Factors Predicting Engagement of Older Adults With a Coach-Supported eHealth Intervention Promoting Lifestyle Change and Associations Between Engagement and Changes in Cardiovascular and Dementia Risk: Secondary Analysis of an 18-Month Multinational Randomized Controlled Trial.

BACKGROUND: Digital health interventions could help to prevent age-related diseases, but little is known about how older adults engage with such interventions, especially in the long term, or whether engagement is associated with changes in clinical, behavioral, or biological outcomes in this population. Disparities in engagement levels with digital health interventions may exist among older people and be associated with health inequalities. OBJECTIVE: This study aimed to describe older adults' engagement with an eHealth intervention, identify factors associated with engagement, and examine associations between engagement and changes in cardiovascular and dementia risk factors (blood pressure, cholesterol, BMI, physical activity, diet, and cardiovascular and dementia risk scores). METHODS: This was a secondary analysis of the 18-month randomized controlled Healthy Ageing Through Internet Counselling in the Elderly trial of a tailored internet-based intervention encouraging behavior changes, with remote support from a lifestyle coach, to reduce cardiovascular and cognitive decline risk in 2724 individuals aged ≥65 years, recruited offline in the Netherlands, Finland, and France. Engagement was assessed via log-in frequency, number of lifestyle goals set, measurements entered and messages sent to coaches, and percentage of education materials read. Clinical and biological data were collected during in-person visits at baseline and 18 months. Lifestyle data were self-reported on a web-based platform. RESULTS: Of the 1389 intervention group participants, 1194 (85.96%) sent at least one message. They logged in a median of 29 times, and set a median of 1 goal. Higher engagement was associated with significantly greater improvement in biological and behavioral risk factors, with evidence of a dose-response effect. Compared with the control group, the adjusted mean difference (95% CI) in 18-month change in the primary outcome, a composite z-score comprising blood pressure, BMI, and cholesterol, was -0.08 (-0.12 to -0.03), -0.04 (-0.08 to 0.00), and 0.00 (-0.08 to 0.08) in the high, moderate, and low engagement groups, respectively. Low engagers showed no improvement in any outcome measures compared with the control group. Participants not using a computer regularly before the study engaged much less with the intervention than those using a computer up to 7 (adjusted odds ratio 5.39, 95% CI 2.66-10.95) or ≥7 hours per week (adjusted odds ratio 6.58, 95% CI 3.21-13.49). Those already working on or with short-term plans for lifestyle improvement at baseline, and with better cognition, engaged more. CONCLUSIONS: Greater engagement with an eHealth lifestyle intervention was associated with greater improvement in risk factors in older adults. However, those with limited computer experience, who tended to have a lower level of education, or who had poorer cognition engaged less. Additional support or forms of intervention delivery for such individuals could help minimize potential health inequalities associated with the use of digital health interventions in older people.

Is more always better? Dose effect in a multidomain intervention in older adults at risk of dementia.

BACKGROUND: Little is known regarding the dose-response function in multidomain interventions for dementia prevention. METHOD: The Multidomain Alzheimer Preventive Trial is a 3-year randomized controlled trial comprising cognitive training, physical activity, nutrition, and omega-3 polyunsaturated fatty acids for at-risk older adults. The dose delivered (number of sessions attended) was modeled against global cognition, memory, and fluency in 749 participants. Interaction effects were assessed for age, sex, education, dementia score (CAIDE), frailty score, and apolipoprotein E (APOE) ε4 status. RESULTS: The dose-response models were non-linear functions indicating benefits up to about 12 to 14 training hours or 15 to 20 multidomain sessions followed by a plateau. Participants who benefited from a higher dose included women, younger participants, frail individuals, and those with lower education or lower risk of dementia. DISCUSSION: The non-linear function indicates that a higher dose is not necessarily better in multidomain interventions. The optimal dose was about half of the potentially available sessions.

Cognitive decline as an outcome and marker of progression toward dementia, in early preventive trials.

