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The isoform E4 of the Apolipoprotein E (ApoE) represents one of the strongest genetic risk factors for late-onset Alzheimer's disease (AD). ApoE has key roles in cholesterol transport and amyloid-β (Aβ) metabolism, which are both central to AD pathogenesis. The E4 isoform has been implicated in reduced cholesterol homeostasis, increased Aβ aggregation, and heightened tau phosphorylation, contributing to amyloid plaques and neurodegeneration. This manuscript examines the complex interactions among ApoE isoforms, cholesterol metabolism, and amyloid pathology. Moreover, the therapeutic challenges associated with lipid-lowering agents (e.g., statins, PCSK9 inhibitors), anti-amyloid immunotherapies, and anticoagulants are described, focusing on ApoE4 carriers. Decision-making challenges are discussed by analyzing the pros and cons of these therapies.

Nanotechnology is transforming therapeutics for brain disorders, especially in developing drug delivery systems. Intrathecal immunoselective nanopheresis with soluble monoclonal antibodies represents an innovative approach in the realm of drug delivery systems for Central Nervous System conditions, especially for targeting soluble beta-amyloid in Alzheimer's disease. This review delves into the concept of intrathecal immunoselective nanopheresis. It provides an overall description of devices to perform this technique while discussing the nanotechnology behind its mechanism of action, its potential advantages, and clinical implications. By exploring current research and advancements, we aim to provide a comprehensive understanding of this novel method, addressing the critical questions of what it is, how it works, why it is needed, and when it should be applied. Special attention is given to patient selection and the optimal timing for therapy initiation in Alzheimer's, coinciding with the peak accumulation of amyloid oligomers in the early stages. Potential limitations and alternative targets beyond beta-amyloid and future perspectives for immunoselective nanopheresis are also described.

Unlabelled: Cerebral amyloid angiopathy (CAA) might alter cerebral hemodynamics. Impairment of vasomotor reactivity may constitute a biomarker of amyloid angiopathy and therefore it may be useful to distinguish disorders with CAA from other conditions. The aim of this study was to assess the vasomotor reactivity in two conditions characterized by CAA: Alzheimer's disease and amyloid hemorrhage., Methods: We assessed the vasomotor using transcranial Doppler and the breath-holding method., Results: Responses obtained in controls were higher than in patients with Alzheimer's or with antecedent of amyloid hemorrhage while there was no statistical difference in the comparison between these last two groups., Conclusion: The vasomotor reactivity seems to be similarly impaired in Alzheimer's disease and amyloid hemorrhage patients., (Copyright © 2009 by the American Society of Neuroimaging.)

The search for molecular biomarkers for diagnosing and classifying dementias is becoming a high priority need. Neurosin (Kallikrein 6, hk6) is one molecule with promising preliminary results since its levels in brain tissue, cerebrospinal fluid and blood have been found to be abnormal in Alzheimer's disease (AD). In this study, we measured plasmatic levels of neurosin in healthy individuals and patients with cognitive symptoms independently of what the final diagnosis was. We collected plasma samples from 228 controls and 447 patients finally diagnosed with either AD, Mild Cognitive Impairment, Dementia with Lewy Bodies or Parkinson-Dementia, Frontotemporal Dementia, Huntington's disease, Primary Progressive Aphasia, Corticobasal degeneration, Creutzfeldt-Jakob's disease or Pseudodementia. We found that plasmatic levels of neurosin increase with age in healthy individuals and decrease in patients with AD. Plasmatic levels of neurosin differ significantly between AD and Vascular Dementia, Pseudodementia and the control group. Analyses comparing any other form of neurodegenerative dementia to the AD group did not show significant differences. In conclusion, measurement of plasmatic levels of neurosin is useful to distinguish AD patients from subjects without neurodegenerative dementia (either Pseudodementia, Vascular Dementia or controls) although it is not useful to distinguish among neurodegenerative dementias.