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BACKGROUND: Alzheimer's disease (AD) patients display alterations in cerebrospinal fluid (CSF) and plasma sphingolipids. The APOE4 genotype increases the risk of developing AD.OBJECTIVE: To test the hypothesis that the APOE4 genotype affects common sphingolipids in CSF and in plasma of patients with early stages of AD.METHODS: Patients homozygous for APOE4 and non-APOE4 carriers with mild cognitive impairment (MCI; n = 20 versus 20) were compared to patients with subjective cognitive decline (SCD; n = 18 versus 20). Sphingolipids in CSF and plasma lipoproteins were determined by liquid-chromatography-tandem mass spectrometry. Aβ42 levels in CSF were determined by immunoassay.RESULTS: APOE4 homozygotes displayed lower levels of sphingomyelin (SM; p = 0.042), SM(d18:1/18:0) (p = 0.026), and Aβ42 (p 0.49; p CONCLUSION: The APOE4 genotype affects sphingolipid profiles of CSF and plasma lipoproteins already at early stages of AD. ApoE4 may contribute to the early development of AD through modulation of sphingolipid metabolism.

Background Axons, crucial for impulse transmission and cellular trafficking, are thought to be primary targets of neurodegeneration in Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Axonal degeneration occurs early, preceeding and exceeding neuronal loss, and contributes to the spread of pathology, yet is poorly described outside the nigrostriatal circuitry. The insula, a cortical brain hub, was recently discovered as highly vulnerable to pathology and plays a role in cognitive deficits in PD and DLB. The aim of this study was to evaluate morphological features and burden of proteinopathy and axonal degeneration in the anterior insular sub-regions in PD, PD with dementia (PDD), and DLB. Methods α-Synuclein (α-syn), phosphorylated (p-)tau, and amyloid-β pathology load were evaluated in the anterior insula (agranular and dysgranular) subregions of brain donors (n = 27). Axonal loss was evaluated using modified Bielschowsky silver staining and quantified using stereology. Cytoskeletal damage was comprehensively studied using immunofluorescent multi-labelling and 3D confocal laser-scanning microscopy. Results Compared to PD(D), DLB showed significantly higher α-syn and p-tau pathology load, argyrophilic grains, and most severe axonal loss, particularly in the anterior agranular insula. Alternatively, the dysgranular insula showed a significant higher load of amyloid-β pathology. Using mixed model analysis, p-tau contributed most to axonal loss in the DLB group, highest in the anterior agranular insula. Neurofilament and myelin showed degenerative changes including swellings, demyelination, and detachment of the axon-myelin unit. Conclusions Our results highlight the selective vulnerability of the anterior agranular insular sub-region to various converging pathologies, leading to impaired axonal integrity in PD(D) and DLB, disrupting its functional properties and potentially contributing to cognitive, emotional, and autonomic deficits.