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The AUstralian multidomain Approach to Reduce dementia Risk by prOtecting brain health With lifestyle intervention study (AU-ARROW): A study protocol for a single-blind, multi-site, randomized controlled trial.
Gardener, SL, Fuller, SJ, Naismith, SL, Baker, L, Kivipelto, M, Villemagne, VL, Grieve, SM, Yates, P, Rainey-Smith, SR, Chen, J, et al
Alzheimer's & dementia (New York, N. Y.). 2024;(2):e12466
Abstract
INTRODUCTION The Finnish Geriatric Intervention Study (FINGER) led to the global dementia risk reduction initiative: World-Wide FINGERS (WW-FINGERS). As part of WW-FINGERS, the Australian AU-ARROW study mirrors aspects of FINGER, as well as US-POINTER. METHOD AU-ARROW is a randomized, single-blind, multisite, 2-year clinical trial (n = 600; aged 55-79). The multimodal lifestyle intervention group will engage in aerobic exercise, resistance training and stretching, dietary advice to encourage MIND diet adherence, BrainHQ cognitive training, and medical monitoring and health education. The Health Education and Coaching group will receive occasional health education sessions. The primary outcome measure is the change in a global composite cognitive score. Extra value will emanate from blood biomarker analysis, positron emission tomography (PET) imaging, brain magnetic resonance imaging (MRI), and retinal biomarker tests. DISCUSSION The finalized AU-ARROW protocol is expected to allow development of an evidence-based innovative treatment plan to reduce cognitive decline and dementia risk, and effective transfer of research outcomes into Australian health policy. HIGHLIGHTS Study protocol for a single-blind, randomized controlled trial, the AU-ARROW Study.The AU-ARROW Study is a member of the World-Wide FINGERS (WW-FINGERS) initiative.AU-ARROW's primary outcome measure is change in a global composite cognitive score.Extra significance from amyloid PET imaging, brain MRI, and retinal biomarker tests.Leading to development of an innovative treatment plan to reduce cognitive decline.
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Study design and methods: U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER).
Baker, LD, Snyder, HM, Espeland, MA, Whitmer, RA, Kivipelto, M, Woolard, N, Katula, J, Papp, KV, Ventrelle, J, Graef, S, et al
Alzheimer's & dementia : the journal of the Alzheimer's Association. 2024;(2):769-782
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INTRODUCTION The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans. METHODS U.S. POINTER was planned as a 2-year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well-established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER. RESULTS U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide network of similar trials for harmonization of methods and data sharing. DISCUSSION U.S. POINTER is testing a potentially sustainable intervention to support brain health and Alzheimer's prevention for Americans. Impact is strengthened by the targeted participant diversity and expanded scientific scope through ancillary studies.
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A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol.
Barbera, M, Lehtisalo, J, Perera, D, Aspö, M, Cross, M, De Jager Loots, CA, Falaschetti, E, Friel, N, Luchsinger, JA, Gavelin, HM, et al
Alzheimer's research & therapy. 2024;(1):23
Abstract
BACKGROUND Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer's Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60-79 years) at increased risk of dementia. METHODS MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. CONCLUSION MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field. TRIAL REGISTRATION ClinicalTrials.gov (NCT05109169).
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GOIZ ZAINDU study: a FINGER-like multidomain lifestyle intervention feasibility randomized trial to prevent dementia in Southern Europe.
