Shorter Telomeres in White Blood Cells Linked to Higher Risk of Dementia

Shorter telomeres on the ends of white blood cell chromosomes may signal a heightened dementia risk, suggest the results of a large, long-term study by researchers at Hangzhou Normal University, Zhejiang University School of Medicine, and Capital Medical University.

The team’s analysis of leukocyte telomere length (LTL) data and electronic health records from more than 400,000 U.K. Biobank participants found that shorter LTL was associated with a higher risk of dementia and Alzheimer’s disease (AD).

The shorter blood cell telomere length was linked with smaller total and white matter brain volume, which helps the body process information, and may be a predictor of future brain health, say the researchers. Reporting on their results in General Psychiatry, “Leukocyte telomere length, brain volume and risk of dementia: a prospective cohort study,” Zhi Cao, PhD, Yabing Hou, PhD, and Chenjie Xu, PhD, said the identified link between LTL and dementia could have potential public and clinical applications. “People who inherit shorter LTL may be predisposed to dementia, making LTL an effective biomarker for dementia prevention,” they stated.

The number of people living with dementia is projected to triple in the upcoming 30 years, making dementia one of the greatest challenges for health and social care in the 21st century due to the ageing global population, the authors noted. And while a number of pathological mechanisms underlying dementia have been discovered, “chronological age remains the most important risk factor for dementia.”

Akin to the cap on the end of a shoelace, telomeres are protein-DNA complexes at the end of chromosomes that prevent the loss of coding DNA by a chromosome fraying or unravelling when it replicates, the team further explained. Each time a cell divides, chromosomes replicate, and telomeres shorten slightly, so telomeres have emerged as a promising marker for cellular ageing and the risk of age-related diseases. But studies looking at telomere length and brain health are few and far between. “Because the measurement of leukocyte telomere length (LTL) by quantitative polymerase chain reaction (qPCR) in large-scale population-based studies is impractical, current evidence has yet not supported LTL as a predictive biomarker in disease prevention and screening,” the investigators noted. Even so, a number of small observational studies have reported an association between shortening LTL and age-related diseases such as mild cognitive impairment, dementia and AD. “However, the associations between LTL and these brain-related disorders remain inconsistent.”

For their reported study the researchers drew on data from the U.K. Biobank to look at potential associations between the telomere length of leukocytes and the risk of dementia, including Alzheimer’s disease and vascular dementia, and total and regional brain volumes. The U.K. Biobank is a large biomedical database containing in-depth genetic and health information for around half a million people in the U.K. who were enrolled between 2006 and 2010. “Based on the U.K. Biobank dataset, we aimed to examine the prospective association between LTL and the risk of dementia and to identify the linear associations of LTL with total and regional brain structures,” the scientists stated.

Leukocyte telomere length was measured by analysing blood samples taken at enrolment. These data were available for 439, 961 people aged 37 to 73 at the time (average age 56 years). The proportion of women was 54.1%.

During an average monitoring period of nearly 12 years, 1551 (0.4%) participants were diagnosed with Alzheimer’s disease; 767 (0.2%) with vascular dementia, and 5820 (1.3%) with other type of dementia. And analysis of the data revealed a significant association between leukocyte telomere length and subsequent risk of dementia.

After accounting for sex and age, participants with the shortest leukocyte telomeres were 14% more likely to be diagnosed with dementia and 28% more likely to be diagnosed with Alzheimer’s disease than those with the longest leukocyte telomeres. The risk of vascular dementia was also increased (18%), although this  wasn’t statistically significant.

Brain structure, which had been visualized on MRI full body scans for 38,740 participants, revealed a linear association between shorter leukocyte telomeres and smaller total brain volume, white matter, as well as brain structures including the hippocampus (which is involved in learning and memory), the thalamus (the sensory processing centre), and the nucleus accumbens (also known as the ‘pleasure centre’).

“We found that leukocyte telomere length acts as an aging biomarker associated with the risk of dementia,” the team reported. “Furthermore, we also observed linear associations of leukocyte telomere length with total and regional brain structure.”

The exact biological mechanisms of the observed association between LTL and dementia should be explored, the team continued. In particular “… those pathways that shorten telomeres, modulate the function of immune cells in the central nervous system and induce senescence of T cells in the blood.” More work will be needed to focus on how telomere shortening affects brain structure, they noted. In addition, “Further studies are needed to unravel any underlying biological pathways from LTL to dementia.”

The authors acknowledged that their observational wasn’t designed to establish cause. Even so, they stated, “Compared with prior studies, this study is the largest single-site study of LTL that examined its association with brain volume and dementia.” Strengths of the study include its large sample size, prospective study design and the ability to adjust for potential confounders.

There were also limitations to the study, however, telomere length was measured only once, so it was impossible to find out whether changes over time might have affected the chances of dementia. In addition, telomere length was measured only in leukocytes. And while measurement of telomere length in glial cells (non-neuronal cells in the central nervous system) might have been even more informative, the researchers suggest, these data weren’t available from the U.K. Biobank. In addition, dementia diagnoses were obtained only from electronic health records, which may not have been up to date and may not have mentioned milder forms. Nevertheless, the researchers concluded, “Our findings underscore a relationship between LTL and dementia, providing potential clinical implications.” Since LTL is largely inherited, they pointed out, individuals who inherit shorter LTL may be predisposed to dementia.

This makes LTL “an appealing predictive biomarker for dementia”. In addition, they noted, shorter LTL is widely regarded as an indicator of poorer neuropsychological condition, “… so measurement of LTL might be considered as an option offered to the public to motivate healthy lifestyle choices in the general population.”