Using genetics to understand causes of Alzheimer's

Neuropsychiatric and neurogenerative disorders have poorly defined neurobiological bases. They involve many genes and potentially thousands of genetic variants. This makes it difficult to map biological pathways, particularly as living brain tissue cannot be studied. Novel methods to explore causation and identify biomarkers are therefore crucial for these disorders, and more so than for other medical specialties.

Blood metabolites as markers for disease

Blood metabolites – small molecules such as lipids and vitamins – can represent the crosstalk between genetics and environmental influences and provide a snapshot of health status. Metabolites are easy to measure and are potentially modifiable through diet and medication. This makes them useful as markers of disease and as promising targets for intervention.

Most dementias, including Alzheimer’s disease (AD), have a long pre-symptomatic phase, and targets for early intervention must be identified during this phase. Metabolites are potentially important markers of this pre-symptomatic stage as the brain is enriched in lipids, and genes involved in lipid processes are associated with Alzheimer's.

Our work focuses on the discovery of Alzheimer's-linked metabolites early in disease, in collaboration with the MRC Unit for Lifelong Ageing at UCL and funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre, Alzheimer’s Research UK and the van Geest Endowment Fund.

Mapping metabolites to brain structure and outcomes

We characterised the metabolic basis of outcomes related to early dementia and demonstrated that networks of fatty acids were associated with worse cognition and decreased brain volumes. We also found a network of sphingolipids associated with improved outcomes, although only the association with brain volumes survived adjustment for social factors and childhood cognition (see also research published in this pre-print).

Using Mendelian Randomisation, a method that uses genetic information to explore causal effects, we further showed that higher levels of some molecules in the blood seemed to protect against Alzheimer's whilst others - particularly those involved in inflammation - increased risk (see research published in Biological Psychiatry). All these associations need further investigation as potential targets for intervention.

Future research into risk factors

Our next research studies aim to understand how metabolites influence risk factors for Alzheimer's, such as diabetes, hypertension or depression, and how they interact with proteins and the established Alzheimer's markers of amyloid status and phosphorylated tau.

This work highlights new mechanistic and developmental pathways in Alzheimer's disease. From a public health perspective, metabolome biomarkers provide a powerful roadmap for effective and individualized early intervention strategies, through lifestyle alterations and drug repurposing.

 

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