Debora Rizzuto

OVERALL AIM This PhD project directly aligns with KI’s 2025 research priorities by investigating the biological mechanisms linking air pollution (AP) to brain aging. It integrates bio-behavioral health care science, a core KI focus, by exploring how environmental exposures contribute to neurodegeneration. It also supports MedH 2025 Strategy, which prioritizes addressing critical clinical challenges in aging and dementia research. HYPHOTHESES Two overarching hypotheses will be tested. The first suggests that AP exposure is linked to increased amyloid deposition and neurodegeneration. Pollutants may translocate to the brain via the olfactory bulb, directly inducing damage. The second proposes that AP increases the release of pro-inflammatory signals, either due to airway inflammation or by bypassing the lung-blood barrier and entering systemic circulation. These hypotheses will be tested using in vivo markers of neurodegeneration, cardiovascular damage, and systemic inflammation. METHODS This project benefits from KI and VR’s investment in research infrastructure by utilizing the National E-Infrastructure on Aging Research (NEAR), which pools together data from 3 major Swedish brain aging studies: SNAC-K (Stockholm), Betula (Umeå), and H70 (Gothenburg). Overall, comprising over 9,000 individuals aged 50+ with follow-ups ranging from 20 to 30 years and response rates between 72% and 85%. Data collection. Air pollution. Several air pollution levels at home addresses are estimated with high-resolution spatiotemporal methods. Key pollutants include particulates (PM10, PM2.5, BC) and gases (NOx, NO2). Brain Imaging. Participants underwent multiple scams during follow-up: 3 times for SNAC-K and Betula, and 2 for H70. Total gray matter volume (GMV) and white matter volume (WMV) were calculated using SPM12 software with unified segmentation. Total brain tissue (TBT) volume was derived by adding GMV and WMV, and total intracranial volume was calculated by adding TBT and cerebrospinal fluid volumes. Hippocampal segmentation was performed using FreeSurfer, with manual accuracy checks. Biomarker. In the SNAC-K study, a battery of 19 cytokines involved in pro- and anti-inflammatory processes was measured in participants’ baseline serum (e.g., beta-2-microglobulin, IL-1, IL-6, etc.). Similarly, a selected pool of biomarkers of AD has been measured (e.g., Total Tau, phospho-Tau 181, S100B, BDNF, amyloid beta 40/42, Neurofilament light chain, Glial fibrillary acidic protein, alpha-synucleine). Diagnosis of dementia follows the criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Control and moderation measures. The data from the 3 databases allow exploration of various factors, such as occupation, neighborhood household, educational level, physical activity, alcohol, smoking, genotyping of SNPs, green space availability, and road traffic noise.   Analytic Strategies. For study 1 and 2 we will use MRI data from SNAC-K, BETULA and H70 cohorts. Linear mixed models for repeated measures will be used to estimate associations of AP with brain volumes over the follow-up period. Mediation by neurodegeneration and/or cerebrovascular lesion load of effects of AP on dementia (and subtypes) will be tested by linear mixed-effects models, with bootstrapped 95% confidence intervals for the mediation effect.  For study 3 and 4 using data from SNAC-K, robust linear regression will assess the relationship between biomarkers and AP, employing Huber M estimation. The potential mediating effect of the inflammatory biomarkers on the AP-dementia will be evaluated by the degree of attenuation of per SD increment effect by further adjusting for the potential mediator in the linear regression models. STUDIES PLANNED To achieve the project’s goal, we have outlined 4 studies with the following aims: Explore the association of AP with brain structural changes, using MRI repeated measures. Verify the extent to which the dementia risk linked to AP is mediated by neurodegenerative and/or vascular brain pathology. Investigate whether the exposure to AP is linked to an increased level of Alzheimer's disease biomarkers. To explore a pool of biomarkers in relation to the possible pathways linking AP to dementia. SIGNIFICANCE AND RELEVANCE FOR DOCTORAL EDUCATION By investigating the biological mechanisms linking AP to neurodegeneration, this project advances KI’s priority area of bio-behavioral health care science. This research also aligns with KI’s commitment to addressing critical clinical challenges by integrating advanced neuroimaging, biomarker analysis, and epidemiological methods to assess dementia risk factors. Furthermore, the study has strong public health implications, reinforcing KI’s mission to translate research into actionable policies that promote population health. Given the global prevalence of AP exposure, findings from this project can inform environmental regulations and dementia prevention strategies at both national and international levels. Additionally, this work embodies KI’s co-creation approach, involving multidisciplinary expertise from geriatrics, neurology, environmental epidemiology, and public health to foster an innovative, collaborative research environment. LEARNING OUTCOMES AND ACTIVITIES This project aligns with the core requirements of doctoral education at KI, focusing on advanced general knowledge, scientific methodology, and innovative research in geriatric epidemiology. It follows a structured approach, allowing the PhD student to lead each stage of the research process, from data cleaning to manuscript outlining. Through active participation, the student will gain expertise in geriatric and environmental epidemiology, longitudinal data analysis, and research methodology, preparing them for future professional and scientific endeavours. The project also emphasizes continuous learning through doctoral courses, seminars, and international conferences.

People in the Nordic countries are living longer than ever before. While this is a great achievement, it also creates new challenges: how can our health systems, communities, and societies support people to age well? And how can we ensure that future generations benefit from healthier, more active later lives? The Nordic countries already lead in aging research and have built rich datasets from population studies on health, lifestyle, and aging. But these valuable resources are often limited to national use, with little coordination across countries. This means missed opportunities to learn from each other, compare systems, and find shared solutions. NEXT-NORD is a Nordic cooperation project that brings together universities and research institutes from Sweden, Denmark, Norway, Iceland, and Finland. The goal is to strengthen collaboration on aging research across borders, making better use of the data and knowledge already available. We will do this by supporting young researchers through exchanges and joint training, developing shared approaches to compare health data between countries, and creating common practices for using data ethically and responsibly. We will also involve stakeholders like policymakers, funders, and data owners to make sure our work supports real-world decisions. Rather than creating new data, NEXT-NORD will focus on connecting what already exists, helping researchers work together more efficiently and laying the groundwork for a future Nordic research infrastructure on aging. The long-term result? A stronger, more connected Nordic region that can lead globally in aging research and support better health for all as we grow older.

