References: Chapter 14
1.
Oppezzo, M. and D.L. Schwartz, Give Your Ideas Some Legs: The Positive Effect of Walking on Creative Thinking. Journal of Experimental Psychology: Learning, Memory, and Cognition, 2014. 40(4): pp. 1142–52.
2.
Weller, R.B., Sunlight: Time for a Rethink? Journal of Investigational Dermatology, 2024. 144(8): pp. 1724–32.
3.
Taniguchi, Y., et al., Protective Effects of Dog Ownership Against the Onset of Disabling Dementia in Older Community-Dwelling Japanese: A Longitudinal Study. Preventitive Medicine Reports, 2023. 36: 102465.
4.
Boyle, P.A., et al., Person-Specific Contribution of Neuropathologies to Cognitive Loss in Old Age. Annals of Neurology, 2018. 83(1): pp. 74–83.
5.
Eisenberg, D.T., C.W. Kuzawa, and M.G. Hayes, Worldwide Allele Frequencies of the Human Apolipoprotein E Gene: Climate, Local Adaptations, and Evolutionary History. Americal Journal of Physical Anthropology, 2010. 143(1): pp. 100–111.
6.
Régy, M., et al., The Role of Dementia in the Association Between APOE4 and All-Cause Mortality: Pooled Analyses of Two Population-Based Cohort Studies. The Lancet Healthy Longevity, 2024. 5(6): pp. e422–e430.
Dunk, M.M. and I. Driscoll, Total Cholesterol and APOE-Related Risk for Alzheimer’s Disease in the Alzheimer’s Disease Neuroimaging Initiative. Journal of Alzheimer’s Disease, 2022. 85(4): pp. 1519–28.
7.
Raulin, A., et al., ApoE in Alzheimer’s Disease: Pathophysiology and Therapeutic Strategies. Molecular Neurodegeneration, 2022. 17(1): 72.
Shvetcov, A., et al., APOE ε4 Carriers Share Immune-Related Proteomic Changes Across Neurodegenerative Diseases. Nature Medicine. 2025 Aug;31(8):2590-2601.
8.
Trumble, B.C., et al., Apolipoprotein E4 Is Associated with Improved Cognitive Function in Amazonian Forager-Horticulturalists with a High Parasite Burden. FASB Journal, 2017. 31(4): pp. 1508–15.
Gureje, O., et al., APOE Epsilon4 Is Not Associated with Alzheimer’s Disease in Elderly Nigerians. Annals of Neurology, 2006. 59(1): pp. 182–85.
Suchy-Dicey, A., et al., APOE Genotype, Hippocampus, and Cognitive Markers of Alzheimer’s Disease in American Indians: Data from the Strong Heart Study. Alzheimer’s & Dementia, 2022. 18(12): pp. 2518–26.
9.
Gurinovich, A., et al., Varying Effects of APOE Alleles on Extreme Longevity in European Ethnicities. The Journals of Gerontology: Series A, Biological Sciences and Medical Sciences, 2019. 74(Suppl. 1): pp. s45–s51.
10.
Kivipelto, M., et al., Apolipoprotein E Epsilon4 Magnifies Lifestyle Risks for Dementia: A Population-Based Study. Journal of Cellular and Molecular Medicine, 2008. 12(6b): pp. 2762–71.
11.
O’Shea, D.M., et al., APOE ε4 Carrier Status Moderates the Effect of Lifestyle Factors on Cognitive Reserve. Alzheimer’s & Dementia, 2024. 20(11): pp. 8062–73.
Raichlen, D.A. and G.E. Alexander, Exercise, APOE Genotype, and the Evolution of the Human Lifespan. Trends in Neurosciences, 2014. 37(5): pp. 247–55.
Liu, Y., et al., Interplay of Genetic Predisposition, Plasma Metabolome and Mediterranean Diet in Dementia Risk and Cognitive Function. Nature Medicine. 2025 Aug 25.
Yassine, H.N., et al., Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers: A Review. JAMA Neurology. 2017 Mar 1;74(3):339-347.
