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Association of Shorter Leukocyte Telomere Repeat Length With Dementia and Mortality

Lawrence S. Honig, MD, PhD; Min Suk Kang, PhD; Nicole Schupf, PhD, MPH; Joseph H. Lee, DrPH, MPH; Richard Mayeux, MD, MSc
Arch Neurol. 2012;69(10):1332-1339. doi:10.1001/archneurol.2012.1541.
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Background  Shortening of chromosomal telomeres is a consequence of cell division and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging.

Objective  To determine whether shorter telomere length (TL), as measured in human blood samples, is associated with the development of Alzheimer disease and mortality.

Design  We studied available stored leukocyte DNA from a community-based study of aging using real-time polymerase chain reaction analysis to determine mean TL in our modification of a method measuring the ratio of telomere sequence to single-copy gene sequence.

Setting  A multiethnic community-based study of aging and dementia.

Participants  One thousand nine hundred eighty-three subjects 65 years or older. Mean (SD) age at blood draw was 78.3 (6.9) years; at death, 86.0 (7.4) years. Median follow-up for mortality was 9.3 years; 190 (9.6%) developed incident dementia.

Results  The TL was inversely related to age and shorter in men than women. Persons dying during follow-up had a shorter TL compared with survivors (mean [SD], 6218 [819] vs 6491 [881] base pairs [bp] [P < .001]), even after adjustment for age, sex, education, and apolipoprotein E genotype. Individuals who developed dementia had significantly shorter TL (mean [SD], 6131 [798] bp for prevalent cases and 6315 [817] bp for incident cases) compared with those remaining dementia-free (6431 [864] bp). Cox-regression analyses showed that shorter TL was a risk for earlier onset of dementia (P = .05), but stratified analyses for sex showed that this association of age at onset of dementia with shorter TL was significant in women only.

Conclusion  Our findings suggest that shortened leukocyte TL is associated with risks for dementia and mortality and may therefore be a marker of biological aging.

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Figures

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Grahic Jump Location

Figure 1. A scatterplot of telomere length (TL) vs age at blood draw reveals that individuals who are older at the time of blood draw have shorter TL. Linear regression analysis of TL vs age at blood draw with sex as a covariate reveals a mean (SD) least-squares decline of 31.1 (2.7) base pairs (bp) per year of age (95% CI, 25.7-36.5; P < .001), with shorter length in men compared with women by a mean (SD) of 128 (41) bp (95% CI, 48-208; P = .002).

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Grahic Jump Location

Figure 2. Survival analyses of mortality and dementia for participants with different telomere lengths (TLs). Cox regression models show the effects of TL quartile on outcomes of mortality or dementia over time, with adjustment for covariates. A, Analysis for the outcome measure of mortality. Compared with the longest quartile TL (quartile 4 [Q4]), the following hazard ratios (HRs) for shorter quartiles were found: 1.72 (95% CI, 1.40-2.11; P < .001) for Q1, 1.57 (95% CI, 1.28-1.94; P < .001) for Q2, and 1.35 (95% CI, 1.09-1.67; P = .005) for Q3. Covariates, with their effect significance, included age at blood draw (P < .001), sex (P < .001), ethnicity (P = .06 for Hispanic), education (P = .08), and apolipoprotein E ϵ4 carrier status (P = .25). B, Outcome measures of dementia for women. C, Outcome measures of dementia for men. When stratified by sex in this fashion, the numbers are small, particularly for men, of whom 56 had incident dementia, compared with women, of whom 134 had incident dementia. Only female participants show a significant effect of shorter TL (Q1, Q2, and Q3) on shorter time to dementia compared with those with longer TL (Q4). Bp indicates base pair; Q1, 5803 bp or less; Q2, 5804 to 6271 bp; Q3, 6272 to 6851 bp; and Q4, 6852 bp or more.

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