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Telomere Shortening a Cause of Alzheimer's Disease?

A new study provides evidence for the first time of a causal relationship between telomere length (TL) and Alzheimer's disease (AD), say investigators from Sweden.

"This is the first study addressing the causal effect of TL on AD," principal investigator Sara Hägg, PhD, docent of molecular epidemiology, Karolinska Institutet, Stockholm, told Medscape Medical News.

Telomeres are repetitive DNA sequences at the ends of chromosomes that progressively shorten with age. Observational studies suggest that shorter telomeres are associated with shorter life expectancy and greater risk for age-related diseases, including AD. However, these studies could have residual confounding or reverse causation, making it difficult to draw conclusions on whether TL is causally associated with AD.

Dr Hägg and colleagues investigated the causal effect of TL on AD by applying instrumental variable analysis and Mendelian randomization methods to genome-wide association study (GWAS) data.

The Mendelian randomization analysis "has the advantage of being independent of any measured or unmeasured confounders by using genetic variants" as instrumental variables, the authors explain in a Research Letter in the October issue of JAMA Neurology.

They report that a genetic risk score for TL, including 7 single-nucleotide polymorphisms (SNPs) known to be involved in TL and AD, was significantly associated with shorter telomeres and higher risk for AD (odds ratio [OR], 1.02 for per TL-decreasing allele).

Shorter TL was causally associated with a higher risk for AD (OR, 1.36 per SD decrease of TL; P = .002), Dr Hägg and colleagues report. They "roughly estimate" that 1 SD decrease in TL to be equal to an attrition rate of 1226 TL base pairs in 40 to 60 years, "corresponding to a 36% higher risk for AD."

"We knew there was an association (between TL and AD), but most researchers did not think telomeres were involved in the actual mechanism itself but rather a biomarker of the underlying pathological process," Dr Hägg told Medscape Medical News. "There is an ongoing discussion in the field concerning the cause or consequence of telomeres in aging related diseases. This paper adds information in this regards," she said.

"The effects are small," she noted, "and one cannot measure the lengths of the telomeres and know the individual biological age. There are in fact companies in the US offering this service, which I think is questionable. However, increasing knowledge of how the mechanisms for disease works is always promising for future therapeutics," Dr Hägg said.

This study was funded by grants from the Karolinska Institutet, the Loo & Hans Osterman Foundation, the Foundation for Geriatric Diseases, the Swedish Council for Working Life and Social Research, and the Swedish Research Council. The authors have disclosed no relevant financial relationships.

http://www.medscape.com/viewarticle/853530