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Background: U.S. POINTER is a Phase 3, multicenter, randomized 2‐year clinical trial of two multidomain lifestyle interventions in 2111 older adults who are at increased risk of cognitive decline and dementia due sedentary lifestyle, poor diet, and other factors such as family history of memory impairment and suboptimum cardiovascular health. Method: Enrollment took place at five geographically diverse sites, beginning in 2019 and completing in early 2023. Participants are randomly assigned to one of two lifestyle intervention groups that differ in format, intensity, and accountability. Those randomized to the Self‐Guided Lifestyle Intervention receive annual medical monitoring and health education information, tools, and support to encourage increased physical and cognitive activity and a healthier diet through 2‐3 annual group meetings. Those randomized to the Structured Lifestyle Intervention receive frequent medical monitoring of cardiovascular health and a structured program of exercise (primarily aerobic), nutritional counseling, cognitive training and social engagement initially through weekly and then monthly group meetings. U.S. POINTER includes partnerships with local chapters of the Alzheimer's Association and lifestyle specialists to assist with intervention delivery. The primary outcome is 2‐year change in cognitive function measured with a global cognition composite score that permits harmonization with FINGER and other trials. Secondary and tertiary outcomes include measures of executive function and episodic memory, physical activity, diet, cognitive and physical activity, cardiometabolic disease risks, mood, quality of life, health care costs, and health care utilization. Result: U.S. POINTER is generating a richly phenotyped cohort that will provide a rigorous comparison of two lifestyle interventions designed to preserve cognitive function. It has nurtured 4 ancillary studies to assess intervention effects on outcomes related to sleep quality, brain structure and pathology, peripheral and neurovascular function, and the microbiome. It also partners with clinical trials within the World‐Wide FINGERS international network. The study is generating an archive of biospecimens and de‐identified public use data. Plans for a post‐intervention observational study of the U.S. POINTER cohort are underway. Conclusion: U.S. POINTER provides an important national resource to advance the field in understanding the role of nonpharmacological interventions in reducing risk for cognitive decline and Alzheimer's disease and related dementia. [ABSTRACT FROM AUTHOR]

Background: Lifestyle factors such as nutrition and diet are modifiable risk factors for the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). A small number of interventions recently showed cognitive and functional benefits. It is unclear however how long these benefits will last, requiring long‐term studies.LipiDiDiet was the first AD double‐blind, placebo‐controlled trial clinical trial to show a significant and sustainable benefit, including a 45% reduction in decline on CDR‐SB performance in a prodromal study population evaluating a multinutrient formulation (Soininen Lancet Neurology 2017; Soininen Alz&Dem 2021). We now extended the analysis from 3 years to up to 6 years of active intervention to investigate long‐term effects. Method: LipiDiDiet is a 6‐year randomised, double‐blind, placebo‐controlled trial, investigating the effects of a nutritional intervention in individuals with prodromal AD/MCIAD. 311 individuals with prodromal AD (IWG‐1) were randomized to active (125ml once‐a‐day drink; Fortasyn Connect [Souvenaid]) or a calorie‐matched control. Following the first 2 years of intervention, participants could opt‐in for annual extensions up to a maximum of 6‐year double‐blind intervention. Individual participants progressing to mild dementia were provided AD medication and/or open‐label active product and could continue in the trial. Main outcomes included Neuropsychological Test Battery (NTB) composites on cognition and memory, and the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). Modified intention‐to‐treat analyses were performed over 4‐6 years of intervention using a joint model combining longitudinal and survival data. Result: Adding data from all participants who completed the 4‐year visit while still on double‐blind treatment (n = 38) to the previously performed joint model analyses on the 3‐year data showed that the initially observed benefits on cognition, memory, and CDR‐SB appear to have continued beyond 3 years. These and other ongoing analyses are addressing the statistical challenges specific to long‐term AD trials including non‐random patterns of missing data. Conclusion: In addition to the already demonstrated sustainable benefits of Fortasyn Connect in individuals with prodromal AD/MCIAD, combined with feasibility of its long‐term use without indications for health concerns, we now report first results indicating that benefits on cognition, memory, and CDR‐SB are sustained over 4 years. [ABSTRACT FROM AUTHOR]

