Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development

Author:

Ahmed Hazem12ORCID,Wang Yuqin3,Griffiths William J3,Levey Allan I4,Pikuleva Irina5ORCID,Liang Steven H6,Haider Ahmed678ORCID

Affiliation:

1. Department of Radiology and Biomedical Imaging, Yale School of Medicine, Yale University , New Haven, CT 06510 , USA

2. Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Institute of Pharmaceutical Sciences ETH , 8093 Zurich , Switzerland

3. Institute of Life Science, Swansea University Medical School , Swansea SA2 8PP , UK

4. Department of Neurology, Emory University School of Medicine , Atlanta, GA 30322 , USA

5. Department of Ophthalmology and Visual Sciences, Case Western Reserve University , Cleveland, OH 44106 , USA

6. Department of Radiology and Imaging Sciences , Emory University School of Medicine, Atlanta, GA 30322 , USA

7. Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School , Boston, MA 02114 , USA

8. Department of Nuclear Medicine, University Hospital Zurich, University of Zurich , 8091 Zurich , Switzerland

Abstract

Abstract Cholesterol homeostasis is impaired in Alzheimer's disease; however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of Alzheimer's disease. Indeed, neuronal cholesterol was linked to the formation of amyloid-β and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies. Furthermore, remarkable advances in translational molecular imaging have now made it possible to probe cholesterol metabolism in the living human brain with PET, which is an important prerequisite for future clinical trials that target the brain cholesterol machinery in Alzheimer's disease patients—with the ultimate aim being to develop disease-modifying treatments. This work summarizes current concepts of how the biosynthesis, transport and clearance of brain cholesterol are affected in Alzheimer's disease. Further, current strategies to reverse these alterations by pharmacotherapy are critically discussed in the wake of emerging translational research tools that support the assessment of brain cholesterol biology not only in animal models but also in patients with Alzheimer's disease.

Funder

Swiss National Science Foundation

NIH

Emory Radiology Chair Fund and Emory School of Medicine Endowed Directorship

Swansea University

Publisher

Oxford University Press (OUP)

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