Tainta, M, Ecay-Torres, M, de Arriba, M, Barandiaran, M, Otaegui-Arrazola, A, Iriondo, A, Garcia-Sebastian, M, Estanga, A, Saldias, J, Clerigue, M, et al
Alzheimer's research & therapy. 2024;(1):44
Abstract
BACKGROUND GOIZ ZAINDU ("caring early" in Basque) is a pilot study to adapt the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) methodology to the Basque population and evaluate the feasibility and adherence to a FINGER-like multidomain intervention program. Additional aims included the assessment of efficacy on cognition and data collection to design a large efficacy trial. METHOD GOIZ ZAINDU is a 1-year, randomized, controlled trial of a multidomain intervention in persons aged 60+ years, with Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score ≥ 6, no diagnosis of dementia, and below-than-expected performance in at least one of three cognitive screening tests. Randomization to a multidomain intervention (MD-Int) or regular health advice (RHA) was stratified by sex, age (>/≤ 75), and cognitive status (mild cognitive impairment (MCI)/normal cognition). MD-Int included cardiovascular risk factor control, nutritional counseling, physical activity, and cognitive training. The primary outcomes were retention rate and adherence to the intervention program. Exploratory cognitive outcomes included changes in the Neuropsychological Test Battery z-scores. Analyses were performed according to the intention to treat. RESULTS One hundred twenty-five participants were recruited (mean age: 75.64 (± 6.46); 58% women). The MD-Int (n = 61) and RHA (n = 64) groups were balanced in terms of their demographics and cognition. Fifty-two (85%) participants from the RHA group and 56 (88%) from the MD-Int group completed the study. More than 70% of the participants had high overall adherence to the intervention activities. The risk of cognitive decline was higher in the RHA group than in the MD-Int group in terms of executive function (p =.019) and processing speed scores (p =.026). CONCLUSIONS The GOIZ-ZAINDU study proved that the FINGER methodology is adaptable and feasible in a different socio-cultural environment. The exploratory efficacy results showed a lower risk of decline in executive function and processing speed in the intervention group. These results support the design of a large-scale efficacy trial. TRIAL REGISTRATION GOIZ ZAINDU feasibility trial was approved and registered by the Euskadi Drug Research Ethics Committee (ID: PI2017134) on 23 January 2018. Retrospectively registered in ClinicalTrials.gov (NCT06163716) on 8 December 2023.
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The Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) score as a predictor for cognitive decline and potential surrogate outcome in the FINGER lifestyle randomized controlled trial.
Hall, A, Barbera, M, Lehtisalo, J, Antikainen, R, Huque, H, Laatikainen, T, Ngandu, T, Soininen, H, Stephen, R, Strandberg, T, et al
European journal of neurology. 2024;(5):e16238
Abstract
BACKGROUND AND PURPOSE The complex aetiology of Alzheimer's disease suggests prevention potential. Risk scores have potential as risk stratification tools and surrogate outcomes in multimodal interventions targeting specific at-risk populations. The Australian National University Alzheimer's Disease Risk Index (ANU-ADRI) was tested in relation to cognition and its suitability as a surrogate outcome in a multidomain lifestyle randomized controlled trial, in older adults at risk of dementia. METHODS In this post hoc analysis of the Finnish Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), ANU-ADRI was calculated at baseline, 12, and 24 months (n = 1174). The association between ANU-ADRI and cognition (at baseline and over time), the intervention effect on changes in ANU-ADRI, and the potential impact of baseline ANU-ADRI on the intervention effect on changes in cognition were assessed using linear mixed models with maximum likelihood estimation. RESULTS A higher ANU-ADRI was significantly related to worse cognition, at baseline (e.g., estimate for global cognition [95% confidence interval] was -0.028 [-0.032 to -0.025]) and over the 2-year study (e.g., estimate for 2-year changes in ANU-ADRI and per-year changes in global cognition [95% confidence interval] was -0.068 [-0.026 to -0.108]). No significant beneficial intervention effect was reported for ANU-ADRI, and baseline ANU-ADRI did not significantly affect the response to the intervention on changes in cognition. CONCLUSIONS The ANU-ADRI was effective for the risk prediction of cognitive decline. Risk scores may be crucial for the success of novel dementia prevention strategies, but their algorithm, the target population, and the intervention design should be carefully considered when choosing the appropriate tool for each context.
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Multimorbidity, cognitive phenotypes, and Alzheimer's disease plasma biomarkers in older adults: A population-based study.
Ren, Y, Li, Y, Tian, N, Liu, R, Dong, Y, Hou, T, Liu, C, Han, X, Han, X, Wang, L, et al
Alzheimer's & dementia : the journal of the Alzheimer's Association. 2024;(3):1550-1561
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INTRODUCTION To examine the burden and clusters of multimorbidity in association with mild cognitive impairment (MCI), dementia, and Alzheimer's disease (AD)-related plasma biomarkers among older adults. METHODS This population-based study included 5432 participants (age ≥60 years); of these, plasma amyloid beta (Aβ), total tau, and neurofilament light chain (NfL) were measured in a subsample (n = 1412). We used hierarchical clustering to generate five multimorbidity clusters from 23 chronic diseases. We diagnosed dementia and MCI following international criteria. Data were analyzed using logistic and linear regression models. RESULTS The number of chronic diseases was associated with dementia (multivariable-adjusted odds ratio = 1.22; 95% confidence interval [CI] = 1.11 to 1.33), AD (1.13; 1.01 to 1.26), vascular dementia (VaD) (1.44; 1.25 to 1.64), and non-amnestic MCI (1.25; 1.13 to 1.37). Metabolic cluster was associated with VaD and non-amnestic MCI, whereas degenerative ocular cluster was associated with AD (p < 0.05). The number of chronic diseases was associated with increased plasma Aβ and NfL (p < 0.05). DISCUSSION Multimorbidity burden and clusters are differentially associated with subtypes of dementia and MCI and AD-related plasma biomarkers in older adults. HIGHLIGHTS We used hierarchical clustering to generate five clusters of multimorbidity. The presence and load of multimorbidity were associated with dementia and mild cognitive impairment. Multimorbidity clusters were differentially associated with subtypes of dementia and Alzheimer's disease plasma biomarkers.