Background: Missing data can complicate the interpretability of a clinical trial, especially if the proportion is substantial and if there are different, potentially outcome-dependent causes. Methods: We aimed to obtain unbiased estimates, in the presence of a high level of missing data, for the intervention effects in a prodromal Alzheimer's disease trial: the LipiDiDiet study. We used a competing risk joint model that can simultaneously model each patient's longitudinal outcome trajectory in combination with the timing and type of missingness. Results: Using the competing risk joint model, we were able to provide unbiased estimates of the intervention effects in the presence of the different types of missingness. For the LipiDiDiet study, the intervention effects remained statistically significant after this correction for the timing and type of missingness. Conclusion: Missing data is a common problem in (Alzheimer) clinical trials. It is important to realize that statistical techniques make specific assumptions about the missing data mechanisms. When there are different missing data sources, a competing risk joint model is a powerful method because it can explicitly model the association between the longitudinal data and each type of missingness. Trial registration: Dutch Trial Register, NTR1705. Registered on 9 March 2009 [ABSTRACT FROM AUTHOR]

Background: Shorter leukocyte telomere length (LTL) is associated with aging and dementia. Impact of lifestyle changes on LTL, and relation to cognition and genetic susceptibility for dementia, has not been investigated in randomized controlled trials (RCTs).Methods: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability is a 2-year RCT enrolling 1260 participants at risk for dementia from the general population, aged 60-77 years, randomly assigned (1:1) to multidomain lifestyle intervention or control group. The primary outcome was cognitive change (Neuropsychological Test Battery z-score). Relative LTL was measured using quantitative real-time polymerase chain reaction (trial registration: NCT01041989).Results: This exploratory LTL substudy included 756 participants (377 intervention, 379 control) with baseline and 24-month LTL measurements. The mean annual LTL change (SD) was -0.016 (0.19) in the intervention group and -0.023 (0.17) in the control group. Between-group difference was nonsignificant (unstandardized β-coefficient 0.007, 95% CI -0.015 to 0.030). Interaction analyses indicated better LTL maintenance among apolipoprotein E (APOE)-ε4 carriers versus noncarriers: 0.054 (95% CI 0.007 to 0.102); younger versus older participants: -0.005 (95% CI -0.010 to -0.001); and those with more versus less healthy lifestyle changes: 0.047 (95% CI 0.005 to 0.089). Cognitive intervention benefits were more pronounced among participants with better LTL maintenance for executive functioning (0.227, 95% CI 0.057 to 0.396) and long-term memory (0.257, 95% CI 0.024 to 0.489), with a similar trend for Neuropsychological Test Battery total score (0.127, 95% CI -0.011 to 0.264).Conclusions: This is the first large RCT showing that a multidomain lifestyle intervention facilitated LTL maintenance among subgroups of older people at risk for dementia, including APOE-ε4 carriers. LTL maintenance was associated with more pronounced cognitive intervention benefits.Clinical Trials Registration Number: NCT01041989. [ABSTRACT FROM AUTHOR]