Hu, W., et al., Telmisartan and Rosuvastatin Synergistically Ameliorate Dementia and Cognitive Impairment in Older Hypertensive Patients With Apolipoprotein E Genotype. Frontiers in Aging Neuroscience. 2020 Jun 9;12:154.
Liu, X., et al., Apolipoprotein E ε4-dependent associations between carotenoids and cognitive decline: Findings from the MIND (Mediterranean-DASH Intervention for Neurodegenerative delay) randomized controlled trial. American Journal of Clinical Nutrition. 2025 Nov;122(5):1289-1297.
Liu, Y., et al., Interplay of genetic predisposition, plasma metabolome and Mediterranean diet in dementia risk and cognitive function. Nature Medicine. 2025 Nov;31(11):3790-3800.
12.
Yassine, H.N., et al., Association of Docosahexaenoic Acid Supplementation with Alzheimer’s Disease Stage in Apolipoprotein E ε4 Carriers: A Review. JAMA Neurology, 2017. 74(3): pp. 339–47.
Royall, D.R. and R.F. Palmer, Statin Use Moderates APOE’s and CRP’s Associations with Dementia and Is Associated with Lesser Dementia Severity in ε4 Carriers. Alzheimer’s & Dementia, 2024. 20(3): pp. 1627–36.
von Cederwald, B.F., et al., Association of Cardiovascular Risk Trajectory with Cognitive Decline and Incident Dementia. Neurology, 2022. 98(20): pp. e2013–22.
Hu, W., et al., Telmisartan and Rosuvastatin Synergistically Ameliorate Dementia and Cognitive Impairment in Older Hypertensive Patients With Apolipoprotein E Genotype. Frontiers in Aging Neuroscience. 2020 Jun 9;12:154.
13.
Gogniat, M.A., et al., Increased Sedentary Behavior Is Associated with Neurodegeneration and Worse Cognition in Older Adults over a 7-Year Period Despite High Levels of Physical Activity. Alzheimer’s & Dementia, 2025. 21(5): e70157.
Merlini, S., et al., Multisystem Failure, Tipping Points, and Risk of Alzheimer’s Disease. Alzheimer’s & Dementia, 2025. 21(5): e70249.
Raichlen and Alexander, Exercise, APOE Genotype, and the Evolution of the Human Lifespan. Trends in Neurosciences, 2014. 37(5): pp. 247–55.
Shvetcov, A., et al., APOE ε4 Carriers Share Immune-Related Proteomic Changes Across Neurodegenerative Diseases. Nature Medicine. 2025 Aug;31(8):2590-2601.
14.
FDA Clears First Blood Test Used in Diagnosing Alzheimer’s Disease. Food and Drug Administration, May 16, 2025. Available↗
Alzheimer’s Association Welcomes FDA Clearance of First Blood Test for Use in Primary Care to Rule Out Alzheimer’s-Related Amyloid Pathology. Alzheimer’s Association, October 13, 2025. Available↗
Palmqvist, S., et al., Plasma Phospho-Tau217 for Alzheimer’s Disease Diagnosis in Primary and Secondary Care Using a Fully Automated Platform. Nature Medicine, 2025.
Schindler, S.E., et al., Acceptable Performance of Blood Biomarker Tests of Amyloid Pathology—Recommendations from the Global CEO Initiative on Alzheimer’s Disease. Nature Reviews, Neurology, 2024. 20(7): pp. 426–39.
Petersen, K.K., et al., Predicting onset of symptomatic Alzheimer's disease with plasma p-tau217 clocks. Nature Medicine. 2026 Feb 19.
Jia, J., et al., Biomarker Changes during 20 Years Preceding Alzheimer's Disease. New England Journal of Medicine. 2024 Feb 22;390(8):712-722.
15.
Grande, G., et al., Blood-Based Biomarkers of Alzheimer’s Disease and Incident Dementia in the Community. Nature Medicine, 2025.
16.
