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Introduction: Evidence on sex differences in the risk for dementia has been mixed. The goal was to assess sex differences in the development of dementia, and in the effects of a lifestyle intervention. Methods: Two strategies were adopted, one using combined data from three large Nordic population‐based cohort studies (n = 2289), adopting dementia as outcome, and 2‐year multidomain lifestyle intervention (n = 1260), adopting cognitive change as outcome. Results: There was higher risk for dementia after age 80 years in women. The positive effects of the lifestyle intervention on cognition did not significantly differ between men and women. Sex‐specific analyses suggested that different vascular, lifestyle, and psychosocial risk factors are important for women and men in mid‐ and late‐life. Conclusion: Women had higher risk for dementia among the oldest individuals. Lifestyle interventions may be effectively implemented among older men and women. [ABSTRACT FROM AUTHOR]

Background: Dementia prevention is a global public health priority. The FINGER multimodal lifestyle intervention is the only intervention model so far that has demonstrated significant cognitive and other health benefits in at‐risk older adults. LETHE proposes a new multimodal precision prevention approach where FINGER intervention is complemented with digital tools to optimize intervention delivery, personalize recommendations based on individual risk profile, and support risk factor self‐management. The multinational 2‐year randomized controlled LETHE pilot trial aims to test the feasibility of a digitally supported, adapted FINGER intervention among older adults at risk of cognitive decline and dementia. Method: A total of 160 individuals aged 60‐77 years and with risk factors for dementia but no substantial cognitive impairment are recruited at four sites (Austria, Finland, Italy, Sweden; N = 40 per country). Digital readiness and experience with smart devices are required. Participants are randomized 1:1 to 1) structured multimodal lifestyle intervention (dietary guidance, exercise, cognitive training, vascular/metabolic risk management, social stimulation, sleep/stress management) where in‐person individual and group‐based activities are supported with the LETHE smartphone app developed in the project; or 2) self‐guided lifestyle intervention (regular health advice and access to a simplified app with no personalized/interactive content). Both groups wear a smartwatch to gather passive data (e.g., activity, sleep). Primary outcomes are retention rate, adherence to intervention and engagement with the app, and change in dementia risk based on validated risk scores (CAIDE, LIBRA). Secondary outcomes are lifestyle changes and changes in cognition, stress‐related symptoms, sleep, health‐related quality of life, and health literacy. Participant experiences will also be explored. The LETHE Advisory Board (members of the public) provided feedback on the trial protocol. Result: Trial is registered at ClinicalTrials.gov (NCT05565170), and ethical approval has been obtained in each country. Recruitment started in September 2022 and will be completed in Spring 2023. Updates and results on study progress will be presented. Conclusion: LETHE pilot trial will inform about the feasibility of technological solutions and a digitally assisted lifestyle program to support brain health among older adults. If proved to induce sustained behavioural changes, digital tools could offer potential for large‐scale, cost‐effective dementia prevention programs. [ABSTRACT FROM AUTHOR]

Background: The successful FINGER multidomain intervention model combined dietary intervention (healthy Nordic diet) with exercise, cognitive training, social activities, and cardiovascular risk monitoring. The FINGER model is being tested and optimized in the World‐Wide FINGERS network of multidomain dementia prevention trials (45+ countries). Advanced FINGER 2.0 models combine lifestyle interventions with multi‐nutrients and/or putative disease‐modifying drugs. Method: The 11‐year extended follow‐up of FINGER trial participants (N:1260, at‐risk general population) was completed in Q1‐2023. The MIND‐AD pilot‐trial (N:93, prodromal Alzheimer's disease (AD)) included medical food (Fortasyn Connect), tested alone or in combination with multidomain lifestyle intervention for 6 months. The MET‐FINGER