Introduction: The LipiDiDiet trial investigates the effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease (AD). Based on previous results we hypothesized that benefits increase with long‐term intervention. Methods: In this randomized, double‐blind, placebo‐controlled trial, 311 people with prodromal AD were recruited using the International Working Group‐1 criteria and assigned to active product (125 mL once‐a‐day drink) or an isocaloric, same tasting, placebo control drink. Main outcome was change in cognition (Neuropsychological Test Battery [NTB] 5‐item composite). Analyses were by modified intention‐to‐treat, excluding (ie, censoring) data collected after the start of open‐label active product and/or AD medication. Results: Of the 382 assessed for eligibility, 311 were randomized, of those 162 participants completed the 36‐month study, including 81 with 36‐month data eligible for efficacy analysis. Over 36 months, significant reductions in decline were observed for the NTB 5‐item composite (−60%; between‐group difference 0.212 [95% confidence interval: 0.044 to 0.380]; P = 0.014), Clinical Dementia Rating‐Sum of Boxes (−45%; P = 0.014), memory (−76%; P = 0.008), and brain atrophy measures; small to medium Cohen's d effect size (0.25–0.31) similar to established clinically relevant AD treatment. Discussion: This multinutrient intervention slowed decline on clinical and other measures related to cognition, function, brain atrophy, and disease progression. These results indicate that intervention benefits increased with long‐term use. [ABSTRACT FROM AUTHOR]

Background: Early pathological changes in white matter microstructure can be studied using the diffusion tensor imaging (DTI). It is not only important to study these subtle pathological changes leading to cognitive decline, but also to ascertain how an intervention would impact the white matter microstructure and cognition in persons at-risk of dementia.Objectives: To study the impact of a multidomain lifestyle intervention on white matter and cognitive changes during the 2-year Finnish Geriatric Intervention Study to prevent Cognitive Impairment and Disability (FINGER), a randomized controlled trial in at-risk older individuals (age 60-77 years) from the general population.Methods: This exploratory study consisted of a subsample of 60 FINGER participants. Participants were randomized to either a multidomain intervention (diet, exercise, cognitive training, and vascular risk management, n = 34) or control group (general health advice, n = 26). All underwent baseline and 2-year brain DTI. Changes in fractional anisotropy (FA), diffusivity along domain (F1) and non-domain (F2) diffusion orientations, mean diffusivity (MD), axial diffusivity (AxD), radial diffusivity (RD), and their correlations with cognitive changes during the 2-year multidomain intervention were analyzed.Results: FA decreased, and cognition improved more in the intervention group compared to the control group (p < 0.05), with no significant intergroup differences for changes in F1, F2, MD, AxD, or RD. The cognitive changes were significantly positively related to FA change, and negatively related to RD change in the control group, but not in the intervention group.Conclusion: The 2-year multidomain FINGER intervention may modulate white matter microstructural alterations. [ABSTRACT FROM AUTHOR]

Background: The oldest old is the fastest growing age group worldwide and the most prone to severe disability, especially in relation to loss of cognitive function. Improving our understanding of the predictors of cognitive, physical and psychosocial wellbeing among the oldest old can result in substantial benefits for the individuals and for the society as a whole. The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study investigated risk factors and determinants of cognitive impairment in a population-based longitudinal cohort, which was first examined between 1972 and 1992, when individuals were in their midlife, and re-assessed in 1998 and 2005-2009. Most of the study participants are currently aged 85 years or older. We aim to re-examine the cohort's survivors and gain further insights on the mechanisms underlying both cognitive and overall healthy ageing at old age.Methods: CAIDE85+ is the third follow-up of the CAIDE study participants. All individuals still alive and living in the Kuopio and Joensuu areas of Eastern Finland, from the original CAIDE cohort (two random samples, N = 2000 + ~ 900), will be invited to a re-examination. The assessment includes self-reported data related to basic demographics and lifestyle, as well as psychosocial and physical health status. Cognitive and physical evaluations are also conducted. Blood biomarkers relevant for dementia and ageing are assessed. Primary outcomes are the measurements related to cognition and daily life functioning (CERAD, Trail Making Test-A, Letter-Digit Substitution Test, Clinical Dementia Rating and Activities of Daily Living). Secondary endpoints of the study are outcomes related to physical health status, psychosocial wellbeing, as well as age-related health indicators.Discussion: Through a follow-up of more than 40 years, CAIDE85+ will provide invaluable information on the risk and protective factors that contribute to cognitive and physical health, as well as ageing and longevity.Study Registration: The present study protocol has been registered at https://clinicaltrials.gov/ (registration nr NCT03938727 , date 03.05.2019). [ABSTRACT FROM AUTHOR]