Widera, E. and K. Covinsky, The Limited Role of Alzheimer Disease Blood-Based Biomarkers in Primary Care. JAMA Internal Medicine, 2025.
17.
Niotis, K., et al., A Blood Biomarker-Guided Precision Medicine Approach for Individualized Neurodegenerative Disease Risk Reduction and Treatment: The Future of Preventive Neurology? (P7-3.016). Neurology, 2025. 104(7_Supplement_1): 201.
Sisser, P., et al., Feasibility of Using Blood-based Biomarkers to Evaluate the Effectiveness of Individualized Neurodegenerative Disease Preventive Care (P4-9.002). Neurology, 2024. 102(7_supplement_1): 2412.
18.
Stocker, H., et al., Association of Nonmodifiable Risk Factors with Alzheimer Disease Blood Biomarkers in Community-Dwelling Adults in the ESTHER Study. Neurology, 2025. 104(9): e213500.
19.
Stocker, H., et al., Alzheimer’s Polygenic Risk Scores, APOE, Alzheimer’s Disease Risk, and Dementia-Related Blood Biomarker Levels in a Population-Based Cohort Study Followed over 17 Years. Alzheimers Research & Therapy, 2023. 15(1): 129.
20.
Clifton, L., et al., Assessing Agreement Between Different Polygenic Risk Scores in the UK Biobank. Scientific Reports, 2022. 12(1): 12812.
Abramowitz, S.A., et al., Evaluating Performance and Agreement of Coronary Heart Disease Polygenic Risk Scores. JAMA, 2025. 333(1): pp. 60–70.
21.
Lourida, I., et al., Association of Lifestyle and Genetic Risk with Incidence of Dementia. JAMA, 2019. 322(5): pp. 430–37.
Wang, S., et al., Association of cardiorespiratory fitness with dementia risk across different levels of genetic predisposition: a large community-based longitudinal study. British Journal of Sports Medicine. 2025 Feb 3;59(3):150-158.
22.
Vrijsen, J., et al., Association Between Dementia Parental Family History and Mid-Life Modifiable Risk Factors for Dementia: A Cross-Sectional Study Using Propensity Score Matching Within the Lifelines Cohort. The BMJ Open, 2021. 11(12): e049918.
23.
Healthy Lifestyle Behaviors Reduced Dementia Risk Despite Family History of Dementia. American Heart Association, May 20, 2021. Available↗
24.
Shekhtman, S.G., et al., Emotional Response to Amyloid Beta Status Disclosure Among Research Participants at High Dementia Risk. Alzheimer’s & Dementia, 2025. 21(5): e70115.
25.
Garo-Pascual, M., et al., Brain Structure and Phenotypic Profile of Superagers Compared with Age-Matched Older Adults: A Longitudinal Analysis from the Vallecas Project. The Lancet Healthy Longevity, 2023. 4(8): pp. e374–85.
Weintraub, S., et al., The First 25 Years of the Northwestern University SuperAging Program. Alzheimers & Dementia. 2025 Aug;21(8):e70312.
Smith, D.G., The One Quality Most ‘Super-Agers’ Share. New York Times, 7 August 2025. Available↗
26.
Carlson, M.C., et al., Lifestyle Activities and Memory: Variety May Be the Spice of Life. The Women’s Health and Aging Study II. Journal of the International Neuropsychological Society, 2012. 18(2): pp. 286–94.
27.
Chen, L.J., et al., Can Physical Activity Eliminate the Mortality Risk Associated with Poor Sleep? A 15-Year Follow-Up of 341,248 MJ Cohort Participants. Journal of Sport Health and Science, 2022. 11(5): pp. 596–604.
Huang, S., et al., Sleep, Physical Activity, Sedentary Behavior, and Risk of Incident Dementia: A Prospective Cohort Study of 431,924 UK Biobank Participants. Molecular Psychiatry, 2022. 27(10): pp. 4343–54.
28.
Chang, Y.K., et al., Effects of acute Exercise on Cognitive Function: A Meta-Review of 30 Systematic Reviews with Meta-Analyses. Psychological Bulletin, 2025. 151(2): pp. 240–59.
