BDNF VAL66MET INCREASES RATE OF MEMORY DECLINE, HIPPOCAMPAL VOLUME LOSS AND TAU ACCUMULATION IN AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE

Abstract

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) is implicated in synaptic excitation and neuronal integrity. In autosomal dominant Alzheimer's disease (ADAD), mutation carriers (MC) who also carry the Met66 allele show worse memory and higher levels of cerebrospinal fluid (CSF) tau, but equivalent amyloid levels compared to MC Val66 homozygotes at baseline. The aim of this study was to determine the extent to which the BDNF Val66Met polymorphism affects changes in memory, brain volume, tau and Aβ in ADAD prospectively. Prospective neuropsychological, biomarker and neuroimaging data collected from the Dominantly Inherited Alzheimer Network (DIAN) over ∼2 years were analyzed in 81 preclinical mutation carriers (MC), all with a clinical dementia rating (CDR) score of 0 and estimated to be 11 years prior to clinical symptom onset, and 78 matched mutation non-carriers (NC). BDNF genotype was obtained for MCs (58 Val66 homozygotes, 23 Met66 carriers). Compared to MC Val66 homozygotes, MC Met66 carriers showed greater decline in episodic memory (p<.001), loss of hippocampal volume (p=.005), and increase of CSF tau (p<.001) (Figure 1). Cortical Aβ accumulation was equivalent between MC Val66 homozygotes and MC Met66 carriers (p=.427) (Figure 1). Compared to NCs, MC Val66 homozygotes showed greater increase in cortical Aβ accumulation (p<.001) but equivalent rates of change in episodic memory decline (p=.700), loss of hippocampal volume (p=.215), and accumulation of CSF tau (p=.266) (Figure 1). ADAD is associated with pathologically increased rates of Aβ and tau accumulation, loss of hippocampal volume and decline in episodic memory. The results of the current study show that for MCs who also carry the BDNF Met66 allele, decline in episodic memory, loss of hippocampal volume and increase in CSF tau is substantially greater than for MCs who are Val66 homozygotes, despite equivalent rates of Aβ accumulation. This is consistent with findings in preclinical sporadic AD, where amyloid positive Met66 carriers also show faster deterioration in episodic memory and hippocampal volume, but not Aβ accumulation, when compared to Aβ+ Val66 homozygotes. Together, these data suggest that the BDNF Val66Met polymorphism modifies the contributions to the neurodegenerative process in ADAD. Episodic memory performance, hippocampal volume, Aβ, and tau in preclinical MC Val66 homozygotes (blue lines) and preclinical MC Met66 carriers (red lines) when compared to mutation non-carriers (black lines).