Objective: As no causal treatment for dementia is available yet, the focus of dementia research is slowly shifting towards prevention strategies. Therefore, this study aimed to examine the predictive accuracy of the "LIfestyle for BRAin Health" (LIBRA) score, a weighted compound score of 12 modifiable risk and protective factors, for dementia and mild cognitive impairment (MCI) in midlife and late-life, and in individuals with high or low genetic risk based on presence of the apolipoprotein (APOE) ε4 allele.Methods: The LIBRA score was calculated for participants from the Finnish Cardiovascular Risk Factors, Aging and Dementia (CAIDE) population-based study examined in midlife (n = 1024) and twice in late-life (n = 604) up to 30 years later. Diagnoses of MCI and dementia were made according to established criteria. Cox proportional hazards models were used to assess the association between LIBRA and risk of dementia and MCI in models adjusted for sex and education (age as timescale).Results: Higher midlife LIBRA scores were related to higher risk of dementia (hazard ratio [HR] = 1.27; 95% confidence interval [CI], 1.13-1.43) and MCI (unadjusted model: HR = 1.12; 95% CI, 1.03-1.22) up to 30 years later. Higher late-life LIBRA scores were related to higher risk of MCI (HR = 1.11; 95% CI, 1.00-1.25), but not dementia (HR = 1.02; 95% CI, 0.84-1.24). Higher late-life LIBRA scores were related to higher dementia risk among apolipoprotein E (APOE) ε4 non-carriers.Conclusions: Findings emphasize the importance of modifiable risk and protective factors for dementia prevention. [ABSTRACT FROM AUTHOR]

Background: Recruitment is often a bottleneck in secondary prevention trials in Alzheimer disease (AD). Furthermore, screen-failure rates in these trials are typically high due to relatively low prevalence of AD pathology in individuals without dementia, especially among cognitively unimpaired. Prescreening on AD risk factors may facilitate recruitment, but the efficiency will depend on how these factors link to participation rates and AD pathology. We investigated whether common AD-related factors predict trial-ready cohort participation and amyloid status across different prescreen settings. Methods: We monitored the prescreening in four cohorts linked to the European Prevention of Alzheimer Dementia (EPAD) Registry (n = 16,877; mean ± SD age = 64 ± 8 years). These included a clinical cohort, a research in-person cohort, a research online cohort, and a population-based cohort. Individuals were asked to participate in the EPAD longitudinal cohort study (EPAD-LCS), which serves as a trial-ready cohort for secondary prevention trials. Amyloid positivity was measured in cerebrospinal fluid as part of the EPAD-LCS assessment. We calculated participation rates and numbers needed to prescreen (NNPS) per participant that was amyloid-positive. We tested if age, sex, education level, APOE status, family history for dementia, memory complaints or memory scores, previously collected in these cohorts, could predict participation and amyloid status. Results: A total of 2595 participants were contacted for participation in the EPAD-LCS. Participation rates varied by setting between 3 and 59%. The NNPS were 6.9 (clinical cohort), 7.5 (research in-person cohort), 8.4 (research online cohort), and 88.5 (population-based cohort). Participation in the EPAD-LCS (n = 413 (16%)) was associated with lower age (odds ratio (OR) age = 0.97 [0.95–0.99]), high education (OR = 1.64 [1.23–2.17]), male sex (OR = 1.56 [1.19–2.04]), and positive family history of dementia (OR = 1.66 [1.19–2.31]). Among participants in the EPAD-LCS, amyloid positivity (33%) was associated with higher age (OR = 1.06 [1.02–1.10]) and APOE ɛ4 allele carriership (OR = 2.99 [1.81–4.94]). These results were similar across prescreen settings. Conclusions: Numbers needed to prescreen varied greatly between settings. Understanding how common AD risk factors link to study participation and amyloid positivity is informative for recruitment strategy of studies on secondary prevention of AD. [ABSTRACT FROM AUTHOR]