INTRODUCTION: Recent Food and Drug Administration guidance endorses cognitive assessment as a possible primary endpoint for early trials for Alzheimer's disease but emphasizes the need for certainty regarding the relationship with progression to dementia. METHODS: We compared the validity of the 2-year change (Y0-Y2) of 11 markers of neuropsychological and functional abilities for the prediction of incident dementia over the following 3 years (Y2-Y5), in 860 subjects aged 70 years or older, who consulted for memory loss and were included in the "GuidAge" prevention trial. RESULTS: The Free and Cued Selective Reminding Test-Free Recall (FCSRT-FR) score showed the most predictive 2-year change (area under the curve = 0.72 95% confidence interval = 0.64;0.81). Changes in other subscores of the FCSRT, verbal fluencies tasks, and composite cognitive score were also significantly predictive. Conversely, 2-year change of Mini-Mental State Examination, Trail Making test (TMT)-A, TMT-B, Clinical Dementia Rating Sum of Boxes, and Instrumental Activities of Daily Living scores did not significantly predict occurrence of dementia. CONCLUSION: The FCSRT, the Fluency Task, and the composite cognitive score appear to be good cognitive markers of progression toward dementia in early prevention trials.

The effect of adherence on cognition in a multidomain lifestyle intervention (FINGER).

INTRODUCTION: Lifestyle interventions may prevent cognitive decline, but the sufficient dose of intervention activities and lifestyle changes is unknown. We investigated how intervention adherence affects cognition in the FINGER trial (pre-specified subgroup analyses). METHODS: FINGER is a multicenter randomized controlled trial examining the efficacy of multidomain lifestyle intervention (ClinicalTrials.gov NCT01041989). A total of 1260 participants aged 60 to 77 with increased dementia risk were randomized to a lifestyle intervention and control groups. Percentage of completed intervention sessions, and change in multidomain lifestyle score (self-reported diet; physical, cognitive, and social activity; vascular risk) were examined in relation to change in Neuropsychological Test Battery (NTB) scores. RESULTS: Active participation was associated with better trajectories in NTB total and all cognitive subdomains. Improvement in lifestyle was associated with improvement in NTB total and executive function. DISCUSSION: Multidomain lifestyle changes are beneficial for cognitive functioning, but future interventions should be intensive enough, and supporting adherence is essential.

Experiences of dementia and attitude towards prevention: a qualitative study among older adults participating in a prevention trial.

BACKGROUND: A better insight into older adults' understanding of and attitude towards cognitive disorders and their prevention, as well as expectations and reasons for participation in prevention trials, would help design, conduct, and implement effective preventive interventions. This qualitative study aimed at exploring the knowledge and perceptions of cognitive disorders and their prevention among participants in a prevention trial. METHODS: Semi-structured interviews were conducted among the participants of a multinational randomised controlled trial testing the efficacy of a lifestyle-based eHealth intervention in preventing cardiovascular disease or cognitive decline in community dwellers aged 65+. Participants were probed on their reasons for participation in the trial and their views on general health, cardiovascular disease, ageing, and prevention. The subset of data focusing on cognitive disorders (15 interviewees; all in Finland) was considered for this study. Data were analysed using content analysis. RESULTS: Participants' knowledge of the cause and risk factors of cognitive disorders and prevention was limited and superficial, and a need for up-to-date, reliable, and practical information and advice was expressed. Cognitive disorders evoked fear and concern, and feelings of hopelessness and misery were frequently expressed, indicating a stigma. Strong heredity of cognitive disorders was a commonly held belief, and opinions on the possibility of prevention were doubtful, particularly in relation to primary prevention. Family history and/or indirect experiences of cognitive disorders was a recurrent theme and it showed to be linked to both the knowledge of and feelings associated with cognitive disorders, as well as attitude towards prevention. Indirect experiences were linked to increased awareness and knowledge, but also uncertainty about risk factors and possibility of prevention. Distinct fear and concerns, particularly over one's own cognition/risk, and high motivation towards engaging in prevention and participating in a prevention trial were also identified in connection to this theme. CONCLUSIONS: Family history and/or indirect experiences of cognitive disorders were linked to sensitivity and receptiveness to brain health and prevention potential. Our findings may be helpful in addressing older adults' expectations in future prevention trials to improve recruitment, maximise adherence, and facilitate the successful implementation of interventions.

