Sebastian Köhler

Background: Modifiable dementia risk factors rarely occur in isolation, yet their co-occurrence and clustering remain poorly characterized, limiting identification of high-risk individuals and development of targeted strategies. Objective: To identify clusters of ten modifiable risk factors in mid-life (45–65 years) and late-life (>65 years), and to examine their association with incident dementia. Methods: Data were drawn from the 2012 Dutch Public Health Monitor Survey (mid-life: n = 121,120; late-life: n = 125,848), with dementia follow-up through 2023. Ten modifiable risk factors: obesity, hypertension, diabetes, hearing loss, visual loss, physical inactivity, excessive alcohol consumption, smoking, loneliness, and depression, were used to derive clusters using latent class analysis. Cox proportional hazards models examined the association between late-life clusters and incident dementia. Results: In mid-life (mean age, 55.7 ± 6.2 years), four risk factor clusters were identified: cardiometabolic, substance use, psychosocial, and lower risk. In late-life (mean age, 73.9 ± 6.4 years), four clusters were identified: cardiometabolic, substance use, psychosocial and physically inactive, and lower risk. After adjustment for sociodemographic factors, the psychosocial and physically inactive cluster was associated with the highest hazard of dementia (hazard ratio (HR), 1.23; 95% CI, 1.16–1.32), followed by the substance use (HR, 1.16; 95% CI, 1.09–1.24) and the cardiometabolic cluster (HR, 1.12; 95% CI, 1.07–1.18). Conclusions: Distinct risk factor clusters were identified at both mid-life and late-life; the psychosocial and physically inactive cluster carried the highest risk of dementia. These findings underscore the importance of considering risk factor clustering when designing targeted interventions to reduce dementia risk across the life course.

Background: Young-onset dementia (YOD) occurs when symptoms start before age 65 and affects about 3.9 million people globally. Variability in first symptoms, the young age, and prevalent non-cognitive symptoms pose challenges in recognizing YOD, leading to diagnostic delays. Better awareness and recognition of warning signs in primary care is essential for early YOD diagnosis, facilitating access to appropriate services and informal care arrangements. Objective: To gain insights into the prediagnostic phase of YOD by exploring literature on early symptoms and factors influencing a timely diagnosis. Methods: A literature search was conducted across PubMed, Embase, Web of Science, and PsycInfo. Two independent reviewers screened 5862 titles and abstracts and assessed 790 full texts. Data extraction used a standardized form, including time to diagnosis, early symptoms, barriers, and facilitators to YOD diagnosis. Review reporting followed PRISMA-ScR guidelines. Focus group discussions with people with YOD, caregivers, and healthcare professionals (HCPs) contextualized the review findings. Results: We included 225 studies. Time to diagnosis ranged from 4 months to 15 years across dementia subtypes. Early symptoms included memory problems, language difficulties, disorientation, personality changes, delusions, hallucinations, apathy, and depression. HCPs, people with YOD, and their caregivers often lacked awareness of YOD, which hindered diagnosis. However, persistence in seeking medical care, YOD-related services, and couples’ agreements to seek professional help were essential facilitators. Conclusions: Early signs of YOD include cognitive, behavioral, and affective symptoms. Lack of YOD awareness hinders diagnosis, highlighting the need to raise awareness among HCPs and the community to promote early identification.

Background: There is an urgent need to better understand the mechanisms of dementia, particularly Alzheimer's disease (AD), the most common subtype. The BioBank Alzheimer Center Limburg (BBACL) study is an ongoing prospective cohort, including consecutive patients from the memory clinic of the Alzheimer Center Limburg, Maastricht University Medical Center+, the Netherlands. It aims to investigate the natural course of cognitive complaints and identify early clinical and biological determinants of disease progression. Objective: To describe the BBACL study design and procedures and present the baseline characteristics of the currently included participants. Methods: Patients undergo standardized assessment, including demographics, comorbidities, cognitive and functional assessments, neuropsychiatric symptoms, MRI cerebrum, and biomaterials [blood and cerebrospinal fluid (CSF) samples (subset)]. Additional blood and CSF samples are stored for future biomarkers research. Follow-up is scheduled at 1, 2, 5, and 10 years. Results: Since its start in 2009, 920 patients have been included at baseline. The mean baseline age was 68.4 (SD 11.3) years, with 41.6% being females. The mean Mini-Mental State Examination score was 27.0 (SD 2.6). At baseline, 39.6% had subjective cognitive decline, 40.0% mild cognitive impairment, and 20.4% dementia (58.0% probable/possible AD and 19.7% mixed AD/vascular dementia), reflecting the study's emphasis on early diagnostics. Cognitive, functional, and biomarker measures varied across diagnostic groups as expected. Conclusions: BBACL combines extensive biospecimens with rich multimodal phenotyping and longitudinal follow-up, creating opportunities for future integrative analyses and omics-based analyses to uncover novel biological signatures.