Background: Multimodal lifestyle interventions have proven successful with at‐risk populations; however, little is known of the interventions effect on patients with prodromal Alzheimer's disease. Even less is known of feasibility and adherence to dietary recommendations within the population. Method: A 6‐month pilot trial was conducted with 93 participants randomized into three intervention arms. Two groups received physical exercise, cognitive training, nutritional guidance, monitoring and management of vascular and metabolic risk factors, and social stimulation, with one group receiving a medical food product. The third group was a self‐guided control group. Intake of individual macro‐ and micronutrients were analyzed from 3‐day food records. Adherence to recommendations assessed from food frequency questionnaires and by using a healthy diet index. Result: For macro‐ and micronutrient intake there were no differences at the end of the intervention and intake was in line with other national food surveys. The group who received intervention and medical food product has significantly better healthy diet index score compared to the other groups. Conclusion: There were few longitudinal significant differences on macro‐ and micronutrient intake, however, dietary intake improved significantly in itself when the intervention was complemented with a medical food product. [ABSTRACT FROM AUTHOR]

Background: Interactions between genetic and lifestyle‐related risk factors for dementia have been investigated mainly in observational studies, with conflicting results. Less is known about whether genetic risk factors for dementia (not just APOE4 allele but also polygenic risk beyond APOE4) have an impact on the effects of multidomain lifestyle preventive interventions on cognition. Although there is overlap between risk factors for dementia and e.g. cardiovascular diseases (CVD), it is unclear if CVD genetic risk may also have an impact on potential intervention benefits. Method: The FINGER randomized controlled trial included 1260 participants aged 60‐77 years and at risk for dementia from the general Finnish population. Cognition improved more during 2 years in the multidomain lifestyle intervention (diet, exercise, cognitive training, social activities and cardiovascular risk monitoring) compared with control (regular health advice) group. Genetic risk scores for Alzheimer's disease (AD‐GRS, excluding APOE) and CVD‐GRS were selected based on existing literature, and calculated using GWAS data from FINGER participants. Result: Previous findings indicated that the FINGER intervention had clear cognitive benefits among APOE4 carriers. Preliminary results suggested a less straightforward impact of AD‐GRS, especially after adjustment for APOE4. There seemed to be a pattern of more intervention‐related cognitive benefit among participants with lower compared with higher CVD‐GRS. Conclusion: APOE4, AD‐GRS and CVD‐GRS may have different impact on the cognitive benefits of multidomain lifestyle interventions for dementia prevention. Ongoing World‐Wide FINGERS trials in populations with a variety of genetic profiles will create opportunities for more detailed investigation of genetic‐lifestyle interactions in the context of preventive interventions. [ABSTRACT FROM AUTHOR]

Background: This exploratory study investigated associations between physical function and neuroimaging biomarkers: brain magnetic resonance imaging (MRI) and Pittsburgh compound B‐positron emission tomography (PiB‐PET) measures during the 2‐year Finnish Geriatric Intervention Study to prevent cognitive impairment and disability (FINGER). Method: FINGER targeted 60–77‐year‐old general population at‐risk and without dementia or substantial cognitive impairment. Measures of physical function (activities of daily living (ADL), hand grip strength, physical performance, Fried's frailty phenotype index and self‐rated health) from baseline and 2‐year visits were used. Baseline neuroimaging measures, MRI (hippocampus, total gray matter volumes, Alzheimer's disease (AD) signature cortical thickness) were available for 115‐132 participants and PiB‐PET (composite score) for 44‐48 participants. Linear and logistic regressions were used to test the cross‐sectional associations and the impact of baseline imaging measures on changes in physical function. Models were adjusted for site, sex and education. Result: Cross‐sectionally, higher ADL were associated with higher hippocampus volume (β = 0.18 p = 0.048), total gray matter volume (β = 0.15 p = 0.005) and AD signature cortical thickness (β = 0.25 p = 0.006) while stronger hand grip and was associated with higher total gray matter volume (β = 0.20 p = 0.041) significantly. Baseline imaging measures were associated with changes in physical function: higher baseline hippocampus volume was associated with maintenance/improvement in the ADL (OR = 0.56 p = 0.039) while lower hippocampus at baseline predicted poorer physical performance over time (OR = 1.66 p = 0.036). Conclusion: Higher brain integrity is associated with better physical function while lower baseline brain integrity predicts poorer physical function over time. [ABSTRACT FROM AUTHOR]