Liu, S. and R. Zhang, Aerobic Exercise Alleviates the Impairment of Cognitive Control Ability Induced by Sleep Deprivation in College Students: Research Based on Go/NoGo Task. Frontiers in Psychology, 2022 Jun 30:13:914568.
Williams, T.B., et al., The Effects of Sleep Deprivation, Acute Hypoxia, and Exercise on Cognitive Performance: A Multi-Experiment Combined Stressors Study. Physiology & Behavior, 2024. 274: 114409.
Korkutata, A., M. Korkutata, and M. Lazarus, The Impact of Exercise on Sleep and Sleep Disorders. npj Biological Timing and Sleep, 2025. 2(1): 5.
29.
Saner, N.J., et al., Exercise Mitigates Sleep-Loss-Induced Changes in Glucose Tolerance, Mitochondrial Function, Sarcoplasmic Protein Synthesis, and Diurnal Rhythms. Molecular Metabolism, 2021. 43: 101110.
30.
Huang, H.H., et al., The Effect of Physical Activity on Sleep Disturbance in Various Populations: A Scoping Review of Randomized Clinical Trials. The International Journal of Behavioral Nutrition and Physical Activity, 2023. 20(1): 44.
31.
Korkutata, Korkutata, and Lazarus, The Impact of Exercise on Sleep and Sleep Disorders. npj Biological Timing and Sleep, 2025. 2(1): 5.
Park, I., et al., Exercise Improves the Quality of Slow-Wave Sleep by Increasing Slow-Wave Stability. Scientific Reports, 2021. 11(1): 4410.
Frisch, N., et al., An Acute Bout of High-Intensity Exercise Affects Nocturnal Sleep and Sleep-Dependent Memory Consolidation. Journal of Sleep Research, 2024. 33(4): e14126.
32.
Yue, T., et al., Different Intensities of Evening Exercise on Sleep in Healthy Adults: A Systematic Review and Network Meta-Analysis. Nature and Science of Sleep, 2022. 14: pp. 2157–77.
Leota, J., et al., Dose-Response Relationship Between Evening Exercise and Sleep. Nature Communications, 2025. 16(1): 3297.
Kim, N., S. Ka, and J. Park, Effects of Exercise Timing and Intensity on Physiological Circadian Rhythm and Sleep Quality: A Systematic Review. Physical Activity and Nutrition, 2023. 27(3): pp. 52–63.
33.
Bloomberg, M., et al., Associations of Accelerometer-Measured Physical Activity, Sedentary Behaviour, and Sleep with Next-Day Cognitive Performance in Older Adults: A Micro-Longitudinal Study. International Journal of Behavioral Nutrition and Physical Activity, 2024. 21(1): 133.
Triana, A.M., et al., Longitudinal Single-Subject Neuroimaging Study Reveals Effects of Daily Environmental, Physiological, and Lifestyle Factors on Functional Brain Connectivity. PLOS Biology, 2024. 22(10): e3002797.
34.
Jin, M.J. and S.M. Bae, The Effect of Social Isolation, Loneliness, and Physical Activity on Depressive Symptoms of Older Adults During COVID-19: A Moderated Mediation Analysis. International Journal of Environmental Research and Public Health, 2024. 21(1): 26.
Creese, B., et al., Loneliness, Physical Activity, and Mental Health During COVID-19: A Longitudinal Analysis of Depression and Anxiety in Adults over the Age of 50 Between 2015 and 2020. International Psychogeriatrics, 2021. 33(5): pp. 505–14.
Benedyk, A., et al., Real-Life Behavioral and Neural Circuit Markers of Physical Activity as a Compensatory Mechanism for Social Isolation. Nature Mental Health, 2024. 2(3): pp. 337–42.
35.
Hamer, M. and A. Steptoe, Association Between Physical Fitness, Parasympathetic Control, and Proinflammatory Responses to Mental Stress. Psychosomadic Medicine, 2007. 69(7): pp. 660–66.
36.
