Can we achieve precise medication use in people living with Alzheimer’s disease?

Alzheimer’s disease (AD) is the most common form of dementia, affecting 1 in 9 people >65 years. AD is featured by progressive neuron loss in the brain and decline in cognitive function. However, recent evidence suggests that AD may also affect peripheral organs. In line with this, we have for the first time demonstrated that the expression and function of drug transporters and metabolising enzymes in the peripheral organs are altered in AD mouse models, leading to altered drug disposition. Some of these changes have been validated in AD human tissues, however, if drug disposition is affected in people with AD is yet to be determined.

Polypharmacy, or the use of multiple medications, is prevalent in older populations and people with AD are prescribed 5-10 more medications than their peers. This heightened polypharmacy places people with AD at a greater risk of adverse drug reactions (ADRs), particularly if the disease alters the drug disposition. For nearly all medications, medical practice is based on single disease guidelines derived from clinical trials that do not include people with AD. If drug disposition is altered in AD, a standard dose may produce unexpected therapeutic outcomes (e.g. increased risk of ADRs) in people with AD. People with cognitive impairment are also less likely to report ADRs, which presents an additional challenge in caring for people with AD and is likely to lead to suboptimal healthcare outcomes.

In this project, we will use high-throughput proteomics to profile drug transporter and drug metabolising enzyme expression in AD and non-AD human tissues, leading to the development of a physiologically based pharmacokinetic models for dose adjustment in people with AD. These models will be validated using plasma samples collected via Australian Imaging, Biomarker & Lifestyle (AIBL) study of aging. The ultimate goal of this research program is to achieve precise medication use in people with AD.