Integrating Exposome into Lifecourse Understanding of Cognitive Ageing and Dementia: Current Evidence, Methodological Challenges, and Future Directions
1. Introduction
2. Methodological Challenges
2.1. Multidimensional Data Complexity
2.2. Temporal and Lifecourse Dynamics
2.3. Confounding and Reverse Causation
2.4. Equity and Generalizability Gaps
3. Future Directions and Innovations
3.1. Toward a Lifecourse and System-Level Exposome Framework
3.2. Technological Advances in Exposome Measurement
3.3. Innovative Index Generation and Profile Clustering
3.4. Interdisciplinary Collaboration for Holistic Insights
5. Conclusions
Funding
Conflicts of Interest
References
- Nichols, E.; Steinmetz, J.D.; Vollset, S.E.; Fukutaki, K.; Chalek, J.; Abd-Allah, F.; Abdoli, A.; Abualhasan, A.; Abu-Gharbieh, E.; Akram, T.T.; et al. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019. Lancet Public Health 2022, 7, e105–e125. [Google Scholar] [CrossRef]
- Livingston, G.; Huntley, J.; Liu, K.Y.; Costafreda, S.G.; Selbæk, G.; Alladi, S.; Ames, D.; Banerjee, S.; Burns, A.; Brayne, C.; et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet 2024, 404, 572–628. [Google Scholar] [CrossRef] [PubMed]
- Kivipelto, M.; Solomon, A.; Ahtiluoto, S.; Ngandu, T.; Lehtisalo, J.; Antikainen, R.; Bäckman, L.; Hänninen, T.; Jula, A.; Laatikainen, T.; et al. The Finnish geriatric intervention study to prevent cognitive impairment and disability (FINGER): Study design and progress. Alzheimer’s Dement. 2013, 9, 657–665. [Google Scholar] [CrossRef] [PubMed]
- Belloy, M.E.; Andrews, S.J.; Le Guen, Y.; Cuccaro, M.; Farrer, L.A.; Napolioni, V.; Greicius, M.D. APOE genotype and Alzheimer disease risk across age, sex, and population ancestry. JAMA Neurol. 2023, 80, 1284–1294. [Google Scholar] [CrossRef] [PubMed]
- Bellenguez, C.; Küçükali, F.; Jansen, I.E.; Kleineidam, L.; Moreno-Grau, S.; Amin, N.; Naj, A.C.; Campos-Martin, R.; Grenier-Boley, B.; Andrade, V.; et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat. Genet. 2022, 54, 412–436. [Google Scholar] [CrossRef]
- Kunkle, B.W.; Grenier-Boley, B.; Sims, R.; Bis, J.C.; Damotte, V.; Naj, A.C.; Boland, A.; Vronskaya, M.; van der Lee, S.J.; Amlie-Wolf, A.; et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet. 2019, 51, 414–430. [Google Scholar] [CrossRef]
- Guo, Y.; You, J.; Zhang, Y.; Liu, W.-S.; Huang, Y.-Y.; Zhang, Y.-R.; Zhang, W.; Dong, Q.; Feng, J.-F.; Cheng, W.; et al. Plasma proteomic profiles predict future dementia in healthy adults. Nat. Aging 2024, 4, 247–260. [Google Scholar] [CrossRef]
- Walker, K.A.; Chen, J.; Shi, L.; Yang, Y.; Fornage, M.; Zhou, L.; Schlosser, P.; Surapaneni, A.; Grams, M.E.; Duggan, M.R.; et al. Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life. Sci. Transl. Med. 2023, 15, eadf5681. [Google Scholar] [CrossRef]
- Walker, K.A.; Chen, J.; Zhang, J.; Fornage, M.; Yang, Y.; Zhou, L.; Grams, M.E.; Tin, A.; Daya, N.; Hoogeveen, R.C.; et al. Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk. Nat. Aging 2021, 1, 473–489. [Google Scholar] [CrossRef]
