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

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;84:424–435.