Pros and Cons of APOE4 Homozygosity and Effects on Neuroplasticity, Malnutrition, and Infections in Early Life Adversity, Alzheimer’s Disease, and Alzheimer’s Prevention

Article type: Review Article

Authors: Oriá, Reinaldo B.^{a; *} | Smith, Carr J.^b | Ashford, J. Wesson^{c; d; *} | Vitek, Michael P.^e | Guerrant, Richard L.^f

Affiliations: [a] Department of Morphology, Laboratory of Tissue Healing, Ontogeny, and Nutrition, School of Medicine, Institute of Biomedicine, Federal University of Ceara, Fortaleza, Brazil | [b] Society for Brain Mapping and Therapeutics, Pacific Palisades, CA, USA | [c] War Related Illness and Injury Study Center, VA Palo Alto Health Care System, Palo Alto, CA, USA | [d] Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA | [e] Department of Neurology, Duke University Medical Center, Durham, NC, USA | [f] Department of Medicine, Division of Infectious Diseases and International Health, School of Medicine, University of Virginia, Charlottesville, VA, USA

Correspondence: [*] Correspondence to: Reinaldo B. Oriá, Department of Morphology, Laboratory of Tissue Healing, Ontogeny, and Nutrition, School of Medicine, Institute of Biomedicine, Federal University of Ceara, Fortaleza, Brazil. E-mail: oria@ufc.br and J. Wesson Ashford, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA. E-mail: ashford@stanford.edu.

Abstract: Fortea et al.’s. (2024) recent data analysis elegantly calls attention to familial late-onset Alzheimer’s disease (AD) with APOE4 homozygosity. The article by Grant (2024) reviews the factors associated with AD, particularly the APOE genotype and lifestyle, and the broad implications for prevention, both for individuals with the lifestyles associated with living in resource-rich countries and for those enduring environmental adversity in poverty settings, including high exposure to enteric pathogens and precarious access to healthcare. Grant discusses the issue of APOE genotype and its implications for the benefits of lifestyle modifications. This review highlights that bearing APOE4 could constitute an evolutionary benefit in coping with heavy enteric infections and malnutrition early in life in the critical formative first two years of brain development. However, the critical issue may be that this genotype could be a health concern under shifts in lifestyle and unhealthy diets during aging, leading to severe cognitive impairments and increased risk of AD. This commentary supports the discussions of Grant and the benefits of improving lifestyle for decreasing the risks for AD while providing further understanding and modelling of the early life benefits of APOE4 amidst adversity. This attention to the pathophysiology of AD should help further elucidate these critical, newly appreciated pathogenic pathways for developing approaches to the prevention and management in the context of the APOE genetic variations associated with AD.

Keywords: Alzheimer’s disease, APOE, Apolipoprotein E, malnutrition, neuroplasticity, prevention

DOI: 10.3233/JAD-240888

Journal: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S179-S185, 2024