Alzheimer’s Disease: Journey into the Dark Genome
SECTION: GENOMICS OF NEURODEGENERATIVE DISEASES AND AGING
(100-plus)
With funding from NWO’s VIDI grant (800,000 euros), Henne Holstege will start a team investigating the heritability of Alzheimer’s Disease to expand the understanding of AD etiology.
The neglected genome
One of the reasons is that, with conventional DNA sequencing or genotyping approaches, we can assess only a fraction of the genetic variation within the genome. Thus far, it has not been possible to systematically investigate the impact of structural variants, such as larger DNA deletions, insertions, duplications, and inversions. However, it is highly likely that a significant fraction of the genetic variations predisposing for AD is located in the this ‘neglected’ or dark genome.
Clues in repetitive DNA patterns
A subset of structural variants is the ‘variable nucleotide tandem repeats’ (VNTRs), which are repetitive stretches of DNA sequence that are highly polymorphic. An increased risk of neurodegenerative diseases, including AD, has been associated with specific VNTRs that exceed a certain size-threshold.
In her VIDI, Henne Holstege proposes to systematically assess the impact of repetitive DNA on AD-risk by examining the characteristics of these structural variants from AD cases and controls.
Dr. Holstege: “We will compare length and sequence of the repetitive sequences between Alzheimer patients and healthy centenarians. The differences between the two groups may reveal additional genetic factors associated with an increased risk of Alzheimer’s Disease.”
Improving risk prediction
The genetically complex nature of AD suggests that each person’s vulnerability for developing Alzheimer’s disease is defined by their unique constellation of genetic risk factors. By considering all risk factors together, it is possible to estimate a personalized polygenic risk score which, when combined with other factors like lifestyle and environment, gives the best approximation of how likely and at what age a person may develop AD.
“Prevention is the best cure. Therefore, my aim is to improve the accuracy of genetic risk prediction algorithms by finding and including novel structural variants that are linked to AD. In the future, better prediction of risk before onset of symptoms will allow us to identify who should be treated and how, so that AD-associated brain damage can be prevented,” concludes Dr. Holstege.
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