Cholesterol metabolites and plant sterols in cerebrospinal fluid are associated with Alzheimer’s cerebral pathology and clinical disease progression

This graphical abstract shows the most important associations between non-cholesterol sterols, oxysterols and Alzheimers’ disease (AD) pathologys’ core biomarkers, as well as associations between sterols and clinical scores. On the right side the individual associations are displayed by bidirectional arrows between the sterols and the biomarkers. We present associations of CSF desmosterol with Aß1−42 and of CSF campesterol with tau and sitosterol with tau and p-tau. Additionally, we show associations of CSF 24S−OHC with tau and p-tau and between the ratio of 24S−OHC/ 27−OHC with tau and p-tau. On the left side the impact of desmosterol on the scores of CDRSoB and MMSE are indicated. As well as the influence of the ratio of 24S−OHC to 27−OHC on score changes of CDRSoB and of the plant sterols, campesterol and sitosterol, on the score changes of MMSE. [Display omitted] •Aß1−42 indicates influence of brain cholesterol synthesis in amyloidogenesis.•Involvement of plant sterols in tau pathology and neurodegeneration.•CNS cholesterol degradation influences neurodegeneration and tau pathology.•CSF desmosterol indicates clinical disease severity.•CSF Plant sterols and 24S−OHC/ 27−OHC predetermine disease progression over time. Altered cholesterol metabolism is associated with increased risk of neurodegeneration and in particular with the development of Alzheimer’s disease (AD). Here, we investigate whether non-cholesterol sterols and oxysterols in the central nervous system are associated with (i) the presence of cerebral AD pathology, (ii) distinct aspects of AD pathology, i.e. amyloid pathology, neuronal injury, and tau pathology, and (iii) cognitive decline over time. One hundred forty-two elder subjects with normal cognition, mild cognitive impairment, or mild dementia participating in a cohort study on cognitive decline and AD were included. Clinical and neuropsychological assessments were performed at inclusion and repeated at follow-up visits at 18 and 36 months. Concentrations of cholesterol, non-cholesterol sterols, and cholesterol metabolites were measured in cerebrospinal fluid (CSF), along with CSF beta-amyloid (Aβ)1−42; Aβ1−42/Aβ1−40 ratio, total-tau (tau), and tau phosphorylated at threonine 181 (p-tau) as markers of amyloid pathology, neuronal injury and tau pathology, respectively. Cognitive decline was assessed by changes in Mini-Mental State Examination and Clinical Dementia Rating sum of boxes at follow-up visits. CSF 24S-hydroxycholesterol (24S