Background: Blood biomarkers show promise in screening for Alzheimer's disease (AD) brain pathology, but best predictors of eligibility for disease‐modifying treatment remain unclear. We have previously reported estimates for potential eligibility for anti‐amyloid treatment in a real‐life memory clinic setting (Rosenberg et al., Neurology 2022); the current study explored associations between AD blood biomarkers and treatment eligibility. Method: Study population consisted of 224 patients from the Karolinska University Hospital Theme Aging Memory Clinic, with complete data (clinical, CSF, MRI, and plasma biomarkers Aβ40, Aβ42, NFL, GFAP, ptau181, ptau231). In total, 57% had subjective cognitive impairment, 21% mild cognitive impairment, and 22% dementia. Blood biomarkers were analysed using ultrasensitive Single molecule array (Simoa). Logistic regression models were used with zero‐skewness log‐transformed blood markers as predictors of treatment eligibility (defined based on the published use recommendations for anti‐amyloid treatment aducanumab). Areas under the curve (AUCs) were calculated for a pragmatic model including age, sex, and global cognition (MoCA) (base model), and for each model including blood biomarkers (alone and in combinations, with or without base model). Result: Thirty‐two out of 224 patients (14%) were classified as potentially eligible for anti‐amyloid treatment. AUC for the base model was 0.65 (95% confidence interval 0.56–0.74). AUCs for models including only blood markers were 0.76 (0.69–0.83; Aβ42/40), 0.77 (0.70–0.84; NFL), 0.80 (0.73–0.88; GFAP), 0.81 (0.74–0.89; ptau181), 0.83 (0.76–0.90; ptau231), and 0.87 (0.82–0.93; all markers). AUC was 0.89 (0.83–0.94) for the full model (all data). In a scenario where the base model was combined with a single blood marker, highest AUCs were observed for models including ptau231 or GFAP (both 0.83, 0.75–0.90). Conclusion: All blood biomarkers, individually and combined, outperformed the commonly available clinical variables in predicting potential eligibility for disease‐modifying treatment. Ptau markers, especially ptau231, and GFAP seem most promising in this context. [ABSTRACT FROM AUTHOR]