Dementia risk scores as surrogate outcomes for lifestyle-based multidomain prevention trials-rationale, preliminary evidence and challenges.

INTRODUCTION: Although not designed as such, dementia risk scores might be useful surrogate outcomes for dementia prevention trials. Their suitability may be improved by using continuous scoring systems, taking into account all changes in risk factors, not only those crossing cut-off values. METHODS: In three large multidomain dementia prevention trials with 1.5 to 2 years of follow-up (Multidomain Alzheimer Preventive Trial, Prevention of Dementia by Intensive Vascular Care and Healthy Ageing Through Internet Counselling in the Elderly) we assessed (1) responsiveness (sensitivity to change) and (2) actual and simulated intervention effects of the original and crude/weighted z-score versions of the cardiovascular risk factors, aging and incidence of dementia, and Lifestyle for Brain Health scores. RESULTS: All versions of the risk scores were generally responsive, and able to detect small though statistically significant between-group differences after multidomain interventions. Simulated intervention effects were well detected in z-score versions as well as in the original scores. DISCUSSION: Dementia risk scores and their z-score versions show potential as surrogate outcomes. How changes in risk scores affect dementia remains to be determined.

Anticholinergic exposure and cognitive decline in older adults: effect of anticholinergic exposure definitions in a 3-year analysis of the multidomain Alzheimer preventive trial (MAPT) study.

AIM: The aim of the present study was to assess the association between anticholinergic (atropinic) burden and cognitive decline in older adults over the course of 3 years. METHODS: We used data from Multidomain Alzheimer Preventive Trial (MAPT) study participants aged ≥70 years and at risk of cognitive decline. Cognitive function was assessed with a composite score [Mini-Mental State Examination (MMSE) orientation, Free and Cued Selective Reminding Test, Category Naming Test, Digit Symbol Substitution Test] at 12, 24 and 36 months. Participants declining by more than 0.236 points on the composite score (representing the lowest quintile of 1-year cognitive change) during any 1-year period were considered to have undergone cognitive decline. Anticholinergic exposure was defined by four methods for each of four anticholinergic scales (Anticholinergic Drug Scale, Anticholinergic Cognitive Burden, Anticholinergic Risk Scale, the Durán list). The association between cognitive decline and time-varying anticholinergic exposure [primary analysis using the Durán list and maximal anticholinergic score (0, 1 or 3)] was assessed using Cox proportional hazards models. Other cognitive decline definitions were used in sensitivity analyses. RESULTS: At baseline, among 1396 patients included, 7.4-23.5% were exposed to anticholinergic agents, depending on the anticholinergic scale used. Sixty-four per cent of participants experienced cognitive decline during follow-up. Regardless of the anticholinergic scale/exposure measurement used, no significant association was observed with cognitive decline {primary analysis: compared with non-anticholinergic agent users, hazard ratio [HR] = 1.14 [95% confidence interval (CI) = 0.95, 1.38] for anticholinergic score = 1; HR = 0.92 [95% CI = 0.65, 1.30] for score = 3}. Results were stable in sensitivity analyses. CONCLUSION: We found no significant association between anticholinergic exposure and cognitive decline in older adults using anticholinergic scales and definitions of exposure.

Adherence to multidomain interventions for dementia prevention: Data from the FINGER and MAPT trials.

INTRODUCTION: Multidomain interventions, targeting multiple risk factors simultaneously, could be effective dementia prevention strategies, but may be burdensome and not universally acceptable. METHODS: We studied adherence rates and predictors in the Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability and Multidomain Alzheimer Preventive Trial prevention trials, for all intervention components (separately and simultaneously). Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability participants received a 2-year multidomain lifestyle intervention (physical training, cognitive training, nutritional counseling, and cardiovascular monitoring). Multidomain Alzheimer Preventive Trial participants received a 3-year multidomain lifestyle intervention (cognitive training, physical activity counseling, and nutritional counseling) with either an omega-3 supplement or placebo. RESULTS: Adherence decreased with increasing intervention complexity and intensity: it was highest for cardiovascular monitoring, nutritional counseling, and the omega-3 supplement, and lowest for unsupervised computer-based cognitive training. The most consistent baseline predictors of adherence were smoking and depressive symptoms. DISCUSSION: Reducing participant burden, while ensuring that technological tools are suitable for older individuals, maintaining face-to-face contacts, and taking into account participant characteristics may increase adherence in future trials.

