Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers

Abstract

Background: Leukocyte telomere length (LTL) has been shown to predict Alzheimer's disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor.

Methods: We analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards.

Results: After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1-24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404-7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947-2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD.

Conclusions: Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research.

Keywords: Competing risks; Death; Dementia; Leukocyte telomere length; Risk factors; Time-to-event analysis; Vascular dementia.

Fig. 1

Cumulative incidence plots estimating the incidence of individuals progressing to Alzheimer’s disease (AD) for (a) non-apolipoprotein E ε4-carriers (non-APOE ε4-carriers) and (b) APOE ε4-carriers according to residualized leukocyte telomere length (rLTL) tertiles. The Fine-Gray hazard function was estimated for a representative 65-year-old female with high levels of cholesterol (> 240 mg/dL), and median values of pulse pressure, plasma glucose, erythrocyte sedimentation rate, lymphocyte proportion, and age squared, including time interactions for short telomere length and lymphocyte proportion in non-APOE ε4-carriers

Fig. 2

Cause-specific hazard ratio plot estimating the risk of individuals to progress to Alzheimer’s disease (AD) in (a) non-apolipoprotein E ε4-carriers (non-APOE ε4-carriers) and (b) APOE ε4-carriers, according to residualized leukocyte telomere length (rLTL) tertiles. The cause-specific hazard function was estimated for a representative female of 65 years old, with high cholesterol levels (> 240 mg/dL), and median values of pulse pressure, plasma glucose, erythrocyte sedimentation rate, lymphocyte proportion, and age squared