Background: Cortisol, one of the most important mediators of stress in humans, is often found increased in Alzheimer's disease (AD) patients and correlates with disease severity. Stress response and inflammation are two systems that are tightly associated to one another. Several lines of evidence suggest that cortisol can promote inflammation. However, less is known on the interaction of cortisol with neuroinflammation in the context of AD, and to the best of our knowledge there are no human studies that have systematically explored the association of these two systems in AD patients so far. The aim of this study was to investigate levels of cerebrospinal fluid (CSF) biomarkers of neuroinflammation and their relationship to salivary cortisol in a memory clinic cohort. Method: A total of 108 memory clinic patients with subjective cognitive decline (SCI, n = 40), mild cognitive impairment (MCI, n = 39) and AD (n = 29), from the Karolinska University Hospital in Stockholm, Sweden, were included in this study. Salivary cortisol was collected at six timepoints during the day on two days, to quantify awakening cortisol, cortisol awakening response (CAR), bedtime cortisol and total cortisol. CSF levels of 37 neuroinflammation and cerebrovascular dysfunction biomarkers were determined by a multiplex immunoassay. Associations among cortisol and neuroinflammation markers were assessed by linear regression models adjusting for age and diagnosis. ANCOVA tests were used to compare biomarker levels between the diagnostic groups. Result: Awakening cortisol was significantly elevated in the AD group compared to the SCI and MCI participants. Higher IP‐10 and placental growth factor (PlGF) levels were associated with decreased CAR independent of age and diagnosis. Thymus and activation‐regulated chemokine (TARC), CRP, intracellular adhesion molecule 1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1) levels were upregulated in MCI participants compared to SCI and AD. Conclusion: We provide evidence that the HPA axis is altered in AD. Moreover, salivary cortisol is associated to neuroinflammation in an age and diagnosis independent manner. Finally, neuroinflammatory and vascular dysfunction regulators are increased in CSF during MCI stages followed by a drop in their levels in AD participants, presumably reflecting a more active role of neuroinflammation at an early state. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular risk factors are associated with cognitive decline and dementia. Timely estimation and targeting of cardiovascular risk burden may contribute towards the prevention of cognitive decline. The cardiovascular risk scores of the European Society of Cardiology's, SCORE (for adults up to 64 years) and SCORE‐OP (for older adults aged 65 years or more), are commonly used tool for estimation of 10‐year CVD mortality and may reflect the impact of cardiovascular risk burden on brain pathology if validated against neuroimaging biomarkers. Method: This study investigated associations between (i) baseline SCORE/SCORE‐OP and baseline neuroimaging biomarkers (brain magnetic resonance imaging [MRI] and Pittsburgh Compound B‐positron emission tomography [PiB‐PET] measures) (ii) change in SCORE/SCORE‐OP and change in neuroimaging measures during the 2‐year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). FINGER targeted at‐risk older adults, aged 60‐77 years, from the general population. Participants were randomized to either multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice). Neuroimaging (MRI and PiB‐PET) data from baseline and 2‐year visits were used. A total of 112 participants had repeated brain MRI measures (hippocampus, total grey matter, and white matter lesion volumes, and Alzheimer's disease signature cortical thickness). Repeated PiB‐PET scans were available for 39 participants. Result: Preliminary results suggest that at baseline higher SCORE/SCORE‐OP, indicating increased risk of CVD mortality was significantly associated with lower hippocampus volume (estimate = ‐0.010; p = 0.004), lower total grey matter volume (estimate = ‐0.016; p = 0.007), higher white matter lesion volume (estimate = 0.048; p = 0.015), and lower AD signature cortical thickness (‐0.004; p = 0.048) but not with PiB‐PET. No significant associations were found for change in neuroimaging measures and baseline SCORE/SCORE‐OP or change in SCORE/SCORE‐OP during the 2‐year follow‐up. Conclusion: Cardiovascular risk scores need to be validated against different brain pathology markers in diverse populations. This will enable more precise identification and estimation of dementia risk profiles, guiding at‐risk persons to precise intervention strategies, good for both, heart, and brain. [ABSTRACT FROM AUTHOR]