Introduction: Multidomain lifestyle interventions may slow down cognitive decline and dementia, but the brain mechanisms underlying these effects remain unclear. We investigated brain, inflammation, cardiometabolic, and gut health changes associated with a six-month multidomain lifestyle intervention in Dutch older adults at risk for cognitive decline and dementia. Method: Participants aged 60–75 years with ≥2 lifestyle-modifiable cardiovascular risk factors (e.g., BMI ≥25, physical inactivity) were recruited and randomised in a 1:1 ratio to a high-intensity intervention or active control group using stratified (2,4) block-randomisation. The multidomain lifestyle intervention included five lifestyle domains (diet, physical activity, stress management and mindfulness, cognitive training, and sleep). Primary outcomes were changes in cerebral perfusion levels, brain activity during working memory, working memory performance, inflammation profile, and microbiota diversity. Secondary outcomes included lifestyle factors and markers of neuroimaging, brain health, cardiovascular and gut health, and cognitive functioning. The effects of the lifestyle intervention were investigated using linear mixed-effect models. Results: A total of 102 participants were randomised into the intervention (n=53) or active control group (n=49), of which 86 participants completed the six-month multidomain lifestyle intervention. Baseline characteristics were similar between the groups. The intervention resulted in improved diet and sleep scores in the intervention group compared to the active control group (Beta 1.67, 95% CI 0.61;2.73, PFDR=0.01, and Beta −1.80, 95% CI −2.79;-0.81, PFDR=0.005, respectively). Within the intervention group, favourable reductions in lifestyle-modifiable cardiovascular risk factors, such as BMI and blood pressure, were observed, but these were not significantly different from changes in the active control group. The intervention did not result in significant changes over time between the intervention and control group in other primary and secondary outcomes. Conclusion: The HELI multidomain lifestyle was able to reduce lifestyle-modifiable cardiovascular risk factors associated with dementia, although not significant compared to the active control group. We did not observe significant intervention effects on brain, cardiometabolic, inflammatory, and gut health outcomes. These results emphasize the complexity of exploring the role of lifestyle on neurobiological brain mechanisms associated with maintaining optimal cognitive functioning in aging and their underlying peripheral (to central) mechanisms. Clinical Trial Registration Information: The HELI study was approved by an accredited Dutch national research ethics committee, the Medical Research Ethics Committee (MREC) Oost-Nederland (file number NL78263.091.21). This study is registered with ClinicalTrials.gov (Trial ID NCT05777863 ).

Background: Individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are at increased risk of dementia and may benefit from lifestyle-based strategies for secondary prevention in clinical practice. Objective: To examine risk awareness, needs and preferences for dementia risk reduction in individuals with self-reported SCD and MCI and memory clinic professionals. Methods: Using a mixed-methods approach, we conducted online surveys to examine risk awareness, needs and preferences, and semi-structured interviews to explore barriers and facilitators related to online dementia risk reduction. Results: 1167 individuals with SCD (n = 1092) and MCI (n = 75), predominantly community-based research volunteers and a smaller group recruited via memory clinics, and 58 professionals completed the survey. Among SCD/MCI individuals, 39.5% were unaware that dementia risk can be reduced through lifestyle changes, 97.5% were interested in obtaining such information, and 97.9% considered using an online dementia risk management tool. Among professionals, 10.3% were unaware of dementia risk reduction, and 87.0% considered using a tool on this topic during consultations. Cardiovascular risk factors were poorly recognized by SCD/MCI individuals and, though acknowledged by professionals, rarely discussed in consultations. Interviews with SCD/MCI individuals (n = 14) and professionals (n = 9) highlighted several areas supporting implementation of an online dementia risk management tool (e.g., personalization, up-to-date information, coaching). Conclusions: Dementia risk awareness was low among SCD/MCI individuals, and high among memory clinic professionals. Both groups showed strong interest in using an online dementia risk management tool, and specific content, design and delivery features may influence engagement. Findings should be interpreted recognizing the mostly online-recruited, higher-educated study sample.

Background: Brain-healthy lifestyle changes could help reduce dementia risk in individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI), but patients and clinicians in memory clinics often lack practical tools to support this. Objective: To explore the acceptability and usability of BreinZorg (English: BrainCare) in a memory clinic setting. BreinZorg is a co-created prototype consisting of a self-management website and hardcopy conversation aid providing dementia risk reduction information. Methods: The website includes a lifestyle assessment, personalized module recommendations, practical information on 16 modifiable dementia risk and protective factors (e.g., smoking, sleep) and a goal-setting feature. The hardcopy conversation aid briefly outlines these factors to support clinical risk reduction discussions. This study used semi-structured interviews based on the Program Participation Questionnaire and think-aloud sessions, which were analyzed through thematic content analysis. Participants were individuals with self-reported SCD or MCI (n = 19) and memory clinic professionals (n = 9), i.e., nurses/nurse practitioners, physicians/medical specialists and neuropsychologists. Results: BreinZorg was generally considered useful, trustworthy, easy to use, and applicable in clinical contexts. The platform's accessible design, nonjudgmental tone, and personalization features were appreciated. Some participants with SCD or MCI, particularly those already interested in brain health, desired more in-depth information. A lack of follow-up on personal goals and misaligned module recommendations after the lifestyle assessment were identified as barriers to sustained engagement. Conclusions: Memory clinic patients and professionals evaluated BreinZorg as practical, useful, and acceptable for supporting dementia risk reduction in clinical care. Offering more detailed information, integrating tailored follow-up support, and enhancing personalization may strengthen long-term user engagement.