trial (N:600, at‐risk general population enriched with APOE4‐carriers, 2‐year intervention) includes different dosages of metformin (in combination with upgraded FINGER lifestyle intervention). Result: New nutrition/metabolic related data will be presented from FINGER where eg. adherence to healthier diet was still relatively high in the multidomain arm after the extended follow‐up. Higher adherence was also related to better cognition. Several dietary and metabolic biomarkers have been analyzed revealing underlying mechanisms and responders (eg persons with insulin resistance, higher HOMA, responded less). In the MIND‐AD trial, participants from 4 European countries were randomized to the multidomain lifestyle intervention alone (N:32), or in combination with medical food (N:31), and 30 to the control group. Adherence was high for all intervention domains (78‐87%). Compared with the control group, the group with lifestyle+medical food showed a decrease in vascular risk burden (P = 0.027) and an increase in healthy diet patterns (P = 0.045), and better cognition after the intervention (CDR‐SOB). There were no significant differences between the lifestyle only and control group. MET‐FINGER trial recruitment started in January 2023 (preliminary data presented). Conclusion: Longer‐term dietary and lifestyle changes are feasible and effective in older adults in the at‐risk spectrum of AD/dementia. Beneficial effects (adherence to and effects of interventions) seemed to improve with the inclusion of medical food in prodromal AD. The unique long follow‐up of FINGER provides important information about long‐term effects and methodological aspects. The MET‐FINGER trial will provide data on synergistic effects between FINGER intervention and a drug targeting both glucose metabolism and AD pathology. [ABSTRACT FROM AUTHOR]

Background: Comorbidities such as hypertension, hypercholesterolemia and diabetes are known contributors to Alzheimer disease (AD) progression. However, their mechanistic contribution to pathology and neurodegeneration has not been clarified. The aim of this study was to investigate cerebrospinal fluid (CSF) levels of markers reflecting brain changes in synaptic integrity, inflammation, oxidative stress, glucose homeostasis and cholesterol metabolism in memory clinic patients without known AD comorbidities. Method: CSF samples from 90 memory clinic patients without diagnosed hypertension, hypercholesterolemia, or diabetes nor other neurodegenerative disorder, were used to investigate 13 molecular markers representing key mechanisms underlying AD pathogenesis. Associations were analyzed by linear regression. Two‐step cluster analysis was used to determine patient clusters. Two key markers were analyzed by immunofluorescence staining in hippocampus from control and AD individuals. Result: CSF angiotensinogen, thioredoxin‐1, and interleukin‐15 had the most prominent associations with AD pathology, synaptic and axonal damage. SNAP‐25 and NFL were increased in MCI and AD cases. Grouping biomarkers by biological function, showed that inflammatory and survival components were associated with AD pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In data‐driven analysis, two patient clusters were identified; cluster 1 had increased CSF markers of oxidative stress, vascular pathology and neuroinflammation and was characterized by elevated synaptic and axonal damage, compared to cluster 2. Clinical groups were evenly distributed between the clusters. Analysis of post‐mortem hippocampal tissue, showed that, compared to non‐demented controls, angiotensinogen staining was higher in AD and co‐localized with phosphorylated‐tau. Conclusion: The identification of biomarker‐driven endophenotypes of cognitive disorder patients, further highlights the biological heterogeneity of AD and the importance of tailored prevention and treatment strategies. [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: The JPND‐funded project EURO‐FINGERS (2019‐2023) is part of the World‐Wide FINGERS network of multidomain trials for dementia risk reduction and prevention. It aims to develop relevant and standardised tools and methods for future trials or multidomain interventions to reduce dementia risk. Method: Since its beginning, EURO‐FINGERS has involved people from the general public in the project by means of an Advisory Board (AB). The AB is composed of 14 people from seven different