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 analysed 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 the cause-specific risk of AD between 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.

Mid-life leukocyte telomere length and dementia risk: a prospective cohort study of 435,046 UK Biobank participants

“…Contrary to our findings, Fani et al [36] reported a U-shaped relationship between TL and risk of AD, where both shorter and longer TL were associated with a higher AD risk. Significantly higher risk of AD with shorter leukocyte TL was also reported in non- APOE e4-carriers only in a prospective population cohort [37]. While previous MR studies reported a protective effect of genetically determined longer TL on AD risk [38,39], we did not find significant genetic associations with AD/ADRD or its subtypes in our MR analyses.…”

“…Significantly higher risk of AD with shorter leukocyte TL was also reported in non-APOE e4carriers only in a prospective population cohort [37]. While previous MR studies reported a protective effect of genetically determined longer TL on AD risk [38,39], we did not find significant genetic associations with AD/ADRD or its subtypes in our MR analyses.…”

Mid‐life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants

“…Longer TL also was associated with a lower risk of AD/ADRD across APOE genotypes (e3e3, e2, or e4). In contrast, a Sweden study (Hackenhaar et al, 2021) showed the association between short TL (first tertile) and a higher risk of AD in APOE non-e4 carriers only.…”

Twenty-year longitudinal evaluation of blood-based DNA methylation biomarkers for early prediction of Alzheimer’s disease

“…Relative leukocyte telomere length (RTL) was compared to the novel DNAm biomarkers, as an established blood-based biomarker previously associated with increased AD incidence in non-APOE ε4-carriers in our sample [63]. Peripheral blood leukocytes DNA was used to estimate normalized RTL as previously described [63,64], using a modi ed Cawthon's polymerase chain reaction method [65,66]. Preliminary visual inspection of our data indicated a potential differential RTL attrition between cases and controls.…”