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Dementia prevention in memory clinics: recommendations from the European task force for brain health services.
Frisoni, GB, Altomare, D, Ribaldi, F, Villain, N, Brayne, C, Mukadam, N, Abramowicz, M, Barkhof, F, Berthier, M, Bieler-Aeschlimann, M, et al
The Lancet regional health. Europe. 2023;:100576
Abstract
Observational population studies indicate that prevention of dementia and cognitive decline is being accomplished, possibly as an unintended result of better vascular prevention and healthier lifestyles. Population aging in the coming decades requires deliberate efforts to further decrease its prevalence and societal burden. Increasing evidence supports the efficacy of preventive interventions on persons with intact cognition and high dementia risk. We report recommendations for the deployment of second-generation memory clinics (Brain Health Services) whose mission is evidence-based and ethical dementia prevention in at-risk individuals. The cornerstone interventions consist of (i) assessment of genetic and potentially modifiable risk factors including brain pathology, and risk stratification, (ii) risk communication with ad-hoc protocols, (iii) risk reduction with multi-domain interventions, and (iv) cognitive enhancement with cognitive and physical training. A roadmap is proposed for concept validation and ensuing clinical deployment.
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Combined Evidence for a Long-Term, Clinical Slowing Effect of Multinutrient Intervention in Prodromal Alzheimer's Disease: Post-Hoc Analysis of 3-Year Data from the LipiDiDiet Trial.
Hendrix, SB, Soininen, H, Solomon, A, Visser, PJ, van Hees, AMJ, Counotte, DS, Nicodemus-Johnson, J, Dickson, SP, Blennow, K, Kivipelto, M, et al
The journal of prevention of Alzheimer's disease. 2023;(3):464-470
Abstract
The LipiDiDiet randomized clinical trial is evaluating the long term effects of a multinutrient intervention (Fortasyn Connect) compared with control in participants with prodromal AD. In this post-hoc analysis we used the Alzheimer's Disease Composite Score (ADCOMS) as a measure of cognition and global function, together with a global statistical test (GST) and Bayesian hierarchical modelling (BHM) to evaluate the totality of evidence for an effect of the intervention over 36 months. The analysis includes 67 participants (39 active, 28 control) with change from baseline data after 36 months intervention. All outcome measures showed a statistically significant effect for the intervention: ADCOMS (P =0.045), GST (P <0.001), and BHM (P =0.008 based on 3 outcomes and P <0.001 including all primary and secondary quantitative clinical outcomes). Fortasyn Connect was associated with significantly less clinical decline over 36 months, suggesting the long-lasting beneficial effects of the multinutrient in prodromal AD.
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Can dementia risk be reduced by following the American Heart Association's Life's Simple 7? A systematic review and dose-response meta-analysis.
Wu, J, Xiong, Y, Xia, X, Orsini, N, Qiu, C, Kivipelto, M, Rizzuto, D, Wang, R
Ageing research reviews. 2023;83:101788
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The American Heart Association (AHA) has defined ideal levels of seven modifiable cardiovascular health (CVH) factors, known as Life's Simple 7, that consist of smoking, physical activity, diet, body mass index, fasting blood glucose, total cholesterol, and blood pressure. Maintaining ideal levels of these factors has been recommended as a prevention strategy against not only cardiovascular diseases but also neurodegenerative disorders, e.g., cognitive decline and dementia. However, studies exploring the beneficial effects of the AHA’s CVH metrics on cognitive outcomes, especially among older populations, have been uncertain, and solid evidence is lacking in this field. This systematic review and meta-analysis aimed to quantify the relationship between the AHA’s CVH metrics and cognitive outcomes. 14 longitudinal studies were included in the meta-analysis. The results showed a considerable effect of a favourable total CVH score on reduced risk of incident dementia in adults aged 70 years or older. When looking at the individual factors, dementia risk can be reduced significantly if older adults achieved the recommended level of physical activity, blood glucose, or total cholesterol. The association with smoking appeared to be borderline, and there was no association between diet, body mass index hazard ratio or blood pressure and dementia risk. The authors concluded that their findings provide evidence that maintaining a favourable level of CVH score, either in mid- or late- life, would substantially reduce the risk of dementia among older adults. Preserving cardiovascular health by quitting smoking, engaging in physical exercise, controlling blood glucose and total cholesterol might be especially effective for forestalling cognitive decline and dementia.