- Gong, J.; Williams, D.M.; Scholes, S.; Assaad, S.; Bu, F.; Hayat, S.; Zaninotto, P.; Steptoe, A. Unraveling the role of proteins in dementia: Insights from two UK cohorts with causal evidence. Brain Commun. 2025, 7, fcaf097. [Google Scholar] [CrossRef]
- Kivimäki, M.; Frank, P.; Pentti, J.; Jokela, M.; Nyberg, S.T.; Blake, A.; Lindbohm, J.V.; Oh, H.S.-H.; Singh-Manoux, A.; Wyss-Coray, T.; et al. Proteomic organ-specific ageing signatures and 20-year risk of age-related diseases: The Whitehall II observational cohort study. Lancet Digit. Health 2025, 7, e195–e204. [Google Scholar] [CrossRef] [PubMed]
- Lindbohm, J.V.; Mars, N.; Walker, K.A.; Singh-Manoux, A.; Livingston, G.; Brunner, E.J.; Sipilä, P.N.; Saksela, K.; Ferrie, J.E.; Lovering, R.C.; et al. Plasma proteins, cognitive decline, and 20-year risk of dementia in the Whitehall II and Atherosclerosis Risk in Communities studies. Alzheimer’s Dement. 2022, 18, 612–624. [Google Scholar] [CrossRef]
- Huo, Z.; Yu, L.; Yang, J.; Zhu, Y.; Bennett, D.A.; Zhao, J. Brain and blood metabolome for Alzheimer’s dementia: Findings from a targeted metabolomics analysis. Neurobiol. Aging 2020, 86, 123–133. [Google Scholar] [CrossRef]
- Jiang, Y.; Zhu, Z.; Shi, J.; An, Y.; Zhang, K.; Wang, Y.; Li, S.; Jin, L.; Ye, W.; Cui, M.; et al. Metabolomics in the development and progression of dementia: A systematic review. Front. Neurosci. 2019, 13, 343. [Google Scholar] [CrossRef]
- Ibanez, A.; Slachevsky, A. Environmental–genetic interactions in ageing and dementia across Latin America. Nat. Rev. Neurol. 2024, 20, 571–572. [Google Scholar] [CrossRef] [PubMed]
- Llibre-Guerra, J.J.; Jiang, M.; Acosta, I.; Sosa, A.L.; Acosta, D.; Jimenez-Velasquez, I.Z.; Guerra, M.; Salas, A.; Salgado, A.M.R.; Sánchez, N.D.; et al. Social determinants of health but not global genetic ancestry predict dementia prevalence in Latin America. Alzheimer’s Dement. 2024, 20, 4828–4840. [Google Scholar] [CrossRef] [PubMed]
- Puig, M.; Darbra, R.M. Innovations and insights in environmental monitoring and assessment in port areas. Curr. Opin. Environ. Sustain. 2024, 70, 101472. [Google Scholar] [CrossRef]
- Beulens, J.W.J.; Pinho, M.G.M.; Abreu, T.C.; Braver, N.R.D.; Lam, T.M.; Huss, A.; Vlaanderen, J.; Sonnenschein, T.; Siddiqui, N.Z.; Yuan, Z.; et al. Environmental risk factors of type 2 diabetes—An exposome approach. Diabetologia 2022, 65, 263–274. [Google Scholar] [CrossRef]
- Miller, G.W. The Exposome: A New Paradigm for the Environment and Health; Academic Press: Cambridge, MA, USA, 2020. [Google Scholar]
- Vineis, P.; Robinson, O.; Chadeau-Hyam, M.; Dehghan, A.; Mudway, I.; Dagnino, S. What is new in the exposome? Environ. Int. 2020, 143, 105887. [Google Scholar] [CrossRef]
- Tamiz, A.P.; Koroshetz, W.J.; Dhruv, N.T.; Jett, D.A. A focus on the neural exposome. Neuron. 2022, 110, 1286–1289. [Google Scholar] [CrossRef]
- Ibanez, A.; Melloni, L.; Świeboda, P.; Hynes, W.; Ikiz, B.; Ayadi, R.; Eyre, H.A. Neuroecological links of the exposome and One Health. Neuron. 2024, 112, 1905–1910. [Google Scholar] [CrossRef] [PubMed]
