Genetically predicted telomere length and Alzheimer’s disease endophenotypes: a Mendelian randomization study

Telomere length (TL) is associated with biological aging, consequently influencing the risk of age-related diseases such as Alzheimer's disease (AD). We aimed to evaluate the potential causal role of TL in AD endophenotypes (i.e., cognitive performance, N = 2233; brain age and AD-related signatures, N = 1134; and cerebrospinal fluid biomarkers (CSF) of AD and neurodegeneration, N = 304) through a Mendelian randomization (MR) analysis. Our analysis was conducted in the context of the ALFA (ALzheimer and FAmilies) study, a population of cognitively healthy individuals at risk of AD. A total of 20 single nucleotide polymorphisms associated with TL were used to determine the effect of TL on AD endophenotypes. Analyses were adjusted by age, sex, and years of education. Stratified analyses by APOE-epsilon 4 status and polygenic risk score of AD were conducted. MR analysis revealed significant associations between genetically predicted longer TL and lower levels of CSF A beta and higher levels of CSF NfL only in APOE-epsilon 4 non-carriers. Moreover, inheriting longer TL was associated with greater cortical thickness in age and AD-related brain signatures and lower levels of CSF p-tau among individuals at a high genetic predisposition to AD. Further observational analyses are warranted to better understand these associations

Demographic and global cognitive characteristics of the participants.

<p>Note: Values are given in mean (SD). MMSE^a, mini-mental state examination. (M/W) M, male; W, women. WAIS: Wechsler Adult Intelligence Scale. RAVLT: Rey-Auditory Verbal Learning test (delayed recall). VR-WMS-R: Visual Reproduction, Wechsler Memory Scale Revised (delayed recall). t = Student's test. U = U-Mann Whitney test.</p

Effects of rTMS in the DMN present in deactivation task-related networks.

<p>While both groups exhibited increased temporal correlations between the timecourse of this network and rest condition after rTMS, its activity (intensity of the expression) clearly diverged. In the bar graphs it is shown that DMN activity decreased for ε4 non-carriers whereas increased for the ε4-carriers. Corr: Correlation values (r-Pearson) between the timecourse of each network and the ‘resting condition’. Intensity values are thresholded at z = 2.3. Coordinates are given in MNI (x = −4, z = 26). A.U = arbitrary units.</p

Brain Networks related with encoding and subsequent memory performance.

<p>Brain Networks related with encoding and subsequent memory performance.</p

Independent components (networks) that were significantly correlated with the deactivation period (DTBRP = deactivation-task brain related pattern).

<p>Networks are separated for each condition (pre-post TMS) and group (ε4 carriers-noncarriers). DTRP = Dectivation Task Related Patterns. Coordinates are given in MNI space. Intensity values are thresholded at z = 2.3. Brain areas of each network are fully described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051833#pone-0051833-t004" target="_blank">table 4</a>.</p

Effects of rTMS in the DMN present in deactivation task-related networks.

<p>While both groups exhibited increased temporal correlations between the timecourse of this network and rest condition after rTMS, its activity (intensity of the expression) clearly diverged. In the bar graphs it is shown that DMN activity decreased for ε4 non-carriers whereas increased for the ε4-carriers. Corr: Correlation values (r-Pearson) between the timecourse of each network and the ‘resting condition’. Intensity values are thresholded at z = 2.3. Coordinates are given in MNI (x = −4, z = 26). A.U = arbitrary units.</p

Measures of recognition memory before (pre) and after (post) rTMS.

<p>Values are given in mean (ranges). t = repeated measures t test comparing pre vs post rTMS in the whole sample. F = results of the interaction value of the two-factor ANOVA using genetic subgroup as the between subject factor and moment of the evaluation (PRE vs POST) as within subject factor.</p

Independent components (IC, networks) that were highly correlated with the encoding period and performance (ATBRP = activation-task brain related pattern).

<p>Networks are separated for each condition (pre-post TMS) and group (ε4 carriers-noncarriers). Coordinates are given in MNI space. Intensity values are thresholded at z = 2.3. Brain areas of each network are fully described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051833#pone-0051833-t003" target="_blank">table 3</a>.</p