B2824 - Early biomarkers of Alzheimers disease Studying the effects of genetic risk on late myelinating brain regions at midlife - 03/07/2018

B number: 
B2824
Principal applicant name: 
Claudia Metzler-Baddeley | Cardiff University Brain Research Imaging Centre (CUBRIC) (UK)
Co-applicants: 
Professor Risto Kauppinen, Dr Dennis Chan, University of Cambridge, Dr Rebecca Sims, Professor Derek Jones
Title of project: 
Early biomarkers of Alzheimer's disease: Studying the effects of genetic risk on late myelinating brain regions at midlife
Proposal summary: 

To date all drug trials aimed at slowing the progression of late onset Alzheimer’s disease (LOAD) have failed. To a large extent this is due to treatments being given too late in the disease, when people have established memory impairments. As such there is a major need to identify LOAD in its very earliest stages, many years prior to symptom onset at midlife. The aim of this study is to meet this need by detecting changes within the enthorinal cortex (EC)-hippocampal-fornix circuit, representing the first brain regions affected by LOAD.
To do so, this study will investigate people at genetic risk of LOAD in midlife. It is well known that people with the ApoE4 gene are at higher risk of LOAD but more recent genome-wide association studies have now shown other genes whose collective risk for LOAD can be quantified as polygenetic risk score (PRS). This study will therefore test the hypothesis that the EC-hippocampus-fornix circuit is disrupted in people at risk of LOAD (ApoE4 positive and high PRS). Circuit structure will be investigated using high gradient MRI to measure tissue properties of the hippocampus and its connections (notably the fornix) focusing on pathway size, density and insulation (myelin sheaths). Circuit function will be tested in the form of spatial navigation and memory, respectively evaluating the EC, hippocampus and fornix function.
If successful, we will both aid diagnosis of presymptomatic LOAD and provide a means of stratifying at-risk individuals for future treatment trials aimed at prevent the onset of LOAD.

Impact of research: 
This study may lead to the identification of the earliest warning signs for risk of LOAD in midlife in brain structures known to show the earliest neuropathology of LOAD. The study will provide important insights into the underlying mechanisms. For instance if we found genetic risk related selective degeneration of myelin sensitive MRI metrics in late myelinating regions e.g. in the fornix without any evidence of grey matter changes in the hippocampus then this would suggest that white matter/myelin damage may precede neuronal death in grey matter regions. Such evidence would provide the rational for developing therapeutics that slow down myelin breakage (e.g. DHA, anti-inflammatories).
Date proposal received: 
Wednesday, 18 January, 2017
Date proposal approved: 
Wednesday, 25 January, 2017
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Cognitive impairment, Late onset Alzheimer's disease (LOAD), dementias, GWAS, Medical imaging, NMR, Statistical methods, Cognitive assessment; high gradient diffusion MRI and tractography, Ageing, Biological samples -e.g. blood, cell lines, saliva, etc., Cognition - cognitive function, Equipment - MRI, Intelligence - memory