Abstract
This study aimed to quantify the relationships between the American Heart Association (AHA) Cardiovascular Health (CVH) metrics, namely AHA Life's Simple 7, and cognitive outcomes. We searched PubMed and Embase (January 1, 2010-August 24, 2022) and finally included 14 longitudinal studies (311654 participants with 8006 incident dementia cases). Random-effects meta-analysis and one-stage linear mixed-effects models were performed. Increased CVH score seemed to associate with decreased risk of incident dementia in a linear manner, but this relationship varied by the measurement age of CVH metrics. That is, midlife CVH tended to have a linear association with late-life dementia risk, whereas a J-shaped association was observed between the late-life CVH score and dementia. In addition, late-life dementia risk was reduced significantly if individuals maintained an ideal level of AHA's CVH guidelines of physical activity, fasting plasma glucose, total cholesterol, and smoking. However, our meta-analysis did not show a significant association between CVH score and global cognitive decline rate. Following AHA's CVH guidelines and maintaining CVH at an optimal level would substantially reduce the late-life dementia risk. More research is required to explore the link between a favorable CVH score and cognitive trajectories among cognitively asymptomatic older populations.
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Communication about diagnosis, prognosis, and prevention in the memory clinic: perspectives of European memory clinic professionals.
Hendriksen, HMA, van Gils, AM, van Harten, AC, Hartmann, T, Mangialasche, F, Kamondi, A, Kivipelto, M, Rhodius-Meester, HFM, Smets, EMA, van der Flier, WM, et al
Alzheimer's research & therapy. 2023;(1):131
Abstract
BACKGROUND The paradigm shift towards earlier Alzheimer's disease (AD) stages and personalized medicine creates new challenges for clinician-patient communication. We conducted a survey among European memory clinic professionals to identify opinions on communication about (etiological) diagnosis, prognosis, and prevention, and inventory needs for augmenting communication skills. METHODS Memory clinic professionals (N = 160) from 21 European countries completed our online survey (59% female, 14 ± 10 years' experience, 73% working in an academic hospital). We inventoried (1) opinions on communication about (etiological) diagnosis, prognosis, and prevention using 11 statements; (2) current communication practices in response to five hypothetical cases (AD dementia, mild cognitive impairment (MCI), subjective cognitive decline (SCD), with ( +) or without ( -) abnormal AD biomarkers); and (3) needs for communication support regarding ten listed communication skills. RESULTS The majority of professionals agreed that communication on diagnosis, prognosis, and prevention should be personalized to the individual patient. In response to the hypothetical patient cases, disease stage influenced the inclination to communicate an etiological AD diagnosis: 97% would explicitly mention the presence of AD to the patient with AD dementia, 68% would do so in MCI + , and 29% in SCD + . Furthermore, 58% would explicitly rule out AD in case of MCI - when talking to patients, and 69% in case of SCD - . Almost all professionals (79-99%) indicated discussing prognosis and prevention with all patients, of which a substantial part (48-86%) would personalize their communication to patients' diagnostic test results (39-68%) or patients' anamnestic information (33-82%). The majority of clinicians (79%) would like to use online tools, training, or both to support them in communicating with patients. Topics for which professionals desired support most were: stimulating patients' understanding of information, and communicating uncertainty, dementia risk, remotely/online, and with patients not (fluently) speaking the language of the country of residence. CONCLUSIONS In a survey of European memory clinic professionals, we found a strong positive attitude towards communication with patients about (etiological) diagnosis, prognosis, and prevention, and personalization of communication to characteristics and needs of individual patients. In addition, professionals expressed a need for supporting tools and skills training to further improve their communication with patients.