Background: Socioeconomic inequalities in cognitive functioning and dementia risk have been reported, which might partly act through modifiable risk factors. We investigated the association between education, socioeconomic status (SES) and modifiable dementia risk with cognitive performance in older adults at risk of cognitive decline. Methods: We used cross‐sectional data from the Dutch, randomized, controlled, multidomain lifestyle intervention FINGER‐NL multicenter trial of 1210 adults aged 60 to 79. SES was measured by equivalent household income. Modifiable dementia risk was captured with the LIfestyle for BRAin health (LIBRA) index of 12 modifiable health conditions and lifestyle factors. A total score was created from individual test results of neuropsychological test battery (NTB). Associations of SES tertiles and LIBRA with the NTB total score were investigated with multiple linear regression analyses adjusted for demographics and study site. Structural equation modelling was used to examine potential mediation by LIBRA and the role of education. Results: A total of 1048 participants (mean age 67.5, 37.9% men) with full data were included. Being in the low SES tertile was associated with poorer NTB scores, independent of demographics and LIBRA (low vs middle: B=‐0.13, 95%CI=‐0.27 to 0.01; low vs high: B=‐0.20, 95%CI=‐0.34 to ‐0.06). Individuals with low SES also had higher (=worse) LIBRA scores (low vs middle: B=0.72, 95%CI=0.33 to 1.10; low vs high: B=0.53, 95%CI=0.15 to 0.92). Similarly, low educational levels were significantly associated with worse NTB scores (low vs high B=‐0.45, 95%CI=‐0.62 to ‐0.27) and higher LIBRA scores (low vs middle: B=0.65, 95%CI=0.13 to 1.17; low vs high: B=2.01, 95%CI=1.54 to 2.48). However, LIBRA scores did not explain NTB score differences by SES or education. Conclusion: Higher SES and educational level appear protective factors for optimal cognitive performance and a more favorable risk profile, but the latter did not explain cognitive differences. Individual and community‐based prevention programs to reduce social inequalities in brain health should therefore focus on individual as well as more upstream environmental risk factors.

Background: FINGER‐NL aims to investigate the effectiveness of a 2‐year multidomain lifestyle intervention to maintain optimal cognitive functioning in Dutch at‐risk older adults. Here we provide an update on the progress and follow‐up of this study. Methods: Embedded in the World‐Wide FINGERS initiative and as part of the MOCIA research programme, FINGER‐NL is a 24‐month Dutch multi‐center, randomized, controlled, multidomain lifestyle intervention trial among adults at risk for cognitive decline. Inclusion criteria are 60‐80 years of age and presence of both modifiable (based on LIfestyle for BRAin health (LIBRA) score) and non‐modifiable (positive family history of dementia or self‐reported subjective cognitive decline) risk factors. Participants were randomized to either a high‐intensity (personalized, supervised hybrid program with group meetings and individual sessions) or a low‐intensity (digital information) lifestyle intervention group. Efforts are ongoing to expand and enrich FINGER‐NL Results: Between February 2022 and May 2023, we screened 2057 individuals and randomly assigned 1210 eligible individuals to the high‐intensity ( n = 605) or low‐intensity group ( n = 605). One‐year follow‐up assessments have been completed and carried out in 544 (90%) participants in the high‐intensity group and 505 (83%) in the low‐intensity group. Two‐year follow‐up assessments are ongoing, with currently 369 completed assessments in the high‐intensity group (and n = 52 (12%) participants lost to follow‐up) and 358 completed assessments in the low‐intensity group (and n = 92 (20%) participants lost to follow‐up). Using stored biomaterials, blood‐based biomarker analyses and measurement of genetic variations are planned in 2025. Funding has been secured for additional follow‐up measurements at three and four years after baseline to determine sustained effects on cognitive performance and lifestyle after completion of the intervention. Currently, 456 (74%) participants who completed the intervention consented to participate in the extension study. Conclusion: FINGER‐NL is progressing well. Point of attention is participant adherence, especially in the low‐intensity group. There is high interest among participants to continue their participation with additional follow‐up measurements after completion of the intervention. Extension of the project and (inter) national (joint) initiatives expand and enrich FINGER‐NL, which enables and stimulates data sharing and joint analyses across WW‐FINGER studies.