European countries, who 1) have participated in prevention trials, 2) have a diagnosis/label of Subjective Cognitive Decline, Mild Cognitive Impairment, or dementia, and/or 3) take care of someone with dementia. Result: The AB has worked closely with the researchers in the consortium and provided input to the different tools and methods developed in the project. Due to the COVID pandemic, all this work has been online. Conclusion: In the session, we will describe the main principles, challenges and approach used to set up the AB and meaningfully involve people with an interest in/ affected by dementia in the project. Next, we will present some of the work developed with the AB, specifically on the important topic of communication in this complex field. This will include reflections on the terminology to discuss the topic of risk reduction and dementia prevention in different contexts, as well as the more specific topic of dementia risk communication in the context of the memory clinic. The latter is an example of one of the tools which the consortium is developing. To close the session, the project coordinator and a member of the AB will address the topic of impact and value of this type of work for researchers and for members of the public. [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: Interventions simultaneously targeting multiple risk factors are most likely to prevent neurocognitive disorders. This was demonstrated in the 2‐year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). However, the feasibility and effects of multimodal interventions in individuals at an early symptomatic disease stage (prodromal AD) are unclear. The objective of the MIND‐AD trial was to evaluate the feasibility of an adapted FINGER‐based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD. Methods: MIND‐ADMINI is a multinational proof‐of‐concept 6‐month randomized controlled trial (RCT, ClinicalTrials.gov NCT03249688), with four trial sites (Sweden, Finland, Germany, France). The target population is individuals with prodromal AD using the International Working Group‐1 criteria and vascular and/or lifestyle‐related risk factors. The parallel‐group RCT includes three arms: 1) multimodal lifestyle/vascular intervention (diet, exercise, cognitive training and social stimulation, vascular/metabolic risk management); 2) multimodal lifestyle/vascular intervention+medical food (Fortasyn Connect); 3) regular health advice/care (control group). Primary outcomes: feasibility and adherence. Secondary outcomes: adherence to the individual intervention domains and healthy lifestyle changes, Results: Screening began September 2017 and was completed May 2019 in all four countries. Altogether, 93 participants were randomized, and the 6‐month intervention was completed December 2019. Electronic data entry and processing was completed December 2020 (delays due to Covid‐19). The mean (SD) age of the entire sample was 72.9 years, education level was 12.8 years, and MMSE score 27.6 points. Vascular and lifestyle‐related risk factors were expected based on the inclusion criteria. Impaired fasting glucose (≥ 6,1 mmol/L) was seen in 29%, and 40% were overweight, with BMI ≥25 and, 12% had BMI ≥30. The intervention proceeded as planned and the preliminary results and participant experiences are positive, supporting the feasibility. Detailed results will be presented, and lessons learned will be discussed. Conclusions: For the first time, MIND‐AD tests the feasibility of and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. The positive intervention experiences are important for this patient group currently lacking effective treatments. The trial also offers a model for pharmacological/non‐pharmacological combination therapies and informs larger efficacy prevention trials. [ABSTRACT FROM AUTHOR]

