Dementia and its most common cause Alzheimer’s disease (AD) are global health challenges. With no cure in sight, strategies to prevent or delay dementia onset in at-risk individuals are urgently needed, and multidomain interventions targeting multiple risk factors and mechanisms may be warranted. Several randomized controlled trials (RCT) are ongoing, but their optimal design and conduct are unclear. This thesis used data from three large, completed, pioneering prevention RCTs and a memory clinic, with the aim to offer insights into the selection and engagement of target populations in prevention RCTs. The aim was to assess the response to a multidomain lifestyle intervention in subgroups of participants to understand who benefitted the most (I) and investigate older adults’ knowledge of dementia as well as their motivation and attitudes towards prevention and RCT participation (II, III). In addition, risk factors, biomarkers, and research criteria for AD were explored and their impact on disease progression was assessed in two cohorts (IV, V). Studies I-III included participants of the 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) RCT (N=1,260) and the multinational Healthy Aging Through Internet Counselling in the Elderly (HATICE) eHealth RCT (N=2,724). These subjects did not have significant cognitive impairment but were at risk based on their cognitive performance and/or other risk factors. In FINGER, participant baseline characteristics, including age, sex, socioeconomic status, cognitive performance, and vascular risk factors, were studied as modifiers of the intervention effects on cognition (I). In HATICE, the reasons for participation were studied in all 3 countries (Finland, France, the Netherlands) before randomization with a questionnaire (N=341), followed by semi-structured interviews (N=46) (II). A subset of interviews were analyzed in Study III (interviewees who introduced the topic of dementia, N=15). Studies IV and V included individuals with mild cognitive impairment but no dementia. Study IV focused on a sample of Karolinska University Hospital memory clinic patients (N=318) with normal cerebrospinal fluid (CSF) β-amyloid (Aβ42) based on the cut-off values used at the clinic (low Aβ42 typical for AD), while Study V included participants of the LipiDiDiet RCT with International Working Group-1 (IWG-1) defined prodromal AD (impaired memory + one or several AD biomarkers; N=311, N=287 in the thesis). In the memory clinic cohort, biomarkers and other characteristics, including vascular factors, were studied as predictors of dementia (mean follow-up 3 years) (IV). In LipiDiDiet, the utility of IWG-1 as selection criteria was studied by classifying the participants according to more restrictive criteria (IWG-2, National Institute of Aging and the Alzheimer’s Association (NIA-AA) 2011, NIA-AA 2018) (V). The 2-year cognitive/functional decline and progression to dementia were also assessed. In the FINGER RCT, participant characteristics did not modify the response to intervention. Similar cognitive benefits were observed in the whole population, indicating that the intervention can be implemented in a large elderly population at increased risk of dementia. In the HATICE RCT, contributing to research, improving lifestyle, and receiving medical monitoring were identified as the most important reasons for participation. Interviews suggested some between-country differences (e.g., altruism emphasized in France, health checks in Finland). Having a family history of dementia or other first-hand experience was a recurring theme in the interviews. This was linked to increased awareness of dementia, yet uncertainty about prevention. Concerns over own health and risk were expressed, and those with a family history of dementia were highly motivated to enroll in HATICE and improve their lifestyle. In the memory clinic cohort, 38% developed dementia (mostly AD), and lower Aβ within the normal range was associated with a higher risk. Aβ improved the prediction based on age and cognition; applying a higher cut-off for abnormality did not affect the results. Most other factors did not predict dementia or improve the basic prediction. In the LipiDiDiet RCT, where brain atrophy was often the only biomarker available at screening, most participants with centrally analyzed CSF at baseline met the more restrictive AD criteria (e.g., 64% with NIA-AA 2018 AD, A+T+N+ profile). The dementia risk increased with increasing biomarker evidence. This thesis offers new insights into dementia prevention in different at-risk groups and informs the design, recruitment, and conduct of future RCTs. This is important given the current methodological challenges and disappointing results of RCTs. The results support the use of the FINGER model and selection criteria in RCTs with a similar design. Understanding older adults’ expectations and motivations to participate in RCTs will help design interventions that are perceived as attractive by the target populations. Regarding prodromal AD, less restrictive criteria work well in participant recruitment, and their use in certain RCTs could be preferred due to feasibility. In memory clinic patients, Aβ within the normal range may not rule out AD and risk of dementia could still be high. Future research is needed to understand if there is a window of opportunity for preventive interventions in this population. National Library of Medicine Classification: W 84, WT 101, WT 104, WT 155, WT 160 Medical Subject Headings: Alzheimer Disease/prevention &amp; control; Cognition; Dementia/prevention &amp; control; Aged; Biomarkers; Health Behavior; Healthy Aging; Life Style; Motivation; Risk Factors; Qualitative Research; Patient Participation; Patient Selection; Randomized Controlled Trials as Topic; Research Design

Dementia prevention in at-risk individuals. Focus on selection and engagement of target populations PDF

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