Evaluating the clinical relevance of a cognitive composite outcome measure: An analysis of 1414 participants from the 5-year GuidAge Alzheimer's prevention trial.

INTRODUCTION: Composite cognitive scores have been developed as primary outcome measures for preclinical/prevention trials for Alzheimer's disease (AD), mainly using observational data and with little consideration of clinical relevance. METHODS: Secondary analysis of placebo group data from a 5-year AD prevention trial. The composite score was the average of the following z scores: MMSE orientation items, Free and Cued Selective Reminding Test, Category Fluency, Trail Making Test-part B. RESULTS: Composite score change from baseline differed significantly by age, APOE genotype, and CDR progression and AD dementia status. A 1 point decrease in baseline score was highly predictive of 5-year AD dementia risk (HR = 3.51, 95% CI, 2.62-4.71, P < .001). The 1 year minimum clinically important difference was estimated at -0.3 points and predicted AD dementia. DISCUSSION: We explored the clinical relevance of a composite score in a prevention trial setting. This type of analysis facilitates the interpretation of composite scores and informs power calculations.

Assessing Alzheimer's disease patients' quality of life: Discrepancies between patient and caregiver perspectives.

INTRODUCTION: Quality of life (QOL) is an important dimension to consider in Alzheimer's disease (AD), but few large-scale studies have analyzed self and caregiver reports of patient QOL. METHODS: Patient QOL was evaluated in a cohort of 574 AD patients with the QOL-AD scale over 2 years. RESULTS: Caregiver reports of patient QOL were lower at baseline than self reports. Older patient age was associated with overestimation of QOL by caregivers, whereas neuropsychiatric inventory score and caregiver burden were associated with underestimation. Activities of daily living limitation, depressive symptoms, and caregiver burden were systematically associated with poorer QOL, whereas caregiver relationship and apathy were associated with poorer QOL only for self reports or caregiver reports, respectively. Cognitive function and professional care were not associated with QOL. Self-rated patient QOL did not change over time, whereas disease severity markers and caregiver-rated patient QOL declined. DISCUSSION: It is important to assess both self and caregiver ratings when assessing patient QOL.

Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial.

BACKGROUND: It is unknown whether multidomain interventions, which might preserve late-life cognition, affect Alzheimer's disease pathology. Previous studies measured cerebrospinal fluid and imaging Alzheimer's disease biomarkers in small subsamples of multidomain trial participants. Newly developed assays enable the measurement of blood-based Alzheimer's disease biomarkers in larger samples. We aimed to assess whether plasma tau phosphorylated at threonine 181 (p-tau181) was able to detect or predict 3-year multidomain intervention effects. METHODS: This is a secondary analysis of the randomised, controlled, Multidomain Alzheimer Prevention Trial (MAPT) testing a 3-year multidomain intervention, omega-3 fatty acid supplementation, or both versus placebo, in individuals aged 70 years and older in 13 memory centres in France and Monaco. Plasma p-tau181 was measured in stored blood samples in a subsample of 527 participants on an intention-to-treat basis. Changes in cognitive score were calculated as a composite measure using the average of Z scores for the following tests: Mini Mental State Examination orientation items, Free and Cued Selective Reminding Test (sum of free and total recall scores), category fluency, and Digit Symbol Substitution Test. Intervention effects on 3-year change in p-tau181 concentration were estimated by use of a linear mixed model with centre-specific random intercepts. FINDINGS: Recruitment took place between May 30, 2008, and Feb 24, 2011. Median baseline plasma p-tau181 was 8·8 pg/mL (IQR 6·7-11·9) in the total sample, and significantly higher in older individuals, men, APOE ε4 carriers, and participants with renal dysfunction or a positive PET amyloid scan. During 3-year follow-up, individuals with raised baseline p-tau181 underwent greater cognitive decline (eg, mean difference in 3-year change on the composite cognitive score between control group participants with normal and abnormal baseline levels of p-tau was -0·34 [effect size -0·52; 95% CI -0·61 to 0·07] in the fully adjusted model using a 12·4 pg/mL cutoff for abnormal baseline p-tau181), but there were no intervention effects on change in p-tau181 either in this subgroup or the total population, and no effect on cognitive change in individuals with raised baseline p-tau181 (eg, in the fully adjusted model using the 12·4 pg/mL cutoff for p-tau181 abnormality, the mean difference [95% CI] in this subgroup in 3-year decline on the composite cognitive score between the control group and the multidomain + omega-3 group, the omega-3 group, and the multidomain intervention group, was, respectively: 0·13 [-0·21 to 0·47], 0·03 [-0·30 to 0·36], and 0·10 [-0·26 to 0·46]). Surprisingly, individuals with raised baseline p-tau181 showed a decrease in p-tau181 during follow-up (eg, unadjusted mean [95% CI] 3-year change was -3·01 pg/mL (-4·45 to -1·56) in control group subjects with abnormal baseline p-tau181 [using the 12·4 pg/mL abnormal p-tau cutoff]). INTERPRETATION: Our results support the utility of p-tau181 as a prognostic biomarker, but it did not predict or detect intervention effects in this study. Further investigation of its usefulness as a prevention trial outcome measure is required. FUNDING: Toulouse Gérontopôle, French Ministry of Health and Pierre Fabre Research Institute.