Background: Risk scores for dementia and cardiovascular disease (CVD) predict dementia development, but their link to underlying brain pathology remains unclear. This study explored the cross‐sectional associations between well‐validated CVD and dementia risk scores and dementia‐related cerebrospinal fluid (CSF) and imaging markers in memory clinic patients without dementia, Method: The study population consisted of 207 patients with subjective cognitive impairment or mild cognitive impairment from the Karolinska University Hospital, Theme Aging, Memory Clinic, who had CSF (Aβ42, phosphorylated tau, total tau, neurofilament light chain NfL), visual MRI ratings (medial temporal lobe atrophy MTA, Fazekas for white matter lesions WML), and available clinical data to calculate risk scores. CVD risk score (FINRISK) was calculated for all patients; data for the CAIDE Dementia Risk Score (with and without APOE) were available for a subsample (N=88). The associations between risk scores and biomarkers were analyzed with linear regression (zero‐skewness log‐transformed CSF biomarkers as dependent variables) and ordinal regression (MTA and WML ratings as dependent variables). Risk scores were categorized into 3 similar‐sized groups (lower‐, intermediate‐, and higher‐risk groups; lower‐risk group used as reference), Result: Higher FINRISK score and CAIDE score (with APOE) were associated with lower levels of CSF Aβ42 (coefficients in the higher‐risk groups ‐0.05, p=0.02 for FINRISK and ‐0.08, p=0.04 for CAIDE). Higher CAIDE score (with APOE) was also associated with a lower CSF Aβ42/p‐tau ratio (coefficient ‐0.03, p=0.03 in the higher‐risk group). With respect to neuronal injury markers, a higher risk of CVD and dementia was associated with higher CSF NfL levels (coefficients in the higher‐risk groups 0.58, p<0.001 for FINRISK; 0.38, p=0.001 for CAIDE; 0.34, p=0.005 for CAIDE with APOE). Furthermore, higher‐risk patients had more pronounced MTA (OR 2.3, 95% CI 1.2–4.5 for FINRISK; OR 3.0, 95% CI 1.2–7.4 for CAIDE), and WML (OR 2.4, 95% CI 1.2–4.5 for FINRISK), Conclusion: Having a higher risk of CVD or dementia was associated with several dementia‐related CSF and imaging markers. Follow‐up studies are needed to explore the utility of different risk scores in assessing risk of cognitive decline and disease progression in memory clinic patients. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is multifactorial. Interventions simultaneously targeting multiple risk factors are most likely to be effective, as demonstrated in the 2‐year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). While patients with prodromal AD represent a group with high risk of progressing to dementia, no trials have tested the feasibility of multimodal interventions in prodromal AD. The main purpose of the MIND‐ADMINI was to evaluate the overall adherence to such multimodal intervention. This sub‐study focuses on exploratory outcomes which included physical performance and physical activity (PA) levels. Method: MIND‐ADMINI is a 6‐month multicenter (Sweden, Finland, Germany, France) randomized controlled pilot trial. Participants with prodromal AD, between 60 and 85 years were randomized into three groups: usual care (control (C)), multidomain lifestyle intervention combining nutritional guidance, cognitive training, exercise, and careful monitoring of vascular risk factors (ML), or multidomain lifestyle intervention+medical food (ML+MF) (Fortasyn Connect). The multidomain lifestyle intervention was based on the FINGER model and included a progressive aerobic‐ and strength training program. Moderate to vigorous physical activity (MVPA), light activity, step counts, and time (min/day) spent sedentary were evaluated using data from a hip‐worn accelerometer. For each outcome, 6‐month values were regressed on baseline to estimate change. Results: Baseline accelerometry data was available for 66 of 69 participants in Sweden, Finland, and France. At the 6‐month follow‐up, accelerometry data from 55 participants was included. At baseline mean age (SD) was 72,9 (6,2) years, 50,7% were men, and MMSE score was 27,6 (1,6) points. No significant values were found. At follow‐up, all groups increased their sedentary time, C (8,3%), ML (9,3%) and ML+MF (1,6%). Increased step count (3,4%) time in MVPA (2,8%) and light activity (9,5%) was observed during follow‐up in the ML+MF group. Conclusions: Measurement of physical activity level using a hip‐worn accelerometer was feasible in this population. The observed increased time in MVPA, light activity and step counts in ML+MF group at the same time as sedentary time increased in all three groups between baseline and 6‐months follow‐up highlight the importance of physical activity as a part of multidomain lifestyle interventions in persons with prodromal AD. [ABSTRACT FROM AUTHOR]

