27-Hydroxycholesterol, cognition, and brain imaging markers in the FINGER randomized controlled trial

Abstract

Background: 27-Hydroxycholesterol (27-OH), the main circulating oxysterol in humans and the potential missing link between peripheral hypercholesterolemia and Alzheimer's disease (AD), has not been investigated previously in relation to cognition and neuroimaging markers in the context of preventive interventions.

Methods: The 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) included older individuals (60-77 years) at increased risk for dementia but without dementia or substantial cognitive impairment from the general population. Participants were randomized to a multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice) in a 1:1 ratio. Outcome assessors were masked to group allocation. This FINGER exploratory sub-study included 47 participants with measures of 27-OH, cognition, brain MRI, brain FDG-PET, and PiB-PET. Linear regression models were used to assess the cross-sectional and longitudinal associations between 27-OH, cognition, and neuroimaging markers, considering several potential confounders/intervention effect modifiers.

Results: 27-OH reduction during the intervention was associated with improvement in cognition (especially memory). This was not observed in the control group. The intervention reduced 27-OH particularly in individuals with the highest 27-OH levels and younger age. No associations were found between changes in 27-OH levels and neuroimaging markers. However, at baseline, a higher 27-OH was associated with lower total gray matter and hippocampal volume, and lower cognitive scores. These associations were unaffected by total cholesterol levels. While sex seemed to influence associations at baseline, it did not affect longitudinal associations.

Conclusion: 27-OH appears to be a marker not only for dementia/AD risk, but also for monitoring the effects of preventive interventions on cholesterol metabolism.

Trial registration: ClinicalTrials.gov , NCT01041989 . Registered on 4 January 2010.

Keywords: 27-Hydroxycholesterol; Biomarkers; Cholesterol metabolism; Dementia; Multimodal intervention.

Fig. 1

CONSORT diagram of the FINGER exploratory 27-hydroxycholesterol sub-study. CERAD, Consortium to Establish a Registry for Alzheimer’s Disease

Fig. 2

FINGER intervention effects on the change in 27-OH. Participants were divided into two groups according to their baseline 27-OH levels: the lowest 75% (quartiles 1–3, white boxplots) and the highest 25% (quartile 4, gray boxplots). The graph shows the mean change in 27-OH levels (ng/ml) between the 2-year and baseline measurements. Mann-Whitney non-parametric U test was used to analyze the differences between quartiles 1–3 and 4 of the intervention group (^##< 0.01) and between quartile 4 of the control and intervention group (*p < 0.05)