RESUMO
BACKGROUND: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, has shown promise for Alzheimer's disease (AD) prediction. OBJECTIVE: Testing long-term predictive ability (>15 years) of existing DNAm-based epigenetic age acceleration (EAA) measures and identifying novel early blood-based DNAm AD-prediction biomarkers. METHODS: EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models (LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16 years before clinical onset, and post-onset follow-up. Novel DNAm biomarkers were generated with epigenome-wide LMMs, and Sparse Partial Least Squares Discriminant Analysis applied at pre- (10-16 years), and post-AD-onset time-points. RESULTS: EAA did not differentiate cases from controls during the follow-up time (pâ>â0.05). Three new DNA biomarkers showed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions (p-values: 0.022-<0.00001). Our longitudinally-derived panel replicated nominally (pâ=â0.012) in an external cohort (nâ=â146 cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOEÉ4-carriership (ORâ=â1.38 per 1 SD DNAm score increase versus ORâ=â13.58 for É4-allele carriage; AUCsâ=â77.2% versus 87.0%). Literature review showed low overlap (nâ=â4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with our identified CpGs.
Assuntos
Doença de Alzheimer , Metilação de DNA , Feminino , Humanos , Masculino , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Biomarcadores , Epigênese Genética , Estudos ProspectivosRESUMO
The hippocampus is affected early in Alzheimer's disease (AD) and altered hippocampal functioning influences normal cognitive aging. Here, we used task-based functional MRI to assess if the APOE É4 allele or a polygenic risk score (PRS) for AD was linked to longitudinal changes in memory-related hippocampal activation in normal aging (baseline age 50-95, n = 292; n = 182 at 4 years follow-up, subsequently non-demented for at least 2 years). Mixed-models were used to predict level and change in hippocampal activation by APOE É4 status and PRS based on gene variants previously linked to AD at p ≤ 1, p < 0.05, or p < 5e-8 (excluding APOE). APOE É4 and PRSp<5e-8 significantly predicted AD risk in a larger sample from the same study population (n = 1542), while PRSp≤1 predicted memory decline. APOE É4 was linked to decreased hippocampal activation over time, with the most prominent effect in the posterior hippocampi, while PRS was unrelated to hippocampal activation at all p-thresholds. These results suggests a link for APOE É4, but not for AD genetics in general, on functional changes of the hippocampi in normal aging.