Molecule in blood linked to cognitive decline in old age

A new study has found a molecule that could serve as a biomarker to identify those at greater risk of developing dementia in later life. It could also help scientists develop preventive treatments.

Dementia is a debilitating condition that involves the progressive decline of memory, communication, and thinking.

Globally, the number of people with this condition has more than doubled, rising from 20.2 million in 1990 to 43.8 million in 2016.

The most common form of dementia is Alzheimer’s disease, which accounts for 60-70% of all cases. As populations age, the prevalence of Alzheimer’s and other forms of dementia is expected to continue rising.

Currently, once symptoms occur, they cannot be reversed. With this in mind, researchers are exploring ways to diagnose the condition years or even decades before it develops, and find drugs to prevent its progress.

One promising biomarker of Alzheimer’s is a molecule that circulates in the blood, known as asymmetric dimethylarginine (ADMA).

By inhibiting an enzyme called nitric oxide synthase, ADMA reduces the amount of nitric oxide synthesized by the endothelial cells that line blood vessels.

The role of nitric oxide is to dilate blood vessels, increasing blood flow. When levels are abnormally low, it restricts blood flow to tissues, starving them of oxygen and triggering inflammation.

The importance of childhood intelligence

Low levels of nitric oxide are linked to the development of atherosclerosis, cardiovascular disease, and Alzheimer’s. A few small studies have also found a link between high concentrations of ADMA and cognitive decline in older people.

However, none of these studies have adjusted for the effect of low intelligence in childhood, which accounts for up to 50% of cognitive decline in old age.

Now, researchers at the University of Aberdeen and the University of Oxford in the United Kingdom, and Flinders University in Melbourne, Australia, have found a breakthrough.

They analyzed data from 63-year-olds, who had all taken the same mental ability test at Scottish schools in 1947 when they were 11 years of age.

Two decades ago, the 1936 Aberdeen Birth Cohort was established by medical researchers to follow this unique set of people.

Between 2000 and 2004, 93 of them took part in a research project to study cognitive aging and health. Blood samples were taken in 2000, and the participants underwent a series of cognitive tests at regular intervals over the next 4 years.

After adjusting for their childhood intelligence test scores, the authors of the new study found a link between raised ADMA concentrations in their blood and a decline in cognitive performance four years later.

The researchers now report these findings in a study published in the International Journal of Geriatric Psychiatry.

An early warning sign?

Poor cognitive performance late in middle age is an established risk factor for the development of dementia.

“Therefore the results of this study suggest that ADMA, an easily measurable marker of atherosclerosis and cardiovascular risk, could be an early indicator of cognitive decline in old age — and possibly dementia,” says study author Prof. Arduino Mangoni, head of clinical pharmacology at Flinders University.

However, the study accounts for too few participants to draw definitive conclusions.

“We should be cautious about emphasizing the results with the 93 participants’ results here,” says lead author Dr. Deborah Malden, from the Nuffield Department of Population Health at the University of Oxford.

“We would know much more after repeating this study in a large-scale cohort, potentially tens of thousands of individuals.”

Future research could include genetic information about participants and involve repeated measurements of ADMA at regular intervals, rather than the single analysis used in this study.

Ideally, there would also be follow-up with participants for longer than 4 years.

In addition, the present study could not rule out the possibility of reverse causality. In other words, individuals with early dementia may have changed their resulting behavior, which in turn could have affected their ADMA levels.

Shared pathway

If future research confirms the results of this preliminary study, however, existing drugs could be deployed as preventive treatments.

The investigators write:

“Importantly, ADMA concentrations can be modulated by pharmacological interventions, and therefore ADMA may prove valuable as a future prevention strategy for dementia and [Alzheimer’s disease].”

Intriguingly, previous studies suggest that high levels of ADMA in the bloodstream are a common factor in the development of a wide range of diseases, say the researchers.

High concentrations are linked to type 2 diabetes, chronic obstructive pulmonary disease (COPD), and depression, as well as cardiovascular disease and dementia.

This suggests that a single drug could help address the wide range of medical conditions that develop from this shared metabolic pathway.