Background: Dementia risk scores could be instrumental in the implementation of multidomain lifestyle interventions for dementia prevention. However, as relatively new tools, their performance requires further validation. Given the extensive overlap between risk factors for dementia and cardiovascular disease (CVD), multidomain interventions usually have an important vascular component and better‐established cardiovascular risk scores could become useful in this context. More evidence is needed on their ability to predict the risk of cognitive decline and dementia. SCORE/SCORE‐Older People (OP) are the official tools of the European Society of Cardiology to estimate the 10‐year CVD‐mortality risk. In this study, we investigated the association between SCORE/SCORE‐OP and cognitive function within FINGER, the first large trial showing the efficacy of a multidomain lifestyle‐ and vascular‐based intervention in preventing cognitive decline. Method: SCORE (age<65) and SCORE‐OP (age≥65) were calculated in the population of the 2‐year FINGER trial (N = 1236, baseline and 24 months). The cognitive outcomes (baseline, 12 and 24 months) were the overall z‐score from a Neuropsychological Test Battery (NTB, 14 tests, primary outcome) and the z‐scores of the NTB cognitive domains (Memory, Executive Function, and Processing Speed, secondary outcomes). The associations between (i) SCORE/SCORE‐OP and cognition, (ii) SCORE/SCORE‐OP and changes in cognition, and (iii) changes SCORE‐OP and changes in cognition were assessed using linear mixed‐models repeated‐measures with maximum likelihood estimation. Result: Higher baseline risk of CVD‐mortality, estimated with SCORE/SCORE‐OP, was significantly and consistently associated with worse cognition, (NTB total composite: Estimate = ‐0.036; CI: ‐0.042 to ‐0.030; P‐value>0.0001; individual NTB cognitive domains: P‐values<0.0001) and yearly lower improvement in cognitive performance (NTB total composite: Estimate = ‐0.009, CI: ‐0.011 to ‐0.007, P‐value>0.0001; individual NTB cognitive domains: P‐values<0.0001). 2‐year change in SCORE‐OP was not significantly associated with changes in cognition during the FINGER study period. Conclusion: SCORE/SCORE‐OP could be useful in predicting the risk of cognitive decline in a trial aimed at improving lifestyle and vascular‐related risk factors of dementia. However, more evidence is needed on their efficacy in predicting dementia risk and the response to multidomain lifestyle‐ and vascular‐ based interventions. Future studies on other well‐established and easy‐access cardiovascular risk scores could also provide relevant findings. [ABSTRACT FROM AUTHOR]

Background: Lifestyle factors such as nutrition and diet are increasingly recognized as modifiable risk factors for the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). Previous studies with the multinutrient combination Fortasyn Connect (Souvenaid) have shown benefits in mild AD dementia. The LipiDiDiet1‐3 study was designed to investigate the effects of Fortasyn Connect in individuals with prodromal AD. With up to 6 years of randomised, double‐blind, placebo‐controlled (RCT) intervention and an additional 2 years of open‐label intervention, LipiDiDiet is a unique long‐running RCT with a nutritional intervention in prodromal AD/MCIAD. Method: Individuals with prodromal AD (IWG‐1) were recruited from 11 sites across Finland, Sweden, Germany, and the Netherlands between 2009 and 2013 and randomized to the active product (125ml once‐a‐day drink; Fortasyn Connect) or a calorie‐matched placebo control. Following the first 2 years of intervention, participants could opt in for annual extensions up to a maximum of 6‐year double‐blind and 2‐year open‐label intervention. Main efficacy outcomes included measures of cognition, function, brain atrophy, and disease progression. Inherent to long‐term follow‐up studies like LipiDiDiet, interpretability of the safety data is limited by several factors like decreasing sample size, treatment switching, and potential non‐compliance, differential attrition, and gradual underreporting of events. We will report preliminary results on long‐term safety to the intervention over the full 8‐year intervention period. Result: From the 311 participants randomized at baseline, n = 245, 162, 84, 49, 29, 17, 8 participants completed respectively the 24‐, 36‐, 48‐, 60‐, 72‐, 84‐, and 96‐month intervention periods. The frequency, severity and types of recorded adverse events (AEs) were consistent with the studied population and none of the serious AEs was assessed by the investigators as related to the study product. The overall incidences of (serious)AEs were comparable between groups, both while on double‐blind treatment over the first 6 years and while on open‐label treatment from dementia diagnosis or start open‐label intervention onwards. Conclusion: Preliminary results on safety suggest that there are no health concerns related to the use of Fortasyn Connect for up to 8 years in a prodromal AD/MCIAD population. 1Lancet Neurol. 2017;16:965‐975. 2Alz Dementia. 2021;17:29‐40. 3Funding includes EU‐JPND. [ABSTRACT FROM AUTHOR]