The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=−0.053; 95% CI: −0.087, −0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10⁻⁵), whereas carriers performed better in STROOP (β=−0.074; 95% CI: −0.140, −0.009; P=0.03). Causal associations were found for STROOP only (β=−0.598 per s.d.-increase of TL; 95% CI: −1.125, −0.072; P=0.026), with a larger effect in ɛ4-carriers (β=−0.699; 95% CI: −1.330, −0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.

Epigenetic alterations during aging have been proposed to contribute to decline in physical and cognitive functions, and accelerated epigenetic aging has been associated with disease and all-cause mortality later in life. In this study, we estimated epigenetic age dynamics in groups with different memory trajectories (maintained high performance, average decline, and accelerated decline) over a 15-year period. Epigenetic (DNA-methylation [DNAm]) age was assessed, and delta age (DNAm age - chronological age) was calculated in blood samples at baseline (age: 55-65 years) and 15 years later in 52 age- and gender-matched individuals from the Betula study in Sweden. A lower delta DNAm age was observed for those with maintained memory functions compared with those with average (p = 0.035) or accelerated decline (p = 0.037). Moreover, separate analyses revealed that DNAm age at follow-up, but not chronologic age, was a significant predictor of dementia (p = 0.019). Our findings suggest that young epigenetic age contributes to maintained memory in aging.

Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided. Genome wide promoter DNA methylation analysis was performed in pediatric T-ALL samples (n = 43) using arrays covering >27000 CpG sites. Clinical outcome was evaluated in relation to methylation status and compared with a contemporary T-ALL group not tested for methylation (n = 32). Based on CpG island methylator phenotype (CIMP), T-ALL samples were subgrouped as CIMP+ (high methylation) and CIMP− (low methylation). CIMP− T-ALL patients had significantly worse overall and event free survival (p = 0.02 and p = 0.001, respectively) compared to CIMP+ cases. CIMP status was an independent factor for survival in multivariate analysis including age, gender and white blood cell count. Analysis of differently methylated genes in the CIMP subgroups showed an overrepresentation of transcription factors, ligands and polycomb target genes. We identified global promoter methylation profiling as being of relevance for subgrouping and prognostication of pediatric T-ALL.

The tumor cells in diffuse large B‐cell lymphomas (DLBCL) are considered to originate from germinal center derived B‐cells (GCB) or activated B‐cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC‐based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non‐GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression‐free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression‐free survival differed significantly. Importantly, patients assigned as non‐GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.

Cancer cells display DNA hypermethylation at specific CpG islands in comparison with their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T cells and that display a reciprocal association with H3K27me3 binding. In addition, we reveal that this aberrant methylation profile reflects the epigenetic history of T-ALL and is established already in preleukemic, self-renewing thymocytes that precede T-ALL development. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature in T-ALL is completely resistant to the FDA-approved hypomethylating agent decitabine. Altogether, we provide conceptual evidence for the involvement of a preleukemic phase characterized by self-renewing thymocytes in the pathogenesis of human T-ALL. Significance: We developed a DNA methylation signature that reveals the epigenetic history of thymocytes during T-cell transformation. This human signature was recapitulated by murine self-renewing preleukemic thymocytes that build an age-related CpG island hypermethylation phenotype, providing conceptual evidence for the involvement of a preleukemic thymic phase in human T-cell leukemia. This article is highlighted in the In This Issue feature, p. 215