. Effect of apolipoprotein e genotype and diet on apolipoprotein e lipidation and amyloid peptides: randomized clinical trial. JAMA Neurol. 2013 Aug 1;70(8):972-80. PubMed.

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  1. This is an interesting study showing that both soluble Aβ and apolipoprotein E (ApoE) exist in lipid-depleted cerebrospinal fluid (CSF), and that ApoE4 is linked to cognitive impairment. The results fit well with what we have hypothesized for 20 years: Patients with Alzheimer’s disease bear disease-related metabolic conditions in the central nervous system (CNS), where interaction between lipoproteins and soluble Aβ is impaired, leading to Aβ assembly. According to our experiments, the conversion of lipoprotein-free monomeric soluble Aβ42 into oligomers preferentially occurs in AD CSF. Furthermore, the accumulation of de-lipidated soluble 12-mers precedes the appearance of neuronal loss or cognitive impairment and is enhanced as the Braak neurofibrillary tangle stages progress, confirming that the entorhinal cortex of AD patients establishes metabolic conditions that accelerate Aβ assembly. Although direct evidence is not available in the current paper, the authors propose that lipoprotein-free ApoE may preferentially interact with lipoprotein-free soluble Aβ, inducing and/or maintaining an abnormal β-sheet conformation that initiates a cascade favoring Aβ assembly in an ApoE isoform-dependent manner.

    Another important finding is that diet can improve the above-mentioned risk environment in the brain via the modulation of insulin, which regulates cholesterol metabolism in the CNS. Since cholesterol metabolism in the CNS is quite different from that in systemic circulation, therapeutic intervention for disease-related lipidic environments via insulin appears sound.

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