Prevention of dementia using mobile phone applications (PRODEMOS): a multinational, randomised, controlled effectiveness-implementation trial.

BACKGROUND: The expected increase of dementia prevalence in the coming decades will mainly be in low-income and middle-income countries and in people with low socioeconomic status in high-income countries. This study aims to reduce dementia risk factors in underserved populations at high-risk using a coach-supported mobile health (mHealth) intervention. METHODS: This open-label, blinded endpoint, hybrid effectiveness-implementation randomised controlled trial (RCT) investigated whether a coach-supported mHealth intervention can reduce dementia risk in people aged 55-75 years of low socioeconomic status in the UK or from the general population in China with at least two dementia risk factors. The primary effectiveness outcome was change in cardiovascular risk factors, ageing, and incidence of dementia (CAIDE) risk score from baseline to after 12-18 months of intervention. Implementation outcomes were coverage, adoption, sustainability, appropriateness, acceptability, fidelity, feasibility, and costs assessed using a mixed-methods approach. All participants with complete data on the primary outcome, without imputation of missing outcomes were included in the analysis (intention-to-treat principle). This trial is registered with ISRCTN, ISRCTN15986016, and is completed. FINDINGS: Between Jan 15, 2021, and April 18, 2023, 1488 people (601 male and 887 female) were randomly assigned (734 to intervention and 754 to control), with 1229 (83%) of 1488 available for analysis of the primary effectiveness outcome. After a mean follow-up of 16 months (SD 2·5), the mean CAIDE score improved 0·16 points in the intervention group versus 0·01 in the control group (mean difference -0·16, 95% CI -0·29 to -0·03). 1533 (10%) invited individuals responded; of the intervention participants, 593 (81%) of 734 adopted the intervention and 367 (50%) of 734 continued active participation throughout the study. Perceived appropriateness (85%), acceptability (81%), and fidelity (79%) were good, with fair overall feasibility (53% of intervention participants and 58% of coaches), at low cost. No differences in adverse events between study arms were found. INTERPRETATION: A coach-supported mHealth intervention is modestly effective in reducing dementia risk factors in those with low socioeconomic status in the UK and any socioeconomic status in China. Implementation is challenging in these populations, but those reached actively participated. Whether this intervention will result in less cognitive decline and dementia requires a larger RCT with long follow-up. FUNDING: EU Horizon 2020 Research and Innovation Programme and the National Key R&D Programmes of China. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

Integrating a multimodal lifestyle intervention with medical food in prodromal Alzheimer's disease: the MIND-ADmini randomized controlled trial.