- Finch, C.E.; Kulminski, A.M. The Alzheimer’s disease exposome. Alzheimer’s Dement. 2019, 15, 1123–1132. [Google Scholar] [CrossRef] [PubMed]
- Vermeulen, R.; Schymanski, E.L.; Barabási, A.-L.; Miller, G.W. The exposome and health: Where chemistry meets biology. Science 2020, 367, 392–396. [Google Scholar] [CrossRef]
- Argentieri, M.A.; Amin, N.; Nevado-Holgado, A.J.; Sproviero, W.; Collister, J.A.; Keestra, S.M.; Kuilman, M.M.; Ginos, B.N.R.; Ghanbari, M.; Doherty, A.; et al. Integrating the environmental and genetic architectures of aging and mortality. Nat. Med. 2025, 31, 1016–1025. [Google Scholar] [CrossRef] [PubMed]
- Kidd, S.A.; Gong, J.; Massazza, A.; Bezgrebelna, M.; Zhang, Y.; Hajat, S. Climate change and its implications for developing brains–In utero to youth: A scoping review. J. Clim. Change Health 2023, 13, 100258. [Google Scholar] [CrossRef]
- Schmidt, C.W. Uncertain Inheritance: Transgenerational Effects of Environmental Exposures; National Institute of Environmental Health Sciences: Durham, NC, USA, 2013.
- Wang, X.-J.; Xu, W.; Li, J.-Q.; Cao, X.-P.; Tan, L.; Yu, J.-T. Early-life risk factors for dementia and cognitive impairment in later life: A systematic review and meta-analysis. J. Alzheimer’s Dis. 2019, 67, 221–229. [Google Scholar] [CrossRef]
- Safarlou, C.W.; Jongsma, K.R.; Vermeulen, R. Reconceptualizing and defining exposomics within environmental health: Expanding the scope of health research. Environ. Health Perspect. 2024, 132, 095001. [Google Scholar] [CrossRef]
- Vineis, P.; Chadeau-Hyam, M.; Gmuender, H.; Gulliver, J.; Herceg, Z.; Kleinjans, J.; Kogevinas, M.; Kyrtopoulos, S.; Nieuwenhuijsen, M.; Phillips, D.; et al. The exposome in practice: Design of the EXPOsOMICS project. Int. J. Hyg. Environ. Health 2017, 220, 142–151. [Google Scholar] [CrossRef]
- Argelaguet, R.; Velten, B.; Arnol, D.; Dietrich, S.; Zenz, T.; Marioni, J.C.; Buettner, F.; Huber, W.; Stegle, O. Multi-Omics Factor Analysis—A framework for unsupervised integration of multi-omics data sets. Mol. Syst. Biol. 2018, 14, e8124. [Google Scholar] [CrossRef]
- Reel, P.S.; Reel, S.; Pearson, E.; Trucco, E.; Jefferson, E. Using machine learning approaches for multi-omics data analysis: A review. Biotechnol. Adv. 2021, 49, 107739. [Google Scholar] [CrossRef]
- Wan, M.; Simonin, E.M.; Johnson, M.M.; Zhang, X.; Lin, X.; Gao, P.; Patel, C.J.; Yousuf, A.; Snyder, M.P.; Hong, X.; et al. Exposomics: A review of methodologies, applications, and future directions in molecular medicine. EMBO Mol. Med. 2025, 17, 599–608. [Google Scholar] [CrossRef] [PubMed]
- Thissen, D.; Steinberg, L.; Kuang, D. Quick and easy implementation of the Benjamini-Hochberg procedure for controlling the false positive rate in multiple comparisons. J. Educ. Behav. Stat. 2002, 27, 77–83. [Google Scholar] [CrossRef]
- Rojas-Saunero, L.P.; Young, J.G.; Didelez, V.; Ikram, M.A.; Swanson, S.A. Considering questions before methods in dementia research with competing events and causal goals. Am. J. Epidemiol. 2023, 192, 1415–1423. [Google Scholar] [CrossRef] [PubMed]