Klein, T., et al., Short-Term Isolation Effects on the Brain, Cognitive Performance, and Sleep—the Role of Exercise. Frontiers in Physiology, 2023. 14: 903072.
37.
Pels, F. and J. Kleinert, Loneliness and Physical Activity: A Systematic Review. International Review of Sport and Exercise Psychology, 2016. 9(1): pp. 231–60.
38.
Ourry, V.R., et al., Effect of Cognitive Reserve on the Association Between Slow Wave Sleep and Cognition in Community-Dwelling Older Adults. Aging, 2023. 15(18): pp. 9275–92.
39.
van Leeuwen, W.M., et al., Sleep Restriction Increases the Risk of Developing Cardiovascular Diseases by Augmenting Proinflammatory Responses Through IL-17 and CRP. PLoS One, 2009. 4(2): e4589.
Wang, Y., et al., Phenome-wide Analysis of Diseases in Relation to Objectively Measured Sleep Traits and Comparison with Subjective Sleep Traits in 88,461 Adults. Health Data Science. 2025 Jun 3;5:0161.
40.
Tasali, E., et al., Effect of Sleep Extension on Objectively Assessed Energy Intake Among Adults with Overweight in Real-life Settings: A Randomized Clinical Trial. JAMA Internal Medicine, 2022. 182(4): pp. 365–74.
41.
Goldstein, I., et al., The Serendipitous Story of Sildenafil: An Unexpected Oral Therapy for Erectile Dysfunction. Sexual Medicine Review, 2019. 7(1): pp. 115–28.
42.
Sir Simon Campbell CBE FMedSci FRS. The Royal Society. Available↗
43.
Adesuyan, M., et al., Phosphodiesterase Type 5 Inhibitors in Men with Erectile Dysfunction and the Risk of Alzheimer Disease. Neurology, 2024. 102(4): e209131.
44.
Fang, J., et al., Endophenotype-Based in Silico Network Medicine Discovery Combined with Insurance Record Data Mining Identifies Sildenafil as a Candidate Drug for Alzheimer’s Disease. Nature Aging, 2021. 1(12): pp. 1175–88.
45.
Xiong, Y. and Wintermark, The Role of Sildenafil in Treating Brain Injuries in Adults and Neonates. Frontiers in Cellular Neuroscience, 2022. 16: 879649.
46.
Zhang, K., et al., Concepts and Applications of Digital Twins in Healthcare and Medicine. Patterns, 2024. 5(8): 101028.
Khasentino, J., et al., A Personal Health Large Language Model for Sleep and Fitness Coaching. Nature Medicine. 2025 Aug 14.
Ringeval, M., et al., Advancing Health Care With Digital Twins: Meta-Review of Applications and Implementation Challenges. Journal of Medical Internet Research. 2025 Feb 19;27:e69544.
Iranshahi, K., et al., Digital twins: Recent advances and future directions in engineering fields. Intelligent Systems with Applications, 2025, 26: 200516.
47.
Huh, H., et al., A Wireless Forehead E-Tattoo for Mental Workload Estimation. Device. 0(0): 100781.
Stothart, G., et al., A Passive and Objective Measure of Recognition Memory in Mild Cognitive Impairment using Fastball Memory Assessment. Brain Communications. 2025 Sep 1;7(5):fcaf279.
48.
Lu, J.K., et al., Digital Biomarkers of Ageing for Monitoring Physiological Systems in Community-Dwelling Adults. The Lancet Healthy Longevity. 6(6): 100725.
49.
Park, J., Discriminant Power of Smartphone-Derived Keystroke Dynamics for Mild Cognitive Impairment Compared to a Neuropsychological Screening Test: Cross-Sectional Study. Journal of Medical Internet Research, 2024. 26.
Butler, P.M., et al., Smartwatch- and Smartphone-Based Remote Assessment of Brain Health and Detection of Mild Cognitive Impairment. Nature Medicine, 2025. 31(3): pp. 829–39.
50.