BACKGROUND: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) showed cognitive benefits from a multidomain lifestyle intervention in at-risk older people. The LipiDiDiet trial highlighted benefits of medical food in prodromal Alzheimer's disease (AD). However, the feasibility and impact of multimodal interventions combining lifestyle with medical food in prodromal AD is unclear. METHODS: MIND-ADmini was a 6-month multinational (Sweden, Finland, Germany, France) proof-of-concept randomized controlled trial (RCT). Participants were 60-85 years old, had prodromal AD (International Working Group-1 criteria), and vascular/lifestyle risk factors. The parallel-group RCT had three arms: multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); multimodal lifestyle intervention + medical food (Fortasyn Connect); and regular health advice/care (control). Participants were randomized 1:1:1 (computer-generated allocation at each site). Outcome evaluators were blinded to randomization. Primary outcome was feasibility of the multimodal intervention, evaluated by recruitment rate during a 6-month recruitment phase, overall adherence in each intervention arm, and 6-month retention rate. Successful adherence was pre-specified as attending ≥ 40% of sessions/domain in ≥ 2/4 domains (lifestyle intervention), and consuming ≥ 60% of the medical food (lifestyle intervention + medical food). The secondary outcomes included adherence/participation to each intervention component and overall adherence to healthy lifestyle changes, measured using a composite score for healthy lifestyle. Cognitive assessments were included as exploratory outcomes, e.g. Clinical Dementia Rating scale. RESULTS: During September 2017-May 2019, 93 individuals were randomized (32 lifestyle intervention, 31 lifestyle + medical food, and 30 control group). Overall recruitment rate was 76.2% (64.8% during the first 6 months). Overall 6-month retention rate was 91.4% (lifestyle intervention 87.5%; lifestyle + medical food 90.3%; control 96.7%). Domain-specific adherence in the lifestyle intervention group was 71.9% to cognitive training, 78.1% exercise, 68.8% nutritional guidance, and 81.3% vascular risk management; and in the lifestyle + medical food group, 90.3% to cognitive training, 87.1% exercise, 80.7% nutritional guidance, 87.1% vascular risk management, and 87.1% medical food. Compared with control, both intervention arms showed healthy diet improvements (ßLifestyle×Time = 1.11, P = 0.038; ßLifestyle+medical food×Time = 1.43, P = 0.007); the lifestyle + medical food group also showed vascular risk reduction (P = 0.043) and less cognitive-functional decline (P < 0.05, exploratory analysis). There were 5 serious adverse events (control group: 1; lifestyle intervention: 3; lifestyle + medical food: 1) unrelated to interventions. CONCLUSIONS: The multidomain lifestyle intervention, alone or combined with medical food, had good feasibility and adherence in prodromal AD. Longer-term cognitive and other health benefits should be further investigated in a larger-scale trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT03249688.

Rationale for use of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for Alzheimer's disease clinical trials.

BACKGROUND: We used the database of the Alzheimer's Disease Neuroimaging Initiative (ADNI) to explore the psychometric properties of the Clinical Dementia Rating Sum of Boxes (CDR-SB) to consider its utility as an outcome measure for clinical trials in early and mild, as well as later, stages of Alzheimer's disease (AD). METHODS: We assessed internal consistency, structural validity, convergent validity, and 2-year internal and external responsiveness of the CDR-SB using data from 382 subjects with early or mild AD at entry into the ADNI study. RESULTS: The CDR-SB assesses both cognitive and functional domains of AD disability. Mean scores declined nearly linearly; CDR-SB cognitive and functional subsums contributed equally to total scores at both very mild (early) and mild stages of the disease. CONCLUSIONS: The CDR-SB has psychometric properties that make it attractive as a primary outcome measure that comprehensively assesses both cognitive and functional disability in AD patients. It may prove particularly useful for studies in early, predementia stages of AD.

Randomised controlled trials for the prevention of cognitive decline or dementia: A systematic review.

