Protective genetic variants against Alzheimer's disease.

1. Lancet Neurol. 2025 Jun;24(6):524-534. doi: 10.1016/S1474-4422(25)00116-4. Protective genetic variants against Alzheimer's disease. Marino C(1), Malotaux V(2), Giudicessi A(3), Aguillon D(4), Sepulveda-Falla D(5), Lopera F(4), Quiroz YT(6). Author information: (1)The Schepens Eye Research Institute of Mass Eye and Ear and the Department of Ophthalmology at Harvard Medical School, Boston, MA, USA; Department of Neurology, Sealy Institute for Drug Discovery and Mitchell Center for Neurodegenerative Diseases, The University of Texas Medical Branch, Galveston, TX, USA. (2)Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. (3)Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Boston University, Department of Psychological and Brain Sciences, Boston, MA, USA. (4)The Neuroscience Group of Antioquia, School of Medicine, University of Antioquia, Medellín, Colombia. (5)The Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. (6)Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Boston University, Department of Psychological and Brain Sciences, Boston, MA, USA; The Neuroscience Group of Antioquia, School of Medicine, University of Antioquia, Medellín, Colombia; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: yquiroz@mgh.harvard.edu. Genetic studies can offer powerful insights for the development of disease-modifying therapies for Alzheimer's disease. Protective genetic variants that delay the onset of cognitive impairment have been found in people with sporadic Alzheimer's disease and in carriers of mutations that usually cause autosomal-dominant Alzheimer's disease in mid-life. The study of families who carry autosomal dominant mutations provides a unique opportunity to uncover genetic modifiers of disease progression, including rare variants in genes such as APOE and RELN. Understanding how these variants confer protection can help identify the biological pathways that contribute to cognitive resilience, such as the heparan-sulphate proteoglycan-APOE receptor pathway, the TREM-2-driven signalling pathways in the microglia, and phagocytosis. Therapies able to replicate the beneficial effects of these natural defences could provide novel strategies for slowing or preventing the progression of Alzheimer's disease. Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies. DOI: 10.1016/S1474-4422(25)00116-4 PMCID: PMC12614636 PMID: 40409316 [Indexed for MEDLINE] Conflict of interest statement: Declaration of interests YTQ and FL are named as co-inventors in patents filed by Mass General Brigham-related Alzheimer's therapeutics targeting APOE and Reelin. YTQ and FL serve as consultants for Biogen. All other authors declare no competing conflicts.