaller in volume in Met carriers than in Val homozygotes. Lim et al (2013) found this to be the case in adult Met carriers with high beta-amyloid who also had lower cognitive performance than Val homozygotes. Thus, our results are in agreement with those of Lim et al…”

Section: Discussionmentioning

confidence: 83%

The Val/Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene predicts decline in perceptual speed in older adults.

Ghisletta¹,

Bäckman²,

Bertram³

et al. 2014

Psychology and Aging

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The brain-derived neurotrophic factor (BDNF) promotes activity-dependent synaptic plasticity, and contributes to learning and memory. We investigated whether a common Val66Met missense polymorphism (rs6265) of the BDNF gene is associated with individual differences in cognitive decline (marked by perceptual speed) in old age. A total of 376 participants of the Berlin Aging Study, with a mean age of 83.9 years at first occasion, were assessed longitudinally up to 11 times across more than 13 years on the Digit-Letter task. Met carriers (n ϭ 123, 34%) showed steeper linear decline than Val homozygotes (n ϭ 239, 66%); the corresponding contrast explained 2.20% of the variance in change in the entire sample, and 3.41% after excluding individuals at risk for dementia. These effects were not moderated by sex or socioeconomic status. Results are consistent with the hypothesis that normal aging magnifies the effects of common genetic variation on cognitive functioning. Keywords: cognitive decline, BDNF Val/Met polymorphism, Berlin Aging StudyIn recent years, the field of cognitive aging has enriched its explanatory scope by paying increasing attention to the effects of genetic and epigenetic variation on individual differences in cognitive performance. Two broad approaches can be distinguished

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Association ofBDNFVal66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease

et al. 2022

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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. RESULTSOf 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). ...

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BDNF Val66Met, Aβ amyloid, and cognitive decline in preclinical Alzheimer's disease

Cited by 109 publications

References 34 publications

BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

The Val/Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene predicts decline in perceptual speed in older adults.

Association ofBDNFVal66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease

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