Acrylamide, a widespread food-processing contaminant, poses a major public health concern due to its high exposure level in the general population and its toxicity. While animal evidence shows that acrylamide causes neurological alterations and may play a role in cardiovascular disease, evidence in humans is lacking. Our project aims to investigate whether dietary acrylamide exposure, measured in blood, increases the risk of dementia, Alzheimer´s and Parkinson´s diseases and myocardial infarction. In addition, we aim to improve the understanding of the biological mechanisms underlying these associations integrating small compounds in blood (i.e., OMICS).In two population-based cohorts, the Cohort of 60-Year-Olds and the Swedish Mammography Cohort, acrylamide will be assessed in blood samples using a case-cohort design (around 1,740 individuals, 20-year follow-up). The results will be presented in four scientific publications using adequate data analysis. The project will run from 2024-2028.The project´s findings will help improve public health through safer food and better nutrition. If findings indicate that acrylamide increases the risk of these diseases, this will urge interventions to decrease acrylamide exposure via food production and consumption. In turn, this will help to reduce the burden of these diseases. Even findings showing null association will be equally relevant to avoid unnecessary and costly preventive measures.

Research problem and specific questions: This project aims to contribute key knowledge for optimizing prevention, intervention, and care management of old-age depression by disentangling the complexities of this common and burdensome condition. Compared to earlier in life, old-age depression is characterized by distinct symptom patterns and a more complex clinical course, precipitating intricate care needs and increased healthcare use among older adults. The drivers of these complexities remain poorly understood, and we aim to conduct three interconnected sub-projects scrutinizing them. Specifically, we will: 1) investigate the role of psychosocial, behavioral, and socioeconomic determinants of diverse depressive symptom patterns and transitions between them

2) assess health and survival consequences of different depressive symptom patterns

and 3) evaluate healthcare utilization in people with old-age depression, focusing on complex and avoidable transitions across care settings.Data and method: Longitudinal data on more than 7,000 older adults from four population-based cohorts included in the Swedish National Study on Aging and Care (SNAC) and harmonized via the National E-Infrastructure for Aging Research (NEAR) will be used. We will exploit more than 20 years of already-collected follow-up data, gathered using shared instruments across cohorts. Multi-state transition models will be used to capture diverse shifts across depressive states (no depression, subsyndromal depression, major depression) and care settings (home, formal care, hospital, institution), as well as their associated determinants and consequences.Relevance and utilization: Depression in older adults is a cause of major distress for patients, their families, and the healthcare system. A better understanding of its fluctuating course is required to identify strategies promoting prevention, recovery, and care continuity. Planned in close connection with patient organizations and care provider networks, this project will bring about knowledge sought by multiple stakeholders, ensuring that older adults with depression experience old age with the dignity they deserve.Plan for project realization: The project will be carried out by a multidisciplinary team with expertise in geriatric mental health, epidemiology, and care sciences. Its results will be deployed through the National Association for Social and Mental Health (RSMH). Researcher salaries constitute key budgetary items.

NEAR is a research infrastructure under construction that aims to promote and facilitate Swedish research into ageing by means of integration of a number of national longitudinal population-based projects and databases on ageing and health, to enhance the quality and generalisability of research results and to intensify international collaboration. The purpose of NEAR is to develop a technical platform for handling and coordinating high-quality population-based databases in Sweden in order to give researchers access to the information, and thereby create prerequisites for future high-quality research. NEAR integrates the projects/databases: Betula (memory changes over time) KP (Kungsholmen Project) SNAC (Swedish National Study on Ageing and Care - Kungsholmen, - Nordanstig, - Blekinge, - Skåne) Sweold (Swedish Panel Study of Living Conditions of the Oldest Old) SALT (Screening Across the Lifespan of Twins) SATSA (Swedish Adoption /Twin Study of Ageing) AGECAP (Centre for Ageing and Health/Gothenburg Population Studies) GENDER (Gender Differences in Health Behaviour and Health among Elderly) SHARE (Survey of Health and Retirement in Europe).

Traffic noise is an environmental exposure of growing concern with mounting evidence of serious adverse health effects. At least one in five Europeans (113 million people) are exposed to noise levels exceeding the European Environment Agency indicator level linked to harmful health effects. Besides the increased risk of cardiovascular and metabolic effects, hearing loss, and sleep disturbance, recent studies have indicated that prolonged exposure to noise might accelerate the risk of cognitive impairment, dementia, anxiety, and depression.We take advantage of the pre-existing data within the Nordic Studies on Occupational and Traffic Noise in Relation to Disease (NordSOUND) project, comprising over 185 000 adults from 5 Swedish and 2 Danish cohorts, to investigate whether exposure to traffic and occupational noise is related to dementia and mental health (depression, and anxiety) and to reveal potential mechanisms. We will adjust for individual- and area-level covariates to enable increased precision in the assessment of associations. We will also adjust for residential air pollution exposure and lack of greenness to explore the potential interactions.This collaborative research effort will address a considerable knowledge gap regarding noise exposure, dementia and mental health. Our results may have significant implications for risk assessment and public health policy, especially considering the recently relaxed noise guidelines in Sweden and the rapid urban growth.