- Bulbulia, J.A. Methods in causal inference. Part 2: Interaction, mediation, and time-varying treatments. Evol. Hum. Sci. 2024, 6, e41. [Google Scholar] [CrossRef]
- Althubaiti, A. Information bias in health research: Definition, pitfalls, and adjustment methods. J. Multidiscip. Healthc. 2016, 9, 211–217. [Google Scholar] [CrossRef] [PubMed]
- Saczynski, J.; McManus, D.; Goldberg, R. Commonly utilized data collection approaches in clinical research. Am. J. Med. 2013, 126, 946–950. [Google Scholar] [CrossRef]
- Juggins, S.; Birks, H.J.B. Quantitative environmental reconstructions from biological data. In Tracking Environmental Change Using Lake Sediments: Data Handling and Numerical Techniques; Springer: Dordrecht, The Netherlands, 2012; pp. 431–494. [Google Scholar]
- Rotstein, A.; Kodesh, A.; Goldberg, Y.; Reichenberg, A.; Levine, S.Z. An Examination of Reverse Causation in the Association between Serum Folate Deficiency and Dementia. Alzheimer’s Dement. 2023, 19, e071787. [Google Scholar] [CrossRef]
- Suemoto, C.K.; Gilsanz, P.; Mayeda, E.R.; Glymour, M.M. Body mass index and cognitive function: The potential for reverse causation. Int. J. Obes. 2015, 39, 1383–1389. [Google Scholar] [CrossRef]
- Scharre, D.W. Preclinical, prodromal, and dementia stages of Alzheimer’s disease. Pract. Neurol. 2019, 15, 36–47. [Google Scholar]
- Saltz, J.B. Gene–environment correlation in humans: Lessons from psychology for quantitative genetics. J. Hered. 2019, 110, 455–466. [Google Scholar] [CrossRef]
- Johnson, W.; Turkheimer, E.; Gottesman, I.I.; Bouchard, T.J., Jr. Beyond heritability: Twin studies in behavioral research. Curr. Dir. Psychol. Sci. 2009, 18, 217–220. [Google Scholar] [CrossRef]
- Nwanaji-Enwerem, J.C.; Jackson, C.L.; Ottinger, M.A.; Cardenas, A.; James, K.A.; Malecki, K.M.; Chen, J.-C.; Geller, A.M.; Mitchell, U.A. Adopting a “compound” exposome approach in environmental aging biomarker research: A call to action for advancing racial health equity. Environ. Health Perspect. 2021, 129, 045001. [Google Scholar] [CrossRef] [PubMed]
- Baez, S.; Alladi, S.; Ibanez, A. Global South research is critical for understanding brain health, ageing and dementia. Clin. Transl. Med. 2023, 13, e1486. [Google Scholar] [CrossRef]
- Fatumo, S.; Chikowore, T.; Choudhury, A.; Ayub, M.; Martin, A.R.; Kuchenbäcker, K. Diversity in genomic studies: A roadmap to address the imbalance. Nat. Med. 2022, 28, 243. [Google Scholar] [CrossRef] [PubMed]
- Sieck, C.J.; Sheon, A.; Ancker, J.S.; Castek, J.; Callahan, B.; Siefer, A. Digital inclusion as a social determinant of health. NPJ Digit. Med. 2021, 4, 52. [Google Scholar] [CrossRef] [PubMed]
- Gómez, P.M.; Santiago, A.R.; Seco, G.G.; Casanova, R.; MacKenzie, D.; Tucker, C. Ethics in the use of geospatial information in the Americas. Technol. Soc. 2022, 69, 101964. [Google Scholar] [CrossRef]
- Kuhn, H.G.; Skau, S.; Nyberg, J. A lifetime perspective on risk factors for cognitive decline with a special focus on early events. Cereb. Circ. -Cogn. Behav. 2024, 6, 100217. [Google Scholar] [CrossRef]
