Effect of BDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease

on behalf of the Dominantly Inherited Alzheimer Network

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Objective: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181, and whether these increases are associated with accelerated brain volume loss and memory decline. Methods: A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network. Results: In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical β-amyloid accumulation or change in CSF Aβ42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical β-amyloid accumulation, or change in any CSF measures of tau, ptau181, and CSF Aβ42. Interpretation: As in sporadic AD, the deleterious effects of β-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018.

Original languageEnglish (US)
JournalAnnals of Neurology
DOIs
StateAccepted/In press - Jan 1 2018

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Cerebrospinal Fluid
Alzheimer Disease
Brain-Derived Neurotrophic Factor
Mutation
Amyloid
Cognition
Homozygote
Brain
Memory Disorders
Neuroimaging
Dementia
Genotype
Clinical Trials

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Effect of BDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease. / on behalf of the Dominantly Inherited Alzheimer Network.

In: Annals of Neurology, 01.01.2018.

Research output: Contribution to journalArticle

on behalf of the Dominantly Inherited Alzheimer Network. / Effect of BDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease. In: Annals of Neurology. 2018.
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title = "Effect of BDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease",
abstract = "Objective: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181, and whether these increases are associated with accelerated brain volume loss and memory decline. Methods: A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network. Results: In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical β-amyloid accumulation or change in CSF Aβ42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical β-amyloid accumulation, or change in any CSF measures of tau, ptau181, and CSF Aβ42. Interpretation: As in sporadic AD, the deleterious effects of β-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018.",
author = "{on behalf of the Dominantly Inherited Alzheimer Network} and Lim, {Yen Ying} and Jason Hassenstab and Alison Goate and Fagan, {Anne M.} and Benzinger, {Tammie L.S.} and Carlos Cruchaga and Eric McDade and Jasmeer Chhatwal and Johannes Levin and Martin Farlow and Graff-Radford, {Neill R.} and Christoph Laske and Masters, {Colin L.} and Stephen Salloway and Peter Schofield and Morris, {John C.} and Paul Maruff and Bateman, {Randall J.}",
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T1 - Effect of BDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease

AU - on behalf of the Dominantly Inherited Alzheimer Network

AU - Lim, Yen Ying

AU - Hassenstab, Jason

AU - Goate, Alison

AU - Fagan, Anne M.

AU - Benzinger, Tammie L.S.

AU - Cruchaga, Carlos

AU - McDade, Eric

AU - Chhatwal, Jasmeer

AU - Levin, Johannes

AU - Farlow, Martin

AU - Graff-Radford, Neill R.

AU - Laske, Christoph

AU - Masters, Colin L.

AU - Salloway, Stephen

AU - Schofield, Peter

AU - Morris, John C.

AU - Maruff, Paul

AU - Bateman, Randall J.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Objective: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181, and whether these increases are associated with accelerated brain volume loss and memory decline. Methods: A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network. Results: In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical β-amyloid accumulation or change in CSF Aβ42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical β-amyloid accumulation, or change in any CSF measures of tau, ptau181, and CSF Aβ42. Interpretation: As in sporadic AD, the deleterious effects of β-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018.

AB - Objective: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181, and whether these increases are associated with accelerated brain volume loss and memory decline. Methods: A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network. Results: In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical β-amyloid accumulation or change in CSF Aβ42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical β-amyloid accumulation, or change in any CSF measures of tau, ptau181, and CSF Aβ42. Interpretation: As in sporadic AD, the deleterious effects of β-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018.

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