Dementia prevention research has progressed rapidly in recent years, with publication of several large lifestyle intervention trials, and renewed interest in pharmacological interventions, notably for individuals with Alzheimer's disease biomarkers, warranting an updated review of results and methodology. We identified 112 completed trials testing the efficacy of single-domain pharmacological (n = 33, 29%), nutritional (n = 27, 24%), physical activity (n = 18, 16%) and cognitive stimulation (n = 13, 12%), or multidomain (n = 22, 20%) interventions on incident dementia, or a relevant intermediate marker (e.g. cognitive function, biomarkers or dementia risk scores) in people without dementia. The earliest trials tested pharmacological interventions or nutritional supplements, but lifestyle interventions predominated in the last decade. In total, 21 (19%) trials demonstrated a clear beneficial effect on the pre-specified primary outcome (or all co-primary outcomes), but only two (10%) were large-scale (testing blood pressure lowering (Syst-Eur) or multidomain (FINGER) interventions on incident dementia and cognitive change in cognitive function, respectively). Of the 116 ongoing trials, 40% (n = 46) are testing multidomain interventions. Recent methodological shifts concern target populations, primary outcome measures, and intervention design, but study design remains constant (parallel group randomised controlled trial). Future trials may consider using adaptive trials or interventions, and more targeted approaches, since certain interventions may be more effective in certain subgroups of the population, and at specific times in the life-course. Efforts should also be made to increase the representativeness and diversity of prevention trial populations.

One-Year Impact of COVID-19 Lockdown-Related Factors on Cardiovascular Risk and Mental Health: A Population-Based Cohort Study.

Lockdown measures have obvious psychological impacts, which could, in turn, increase cardiovascular risk. We assessed the association between lockdown-related factors and the worsening of cardiovascular risk, incident anxiety and depression during 12 months' follow-up. During lockdown (April-May 2020), 534 subjects, aged 50-89 years, were included in the PSYCOV-CV study (NCT04397835) and followed for up to 12 months post-lockdown. We found that participants with symptoms of depression during lockdown were more likely to report increased cardiovascular drug treatment (Odds-Ratio (OR) = 5.08 (1.78-14.5), p = 0.002), decreased physical activity (OR = 1.76 (1.10-2.82), p = 0.019) and weight gain (OR = 1.85 (1.08-3.17), p = 0.024) after lockdown. Moreover, changes in sleep patterns (OR = 2.35 (1.13-4.88), p = 0.022) or living in a rural area during lockdown (OR = 1.70 (0.96-3.03, p = 0.069) were associated with higher incident depression, whereas a better relationship with one's partner during lockdown was associated with less incident depression (OR = 0.56 (0.29-1.08), p = 0.084). Finally, we found that continuing to work during lockdown in a role requiring in-person contact with the public (such as cashiers, nurses or physicians) was associated with more incident anxiety after lockdown (OR = 3.38 (1.12-10.2), p = 0.031). Interestingly, decreased consumption of alcohol during lockdown was associated with less incident anxiety (OR = 0.30 (0.10-0.90), p = 0.032). Our study, conducted in a representative sample of an age group at increased risk of both cardiovascular disease and severe COVID-19, increases the understanding of modifiable factors associated with the health impacts of lockdown measures.

Telephone and Smartphone-Based Interventions for Cognitive and Cardio-Metabolic Health in Middle-Aged and Older Adults: A Systematic Review.

Purpose: Dementia and cardio-metabolic diseases share many risk factors. Management of these risk factors could contribute to successful aging, including the prevention of cardio-metabolic disease and dementia. The increasing use of smartphones offers an opportunity for remote preventive interventions. We provided a systematic review of telephone and smartphone-based interventions targeting the prevention of cognitive decline, dementia cardio-metabolic diseases or their risk factors among adults aged over 50 years. Patients and Methods: We searched Pubmed and the International Clinical Trials Registry Platform for experimental studies. We used the Cochrane risk-of-bias tool (Version 2) for randomized trials or TREND (Transparent Reporting of Evaluations with Nonrandomized Designs) checklists to assess study quality for completed studies. Results: We analyzed 21 completed (3 for cognition, 18 for cardio-metabolic outcomes) and 50 ongoing studies (23 for cognition, 27 for cardio-metabolic outcomes). Smartphone interventions were used in 26 studies (3 completed, 23 ongoing). Other interventions involved telephone vocal support and text messaging. Few studies were at low risk of bias. There were heterogeneous cognitive and cardio-metabolic outcomes. The highest quality studies found no significant effects on cognition, and inconsistent results for HbA1c, blood pressure or physical activity. The lower quality-studies found effects on global cognition, working memory, memory and language and inconsistent results for clinical, biological or behavioral cardio-metabolic outcomes. Conclusion and Implications: Despite the large number of commercially available mobile health applications, the magnitude of the scientific evidence base remains very limited. Based on published studies, the added value of telephone and smartphone tools for the prevention of cardio-metabolic diseases, cognitive decline or dementia is currently uncertain, but, there are several ongoing studies expected to be completed in the coming years.