Background: LipiDiDiet is a randomized controlled trial investigating the effects of a multinutrient medical food product on change in cognition among individuals with prodromal AD. This study aimed at investigating participants' baseline AD biomarker profile, including classification according to the IWG‐2 and NIA‐AA 2011 & 2018 diagnostic criteria, and assessing the impact on 2‐year cognitive/functional decline and progression to dementia. Method: LipiDiDiet targeted 311 individuals aged 55–85 years at 11 sites in four countries. Prodromal AD was defined according to the IWG‐1 criteria: evidence for AD pathology (abnormality in any CSF or imaging biomarker) and episodic memory impairment. Key outcomes were e.g. change in cognition and function (Neuropsychological Test Battery NTB z‐scores, CDR‐SB) and progression to dementia. Linear mixed models were used to investigate change in NTB and CDR‐SB scores across different baseline biomarker profiles (biomarker profile x time interactions). Associations between biomarker profiles and risk of progression to dementia were analyzed with Cox proportional hazards models adjusted for randomization group, MMSE, and study site. Result: CSF Aβ, t‐tau, and p‐tau levels were abnormal in 88%, 86%, and 69% of participants with centrally assessed CSF (N=107). 64% had an A+/T+/N+ profile. While cognitive/functional decline tended to be more pronounced in the IWG‐2 prodromal AD, NIA‐AA 2011 high and intermediate AD likelihood, and NIA‐AA 2018 AD groups, few statistically significant differences were observed between diagnostic groups within each set of criteria. Hazard ratio (95% CI) for progression to dementia was 4.7 (1.6–13.7) among participants with IWG‐2 prodromal AD (compared with no prodromal AD); 7.5 (1.0–55.0) for NIA‐AA 2011 high AD likelihood group (compared with SNAP), and 9.4 (1.2–72.7) for NIA‐AA 2018 AD group (compared with non‐Alzheimer's pathologic change). Conclusion: Despite being less restrictive than the more recent diagnostic criteria, IWG‐1 criteria reliably identified individuals with AD pathology. Findings may have implications for future trial design, as these criteria may be preferred due to feasibility in trials conducted in diverse settings, e.g. clinical trials which do not directly target Aβ or tau pathology. [ABSTRACT FROM AUTHOR]

Background: Different research diagnostic criteria and frameworks for Alzheimer's disease have recently been proposed, but their applicability in clinical settings is unclear. This cross‐sectional study aimed at classifying biomarker profiles of memory clinic patients according to the ATN scheme and assessing patient characteristics in each category. Method: 284 consecutive patients from the Karolinska University Hospital, Theme aging, memory clinic with available CSF, MRI and clinical data were included (50% diagnosed with SCI, 24% with MCI, 26% with dementia). ATN classification was based on CSF β‐amyloid42 (A), CSF phosphorylated tau (T), and medial temporal atrophy (N), and clinical cut‐offs were used to determine biomarker positivity. When available, automated ratings of medial temporal lobe atrophy were used in the classification. Comparisons between the ATN categories were conducted with Kruskal‐Wallis and chi‐square tests. Result: The most frequent biomarker profile was A‐T‐N‐ (49% of the whole study population). 36% had a SNAP profile (A‐T+N‐, A‐T‐N+ or A‐T+N+) and 15% had any Alzheimer profile, i.e. abnormal amyloid (A+T‐N‐, A+T+N‐, A+T‐N+ or A+T+N+). Proportion of A+T+N+ patients increased with the severity of symptoms (0% in SCI and MCI, 22% in dementia), whereas the opposite was observed for A‐T‐N‐ patients (72% in SCI, 39% in MCI, 14% in dementia). Some biomarker profiles (A+T‐N‐, A+T‐N+, A+T+N‐) were underrepresented in the whole sample and in all diagnostic groups. Compared to normal biomarker profile, patients with an Alzheimer profile were older and more often APOE4 carriers, had a poorer cognitive performance (MoCa, MMSE, memory, attention), and had fewer depressive symptoms. Except for age and depressive symptoms, same differences were observed between SNAP and normal biomarker profile categories. There were no differences in white matter hyperintensities or education level between the profile categories. Conclusion: Proportion of patients with either a normal or SNAP biomarker profile was high in this memory clinic‐based study. Many of the proposed ATN categories were also not relevant in this patient population. Follow‐up studies are needed to assess cognitive decline and disease progression in the different ATN categories. [ABSTRACT FROM AUTHOR]