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Alzheimer’s disease is a multifactorial disorder with a heterogeneous patient population. Comorbidities such as hypertension, hypercholesterolemia and diabetes are known contributors to the disease progression. Indeed, therapies targeting these disorders have been shown efficient in dementia prevention. However, their mechanistic contribution to Alzheimer’s pathology and neurodegeneration has not been fully clarified.In the current study, we used CSF samples from a memory clinic cohort of 90 patients without diagnosed hypertension, hypercholesterolemia, or diabetes nor other neurodegenerative disorder, to investigate 13 molecular markers representing key mechanisms underlying Alzheimer’s pathogenesis. Levels were compared between clinical groups of subjective cognitive decline, mild cognitive impairment, and Alzheimer’s disease. Associations between markers and groups of markers were analyzed by linear regression. Two-step cluster analysis was used to determine patient clusters. Two key markers were further analyzed by immunofluorescence staining in hippocampus from control and AD individuals without hypertension, hypercholesterolemia nor diabetes.CSF angiotensinogen, thioredoxin-1, and interleukin-15 were the biomarkers with the most prominent associations with Alzheimer’s pathology, synaptic and axonal damage. Synaptosomal-associated protein 25 kDa and neurofilament light chain were increased in mild cognitive impairment and Alzheimer cases. When we grouped biomarkers by biological function, we found that inflammatory and survival components were associated with Alzheimer’s pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In data-driven analysis, two patient clusters were identified; Older participants with increased CSF markers of oxidative stress, vascular pathology and neuroinflammation were assigned to cluster 1, that was also smaller and characterized by increased synaptic and axonal damage, compared to individuals in cluster 2. Clinical groups were evenly distributed between the clusters.Analysis of post-mortem hippocampal tissue, showed that, compared to controls, angiotensinogen staining was higher in Alzheimer’s disease and was also found to co-localize with phosphorylated-tau.In a population free of common comorbidities, we could still find associations between Alzheimer’s disease biomarkers and markers of pathways associated with increased risk for Alzheimer’s disease (i.e., neuroinflammation, vascular function, oxidative stress and cholesterol homeostasis), suggesting that these pathways are contributing to Alzheimer’s disease mechanisms even in absence of clinically diagnosed comorbidities. The identification of distinct biomarker-driven endophenotypes of cognitive disorder patients, further highlights the biological heterogeneity of Alzheimer’s disease and the importance of developing tailored prevention and treatment strategies.

Background: Midlife hypercholesterolemia is a risk factor for dementia, possibly via vascular-related pathways. Another proposed factor linking elevated systemic cholesterol levels and neurodegenerative diseases is the oxidized cholesterol metabolite 27-hydroxycholesterol (27-OH) that is able to pass the blood-brain barrier. High levels of 27-OH harm neuronal integrity and function, yet the effect of high 27-OH levels on oligodendrocyte function remains unexplored. Since abnormal myelin structure results in the disconnection of neural networks that is an early phenomenon in neurodegenerative diseases, this study aimed to determine whether 27-OH affects myelination in the brain. Methods: Effects of 27-OH treatment were investigated both in isolated and co-cultured oligodendrocytes. Transgenic female mice with increased systemic 27-OH levels (Cyp27Tg) underwent behavioural testing and their brains were immunohistochemically stained and lysed for immunoblotting. CSF samples from a memory clinic cohort were analysed for associations between 27-OH and myelin proteins. Results: Whereas human oligodendroglioma cells were resistant to high levels of 27-OH (10 µM), cell death was induced in primary rat oligodendrocytes already at low concentrations (0.5 µM). Long-term effects from treatment with 1 µM 27-OH stimulated differentiation of oligodendrocytes in murine 3D co-cultures. Female Cyp27Tg mice demonstrated learning deficits in the Morris Water Maze compared to non-transgenic littermates. Levels of myelin basic protein were increased in the corpus callosum of Cyp27Tg mice but adenomatous polyposis coli clone 1 (CC1) and platelet-derived growth factor receptor α (PDGFR1α) were unaltered, while levels of myelin oligodendrocyte glycoprotein were decreased in myelin enriched fractions. Levels of 27-OH in the CSF of memory clinic patients were associated with increased levels of the oligodendrogenesis regulating enzyme 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNPase; β = 0.38, p = 0.022). Conclusions: The hypercholesterolemia associated 27-OH alters the rate of differentiation from progenitor cells into mature oligodendrocytes and influences oligodendrocyte viability suggesting that 27-OH reduces the oligodendrocytic ability for appropriate remodelling in the ageing brain by reducing the pool of progenitor cells.