From midlife dementia risk factors to late-life functionality: an examination of targets to support healthy aging
Year: 2025
Type: dissertation
Study design: Observational Study
Abstract: Age-related conditions such as dementia present a large public health burden and thus, there is a need to better understand modifiable risk factors and explore potential targets for prevention and treatment. Study 1 identified three sex-specific modifiable risk profiles among midlife adults: cardiometabolic risk, substance use-related risk, and low risk. In both sexes, the cardiometabolic risk profile was associated with higher incidence of dementia, poorer cognitive performance, and greater brain atrophy and white matter hyperintensities compared with the low risk profile. Compared with the low risk profile, the substance use-related risk profile in males had poorer cognitive performance and greater white matter hyperintensities but no difference in dementia incidence, but in females, this profile demonstrated increased dementia incidence and greater brain atrophy. A polygenic risk score for Alzheimer’s disease (AD) differentially influenced outcomes across profiles and had generally larger effects among females. Study 2 investigated the longitudinal dynamics between depressive symptoms, physical activity, and functional disability, which is tightly linked to cognitive decline, in adults in later late life using a cross-lagged panel model. Although depressive symptoms and physical activity were generally correlated throughout the study period, no direct effects between states were observed. However, several paths connecting depressive symptoms and physical activity through functional disability were observed. Most interestingly, functional disability demonstrated strong autoregressive effects, highlighting the importance of maintaining functional independence later in life. Study 3 explored the potential of repurposing a class of asthma medications, leukotriene receptor antagonists (LTRAs), for prevention and/or treatment of AD. Within people with AD dementia but not normal cognition, LTRA use was associated with slower cognitive decline in non-amnestic cognitive domains and slower clinical progression, adding evidence that LTRAs may be a potential treatment for AD dementia. Altogether, the findings highlight the need for a life-course perspective in dementia prevention and treatment, emphasizing the importance of inter-individual differences in risk prediction and treatment strategies, supporting functional independence especially among older adults, and novel inflammatory targets and pathways. Future studies should focus on replicating these results in more diverse populations, and translating the findings into clinical practice.
Source: TSpace (University of Toronto)
Author: Xiong, Lisa
Institution: University of Toronto
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7133058352