Abstract
APOE-ε4 is a main genetic risk factor for developing late onset Alzheimer’s disease (LOAD) and is thought to interact adversely with other risk factors on the brain. However, evidence regarding the impact of APOE-ε4 on grey matter structure in asymptomatic individuals remains mixed. Much attention has been devoted to characterising APOE-ε4-related changes in the hippocampus, but LOAD pathology is known to spread through the whole of the Papez circuit including the limbic thalamus. Here, we tested the impact of APOE-ε4 and two other risk factors, a family history of dementia and obesity, on grey matter macro- and microstructure across the whole brain in 165 asymptomatic individuals (38–71 years). Microstructural properties of apparent neurite density and dispersion, free water, myelin and cell metabolism were assessed with Neurite Orientation Density and Dispersion (NODDI) and quantitative magnetization transfer (qMT) imaging. APOE-ε4 carriers relative to non-carriers had a lower macromolecular proton fraction (MPF) in the left thalamus. No risk effects were present for cortical thickness, subcortical volume, or NODDI indices. Reduced thalamic MPF may reflect inflammation-related tissue swelling and/or myelin loss in APOE-ε4. Future prospective studies should investigate the sensitivity and specificity of qMT-based MPF as a non-invasive biomarker for LOAD risk.
Highlights
Apolipoprotein E (APOE)-ε4 is a main genetic risk factor for developing late onset Alzheimer’s disease (LOAD) and is thought to interact adversely with other risk factors on the brain
We explored with two separate analyses of covariances whether controlling for differences in (i) systolic and diastolic blood pressure (BP) and (ii) inflammation-related measures of C-Reactive Protein (CRP), Interleukin-8 (IL-8) and leptin/adiponectin ratio (LAR) would account for the effect of APOE on left thalamus macromolecular proton fraction (MPF)
We investigated whether quantitative MRI (qMRI) indices of apparent neurite density and dispersion, free water, myelin, and cell metabolism were sensitive to grey matter differences related to LOAD risk in cognitively healthy individuals
Summary
APOE-ε4 is a main genetic risk factor for developing late onset Alzheimer’s disease (LOAD) and is thought to interact adversely with other risk factors on the brain. We tested the impact of APOE-ε4 and two other risk factors, a family history of dementia and obesity, on grey matter macro- and microstructure across the whole brain in 165 asymptomatic individuals (38–71 years). LOAD is characterized by the development of amyloid-β plaques and neurofibrillary tau tangles that spread from limbic regions to neocortical a reas[2,3,4] As these pathological processes are thought to accumulate over many years[5], it may be possible to identify brain changes related to heightened risk in asymptomatic individuals prior to the onset of memory impairment. Sample size n Age (in years) Females NART-IQ MMSE FH + APOE4 + WHR Systolic BP (mm Hg) Diastolic BP (mm Hg) Smokers Diabetes Alcohol units per week PHQ-9 Depression score
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