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BDNF, Synaptic Dysfunction and Cognitive Decline in Pre-Clinical Alzheimer’s Disease: Development of Biomarkers of Synapse Function and Cognitive Decline for Synapse Repair Therapies

Pradeep J. Nathan1, 2*, Paul Maruff3 and Edward Bullmore2
  • 1 UCB Pharma, United Kingdom
  • 2 University of Cambridge, Psychiatry, United Kingdom
  • 3 Cogstate Ltd, Australia

Introduction

Synaptic dysfunction is a core pathophysiological hallmark for Alzheimer’s disease (AD) leading to cognitive deficits. BDNF is a key synaptogenic molecule that modulates synaptic and cognitive function and is an attractive pharmacological target for cognitive enhancement. In this study we used a genetic approach (i.e. BDNF val66met polymorphism) to identify BDNF sensitive biomarkers of cognitive and synaptic dysfunction that could be utilized to monitor the disease progression and efficacy of synaptic repair therapies. First, we compared a number of “synaptic” and cognitive markers in individuals carrying val/val, val/met, met/met genotypes (Study 1). Second, we examined the interaction between BDNF and Aβ loading (PiB PET) on cognitive decline and hippocampal volume (Study 2).

Methods

For study 1, 60 healthy subjects (20 val/val; 20 val/met and 20 met/met) were recruited. For study 2, 165 healthy older subjects (107 val/val and 58 met carriers) and 34 patients with mild cognitive impairment (MCI) (24 val/val and 10 met carriers) were recruited.

Results

Compared to val homozygotes, met carries (val/met and met/met) showed evidence of “inefficient” synaptic activity as demonstrated by impaired EEG activity (i.e. decreased delta power and phase synchrony) during cognitive processing in an error related negativity task of executive function (all p<0.05) (Figure 1), increased frontal and parietal resting theta EEG power i (all p<0.05), and increased hippocampal (p<0.05) activation during retrieval of a memory task. Compared to val/val homozygotes with high Aβ amyloid (i.e. PIB+), healthy elderly subjects carrying BDNF-met genotype showed significant and moderate-to-large magnitude decline in episodic memory, executive function, and language, as well as greater reductions in hippocampal volume over 36 months (all p<0.05; cohen’s d between 0.73 and 0.8).

Conclusion

Using BDNF val66met polymorphism, we have identified several BDNF sensitive biomarkers of cognitive and synaptic that may potentially be used in AD clinical trials to monitor both disease progression and drug efficacy. We have also demonstrated that Aβ loading (i.e. PIB+) combined with BDNF-met genotype is associated with greater neurodegeneration and cognitive decline. The latter finding is the first evidence linking BDNF and cognitive decline in preclinical AD and highlights the promise of synaptic repair therapies targeting the BDNF system for ameliorating cognitive dysfunction in AD.

Acknowledgements

This work was conducted at GlaxoSmithKline Pharmaceutical in collaboraiton with the University of Cambridge and the Australian Imaging Biomarker and Lifestyle (AIBL) longitudinal study.

Keywords: BDNF, Alzhimer´s disease, Memory, synapse function, brain imaging

Conference: ACNS-2013 Australasian Cognitive Neuroscience Society Conference, Clayton, Melbourne, Australia, 28 Nov - 1 Dec, 2013.

Presentation Type: Oral

Topic: Memory

Citation: Nathan PJ, Maruff P and Bullmore E (2013). BDNF, Synaptic Dysfunction and Cognitive Decline in Pre-Clinical Alzheimer’s Disease: Development of Biomarkers of Synapse Function and Cognitive Decline for Synapse Repair Therapies. Conference Abstract: ACNS-2013 Australasian Cognitive Neuroscience Society Conference. doi: 10.3389/conf.fnhum.2013.212.00172

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Received: 15 Oct 2013; Published Online: 25 Nov 2013.

* Correspondence: Prof. Pradeep J Nathan, UCB Pharma, Cambridge, United Kingdom, pn254@cam.ac.uk