- Koelmel, J.P.; Lin, E.Z.; Guo, P.; Zhou, J.; He, J.; Chen, A.; Gao, Y.; Deng, F.; Dong, H.; Liu, Y.; et al. Exploring the external exposome using wearable passive samplers-The China BAPE study. Environ. Pollut. 2021, 270, 116228. [Google Scholar] [CrossRef]
- Geraci, J.; Searls, E.; Qorri, B.; Low, S.; Li, Z.; Joung, P.; Gifford, K.A.; Pratap, A.; Tsay, M.; Cumbaa, C.; et al. Using Machine Learning to Explore Multimodal Digital Markers for Early Detection of Cognitive Impairment in Alzheimer’s Disease. Alzheimer’s Dement. 2025, 20 (Suppl. S2), e093236. [Google Scholar] [CrossRef]
- Miller, G.W.; Banbury Exposomics Consortium. Integrating exposomics into biomedicine. Science 2025, 388, 356–358. [Google Scholar]
- Liu, W.-S.; You, J.; Chen, S.-D.; Zhang, Y.; Feng, J.-F.; Xu, Y.-M.; Yu, J.-T.; Cheng, W. Plasma proteomics identify biomarkers and undulating changes of brain aging. Nat. Aging 2025, 5, 99–112. [Google Scholar] [CrossRef] [PubMed]
- Moguilner, S.; Baez, S.; Hernandez, H.; Migeot, J.; Legaz, A.; Gonzalez-Gomez, R.; Ibanez, A. Brain clocks capture diversity and disparities in aging and dementia across geographically diverse populations. Nat. Med. 2024, 30, 3646–3657. [Google Scholar] [CrossRef] [PubMed]
- Anderson, G.B.; Bell, M.L.; Peng, R.D. Methods to calculate the heat index as an exposure metric in environmental health research. Environ. Health Perspect. 2013, 121, 1111–1119. [Google Scholar] [CrossRef] [PubMed]
- Pearce, J.R.; Richardson, E.A.; Mitchell, R.J.; Shortt, N.K. Environmental justice and health: The implications of the socio-spatial distribution of multiple environmental deprivation for health inequalities in the United Kingdom. Trans. Inst. Br. Geogr. 2010, 35, 522–539. [Google Scholar] [CrossRef]
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Gong, J.; Zaninotto, P. Integrating Exposome into Lifecourse Understanding of Cognitive Ageing and Dementia: Current Evidence, Methodological Challenges, and Future Directions. Int. J. Environ. Res. Public Health 2025, 22, 815. https://doi.org/10.3390/ijerph22060815
Gong J, Zaninotto P. Integrating Exposome into Lifecourse Understanding of Cognitive Ageing and Dementia: Current Evidence, Methodological Challenges, and Future Directions. International Journal of Environmental Research and Public Health. 2025; 22(6):815. https://doi.org/10.3390/ijerph22060815
Chicago/Turabian StyleGong, Jessica, and Paola Zaninotto. 2025. "Integrating Exposome into Lifecourse Understanding of Cognitive Ageing and Dementia: Current Evidence, Methodological Challenges, and Future Directions" International Journal of Environmental Research and Public Health 22, no. 6: 815. https://doi.org/10.3390/ijerph22060815
APA StyleGong, J., & Zaninotto, P. (2025). Integrating Exposome into Lifecourse Understanding of Cognitive Ageing and Dementia: Current Evidence, Methodological Challenges, and Future Directions. International Journal of Environmental Research and Public Health, 22(6), 815. https://doi.org/10.3390/ijerph22060815