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cause of dementia, and it is significantly influenced by the apolipoprotein E4 (APOE4) gene and gender. This study aimed to use machine learning (ML) algorithms to predict brain age and assess AD risk by considering the effects of the APOE4 genotype and gender. Methods: We collected brain volumetric MRI data and medical records from 1100 cognitively unimpaired individuals and 602 patients with AD. We applied three ML regression models\u2014XGBoost, random forest (RF), and linear regression (LR)\u2014to predict brain age. Additionally, we introduced two novel metrics, brain age difference (BAD) and integrated difference (ID), to evaluate the models\u2019 performances and analyze the influences of the APOE4 genotype and gender on brain aging. Results: Patients with AD displayed significantly older brain ages compared to their chronological ages, with BADs ranging from 6.5 to 10 years. The RF model outperformed both XGBoost and LR in terms of accuracy, delivering higher ID values and more precise predictions. Comparing the APOE4 carriers with noncarriers, the models showed enhanced ID values and consistent brain age predictions, improving the overall performance. Gender-specific analyses indicated slight enhancements, with the models performing equally well for both genders. Conclusions: This study demonstrates that robust ML models for brain age prediction can play a crucial role in the early detection of AD risk through MRI brain structural imaging. The significant impact of the APOE4 genotype on brain aging and AD risk is also emphasized. These findings highlight the potential of ML models in assessing AD risk and suggest that utilizing AI for AD identification could enable earlier preventative interventions.<\/jats:p>","DOI":"10.3390\/bioengineering11090943","type":"journal-article","created":{"date-parts":[[2024,9,20]],"date-time":"2024-09-20T07:38:57Z","timestamp":1726817937000},"page":"943","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Machine Learning-Driven Prediction of Brain Age for Alzheimer\u2019s Risk: APOE4 Genotype and Gender Effects"],"prefix":"10.3390","volume":"11","author":[{"given":"Carter","family":"Woods","sequence":"first","affiliation":[{"name":"Department of Physics, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Nebraska Omaha, Omaha, NE 68182, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subash","family":"Khanal","sequence":"additional","affiliation":[{"name":"Department of Computer Science & Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai-Ling","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Radiology, Biology and Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65211, USA"},{"name":"Sanders-Brown Center on Aging, Department for Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/alz.12694","article-title":"Global Estimates on the Number of Persons across the Alzheimer\u2019s Disease Continuum","volume":"19","author":"Gustavsson","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41514-024-00136-6","article-title":"Cost of Care for Alzheimer\u2019s Disease and Related Dementias in the United States: 2016 to 2060","volume":"10","author":"Nandi","year":"2024","journal-title":"Npj Aging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s004010050717","article-title":"Changes in Weight and Compositions of Major Membrane Components of Human Brain during the Span of Adult Human Life of Swedes","volume":"94","author":"Svennerholm","year":"1997","journal-title":"Acta Neuropathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1212\/01.WNL.0000110315.26026.EF","article-title":"Comparison of Different MRI Brain Atrophy Rate Measures with Clinical Disease Progression in AD","volume":"62","author":"Jack","year":"2004","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.neuroimage.2011.01.010","article-title":"Age-Related Alterations in the Modular Organization of Structural Cortical Network by Using Cortical Thickness from MRI","volume":"56","author":"Chen","year":"2011","journal-title":"NeuroImage"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.neuroimage.2009.06.074","article-title":"Age-Associated Alterations in Cortical Gray and White Matter Signal Intensity and Gray to White Matter Contrast","volume":"48","author":"Salat","year":"2009","journal-title":"NeuroImage"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s10548-011-0198-6","article-title":"Age-Related Changes in the Thickness of Cortical Zones in Humans","volume":"24","author":"McGinnis","year":"2011","journal-title":"Brain Topogr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"fcac109","DOI":"10.1093\/braincomms\/fcac109","article-title":"Structural Progression of Alzheimer\u2019s Disease over Decades: The MRI Staging Scheme","volume":"4","author":"Planche","year":"2022","journal-title":"Brain Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1080\/1028415X.2021.1889452","article-title":"Apolipoprotein E Genotype-Dependent Nutrigenetic Effects to Prebiotic Inulin for Modulating Systemic Metabolism and Neuroprotection in Mice via Gut-Brain Axis","volume":"25","author":"Yanckello","year":"2022","journal-title":"Nutr. 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