Our results support the concept that the interaction of higher serum cholesterol levels with APOEε4 genotype accelerate metabolic decline in AD-related brain regions. Associations were greater in the right hemisphere. Regions affected include the right precuneus (peak t(491) = -3.93, p<0.0001) and the right posterior cingulate gyrus (peak t(491) = -4.12, p<0.0001). We found a negative correlation between cholesterol levels and the 2-year CMRglc variation rates in brain regions affected in early stages of AD, which was driven by the interaction with APOEε4 status (Figure 1). No significant associations were observed at baseline. APOEε4 genotype was used as both, a covariate or an interaction factor. Age, gender, BMI, cholesterol treatment and diagnostic group were set as covariates for adjustment. Voxel-wise general linear modelling was used to assess the baseline association between total serum cholesterol levels and cerebral metabolic rate for glucose (CMRglc), as well as cholesterol’s impact over the 2-year’s rate of metabolic decline.

We evaluated 499 cognitively unimpaired and mild cognitive impaired elderly subjects (age>55 years) from Alzheimer's Disease Neuroimaging Initiative (ADNI) with available total serum cholesterol measurements at baseline and longitudinal FDG-PET scans. We hypothesized that elevated total serum cholesterol levels accelerate metabolic decline in AD-related brain regions. Here, we investigated whether total serum cholesterol levels are associated with cerebral metabolic decline.

Therefore, whether high serum cholesterol levels accelerate brain metabolic decline in older subjects remains a key question to be answered. Since hypometabolism is a pivotal marker of AD progression, understanding the impact of peripheral cholesterol levels over the brain’s metabolic state in older adults has become crucial to clarify these seemingly conflicting findings. However, observational studies in late-life subjects suggested that high cholesterol levels reduce the risk of dementia. Epidemiological investigations have shown that midlife elevated total serum cholesterol levels increase the risk of Alzheimer’s disease (AD).

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