Mazur, A., et al., Evaluation of an AI-Based Voice Biomarker Tool to Detect Signals Consistent with Moderate to Severe Depression. The Annals of Family Medicine, 2025. 23(1): pp. 60–65.
Tokuno, S. and H. Nakamura, editors, Voice Biomarkers: Current Status and Issues in the Development (Springer, 2025).
51.
Tokuda, H., et al., Association Between a Combination of Cognitively Stimulating Leisure Activities and Long-Chain Polyunsaturated Fatty Acid Intake on Cognitive Decline Among Community-Dwelling Older Japanese Individuals. Frontiers in Aging Neuroscience, 2024. 16: 1406079.
Tokuda, H., et al., Association of Open Skill Exercise and Long-Chain Polyunsaturated Fatty Acid Intake with Brain Volume Changes Among Older Community-Dwelling Japanese Individuals. Archives of Gerontology and Geriatrics. 2025 Jan;128:105620.
52.
Yiallourou, S., et al., Short Sleep Duration and Hypertension: A Double Hit for the Brain. Journal of the American Heart Association, 2024. 13(21): e035132.
53.
Baker, L.D., et al., Structured vs Self-Guided Multidomain Lifestyle Interventions for Global Cognitive Function: The US POINTER Randomized Clinical Trial. JAMA. 2025 Aug 26;334(8):681-691.
Oki, Y., et al., An 18-Month Multimodal Intervention Trial for Preventing Dementia: J-MINT PRIME Tamba. Alzheimers & Dementia. 2024 Oct;20(10):6972-6983.
Moon, S.Y., et al., Facility-Based and Home-Based Multidomain Interventions Including Cognitive Training, Exercise, Diet, Vascular Risk Management, and Motivation for Older Adults: a Randomized Controlled Feasibility Trial. Aging. 2021 Jun 18;13(12):15898-15916.
Choi, H.Y., et al., Effectiveness of a 52-week multidomain intervention to maintain cognitive function in patients with mild cognitive impairment: a randomized controlled trial. Scientific Reports. 2025 Nov 20;15(1):41141.
Roach, J.C., et al., Multidomain therapy for Alzheimer's disease: a scoping review of cognitive decline trials. Molecular Neurodegeneration. 2025 Nov 22;20(1):125.
54.
Brodaty, H., et al., An Online Multidomain Lifestyle Intervention to Prevent Cognitive Decline in At-Risk Older Adults: A Randomized Controlled Trial. Nature Medicine, 2025. 31(2): pp. 565–73.
55.
Yaffe, K., et al., Effect of Personalized Risk-Reduction Strategies on Cognition and Dementia Risk Profile Among Older Adults: The SMARRT Randomized Clinical Trial. JAMA Internal Medicine, 2024. 184(1): pp. 54–62.
56.
Ornish, D., et al., Effects of Intensive Lifestyle Changes on the Progression of Mild Cognitive Impairment or Early Dementia Due to Alzheimer’s Disease: A Randomized, Controlled Clinical Trial. Alzheimers Research & Therapy, 2024. 16(1): 122.
57.
Moon, S.Y., et al., South Korean Study to Prevent Cognitive Impairment and Protect Brain Health Through Multidomain Interventions via Face-to-Face and Video Communication Platforms in Mild Cognitive Impairment (SUPERBRAIN-MEET): A Randomized Controlled Trial. Alzheimers & Dementia. 2025 Feb;21(2):e14517.
58.
Joo, J., et al., The Influence of 15-Week Exercise Training on Dietary Patterns Among Young Adults. International Journal of Obesity (London), 2019. 43(9): pp. 1681–90.
59.
van Soest, A.P.M., et al., Concurrent Nutrient Deficiencies Are Associated with Dementia Incidence. Alzheimer’s & Dementia, 2024. 20(7): pp. 4594–601.
60.
Chen, C., et al., B vitamin Intakes Modify the Association Between Particulate Air Pollutants and Incidence of All-Cause Dementia: Findings from the Women’s Health Initiative Memory Study. Alzheimer’s & Dementia, 2022. 18(11): pp. 2188–98.