Suitability of the Clinical Dementia Rating-Sum of Boxes as a single primary endpoint for Alzheimer's disease trials.

BACKGROUND: Clinical measures continue to be used as primary endpoints for disease-modifying trials for Alzheimer's disease (AD). Currently, two co-primary endpoints must be specified, which measure cognitive and functional impairments. Generally, the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is one of the co-primary endpoints, but high variability in this measure results in large sample sizes. We evaluated the psychometric properties of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) to assess its suitability as a single primary endpoint as an alternative to the traditional co-primary approach. METHODS: Internal consistency, structural and convergent validity, and 2-year internal and external responsiveness of the CDR-SB were assessed in 667 very mild to moderate (global Clinical Dementia Rating, 0.5-2) AD patients from the REAL.FR (Réseau sur la Maladie d'Alzheimer Français) study. RESULTS: The CDR-SB showed good internal consistency (Cronbach's alpha = 0.88), and acceptable structural (separate "cognitive" and "functional" factors) and convergent validity. Variability in mean changes over time was low, leading to excellent internal responsiveness (effect size = 1.2; standardized response mean = 1.17 at 2 years) and smaller sample sizes as compared with the ADAS-Cog. External responsiveness was acceptable when compared with "clinically meaningful" changes on the Activities of Daily Living scale but only borderline acceptable when compared with the ADAS-Cog and Instrumental Activities of Daily Living. Levels of missing data and floor/ceiling effects were low. CONCLUSIONS: The CDR-SB measures cognitive and functional impairment simultaneously, and has excellent 2-year internal responsiveness. This makes it a promising candidate as a sole primary endpoint for AD trials, although more work is required to determine the clinical relevance of CDR-SB changes, and its usefulness as an endpoint at other disease stages.

Long-term progression of Alzheimer's disease in patients under antidementia drugs.

BACKGROUND: Patients with Alzheimer's disease (AD), even in the presence of symptomatic relief from medical intervention, face a persistent worsening of cognitive decline and performance in activities of daily living. Data regarding the long-term disease progression outside of therapeutic trials are lacking. We examined the effects of standard of care for AD patients on the prognosis of the disease in a real-life study over a 4-year period. METHODS: A total of 686 patients with mild-moderate AD were enrolled in 16 memory clinics (REseau sur la maladie d' Alzheimer FRançais [REAL.FR] cohort) and followed up twice annually with tools used in therapeutic trials (Mini-Mental Status Examination, Alzheimer Disease Assessment Scale-cognitive subscale [ADAS-cog]: cognitive function, Clinical Dementia Rating: dementia severity, Activity of Daily Living [ADL]: incapacities, NeuroPsychiatric Inventory: neuropsychiatric symptom). RESULTS: More than 90% of the patients used AD-specific medication over 4 years. Patients lost on average 2.4 points per year on the Mini-Mental Status Examination and gained 4.5 points on the ADAS-cog. ADL and NeuroPsychiatric Inventory scores became significantly worse over time. Incidence of incapacities for ADL and worsening of neuropsychiatric symptoms were 52.5 (95% confidence interval [CI]: 47.7-57.4) and 51.1 (95% CI: 46.2-56.1), respectively. Rates of mortality and institutionalization were 7.4 (95% CI: 6.2-8.5) and 13.4 (95% CI: 11.7-15.1). In all, 17% of patients in mild stage at baseline (Clinical Dementia Rating = 0.5) did not experience a major event (functional disabilities, neuropsychiatric symptoms, or death) over a 4-year period. CONCLUSIONS: As compared with previous surveys, the current study shows slower rates of decline in AD patients. The present data also underline the high level of variability of disease progression among AD patients. Outcome measures commonly used in clinical trials will need to take into account the recent changes in the prognosis of the disease.