Hypercholesterolemia and Alzheimer’s Disease: Unraveling the Connection and Assessing the Efficacy of Lipid-Lowering Therapies

Issue title: Therapeutic Trials in Alzheimer’s Disease: Where Are We Now?

Guest editors: Paula I. Moreira, Jesus Avila, Daniela Galimberti, Miguel A. Pappolla, Germán Plascencia-Villa, Aaron A. Sorensen, Xiongwei Zhu and George Perry

Article type: Review Article

Authors: Pappolla, Miguel A.^{a; *} | Refolo, Lorenzo^b | Sambamurti, Kumar^c | Zambon, Daniel^d | Duff, Karen^e

Affiliations: [a] Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA | [b] Translational Research Branch, Division of Neuroscience, Bethesda, MD, USA | [c] Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA | [d] Universitat Internacional de Catalunya, Barcelona, Spain | [e] Karen Duff, UK Dementia Research Institute at University College London, London, UK

Correspondence: [*] Correspondence to: Miguel A. Pappolla, Professor of Neurology, Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA. E-mail: [email protected].

Abstract: This article examines the relationship between cholesterol levels and Alzheimer’s disease (AD), beginning with the early observation that individuals who died from heart attacks often had brain amyloid deposition. Subsequent animal model research proved that high cholesterol could hasten amyloid accumulation. In contrast, cholesterol-lowering treatments appeared to counteract this effect. Human autopsy studies reinforced the cholesterol-AD connection, revealing that higher cholesterol levels during midlife significantly correlated with higher brain amyloid pathology. This effect was especially pronounced in individuals aged 40 to 55. Epidemiological data supported animal research and human tissue observations and suggested that managing cholesterol levels in midlife could reduce the risk of developing AD. We analyze the main observational studies and clinical trials on the efficacy of statins. While observational data often suggest a potential protective effect against AD, clinical trials have not consistently shown benefit. The failure of these trials to demonstrate a clear advantage is partially attributed to multiple factors, including the timing of statin therapy, the type of statin and the appropriate selection of patients for treatment. Many studies failed to target individuals who might benefit most from early intervention, such as high-risk patients like APOE4 carriers. The review addresses how cholesterol is implicated in AD through various biological pathways, the potential preventive role of cholesterol management as suggested by observational studies, and the difficulties encountered in clinical trials, particularly related to statin use. The paper highlights the need to explore alternate therapeutic targets and mechanisms that escape statin intervention.

Keywords: Alzheimer’s disease, amyloid, cholesterol, clinical trials, hypercholesterolemia, lipids, statins

DOI: 10.3233/JAD-240388

Journal: Journal of Alzheimer's Disease, vol. 101, no. s1, pp. S371-S393, 2024