Cognitive impact of multidomain intervention and omega 3 according to blood Aß42/40 ratio: a subgroup analysis from the randomized MAPT trial.

BACKGROUND: In MAPT (Multidomain Alzheimer Preventive Trial), a cognitive effect of multidomain intervention (MI) was showed in non-demented subjects with positive amyloid PET. However, screening eligible patients for multidomain intervention by PET is difficult to generalize in real-world settings. METHODS: MAPT study was a 3-year, randomized, placebo-controlled trial followed by a 2-year observational and optional extension. All participants were non-demented and randomly assigned (1:1:1:1) to the MI plus omega 3, MI plus placebo, omega 3 alone, or placebo alone group. The objectives were to assess the cognitive effect of MAPT interventions (omega 3 supplementation, MI, combined intervention) in non-demented subjects according to amyloid blood status at 12, 36, and 60 months. In this subgroup analysis (n = 483), amyloid status was defined by plasma Aß42/40 ratio (cutoff ≤ 0.0107). The primary outcome measure was the change in cognitive composite score after a 1, 3, and 5-year clinical follow-up. RESULTS: The intention-to-treat (ITT) population included 483 subjects (161 positive and 322 negative amyloid participants based on plasma Aß42/40 ratio). In the positive amyloid ITT population, we showed a positive effect of MI plus omega 3 on the change in composite cognitive score in 12 (raw p = .0350, 0.01917, 95% CI = [0.0136 to 0.3699]) and 36 months (raw p = .0357, 0.2818, 95% CI = [0.0190 to 0.5446]). After correction of multiple comparisons and adjustments, these differences were not significant (adjusted p = .1144 and .0690). In the per-protocol positive amyloid group (n = 154), we observed a significant difference between the combined intervention and placebo groups at 12 (p = .0313, 0.2424, 0.0571 to 0.4276) and 36 months (p = .0195, 0.3747, 0.1055 to 0.6439) persisting after adjustment. In the ITT and per-protocol analyses, no cognitive effect was observed in the positive and negative amyloid group at 60-month visit. CONCLUSIONS: These findings suggest a benefit of MI plus omega 3 in positive blood amyloid subjects. This promising trend needs to be confirmed before using blood biomarkers for screening in preventive trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01513252 .

Development and Validation of a Cutoff for the Chair Stand Test as a Screening for Mobility Impairment in the Context of the Integrated Care for Older People Program.

BACKGROUND: The 5-repetition chair stand test (CST) is increasingly being used to assess locomotion capacity in older adults. However, there is a lack of age-stratified cutoffs for adults aged ≥70 validated against a higher risk of functional loss. METHODS: We used 2 population-based studies (Study on global AGEing and adult health in Mexico [SAGE Mexico] and Toledo Study for Healthy Aging [TSHA]) and receiver operating characteristic (ROC) analyses to develop and cross-validate age-stratified chair stand cutoffs with activities of daily living (ADL) disability as the outcome. Then, we used data from an randomized controlled trial (RCT) (Multidomain Alzheimer Preventive Trial [MAPT]) and a frailty day-hospital for external validation with cross-sectional and longitudinal measures of ADL disability. The merged sample of SAGE Mexico and TSHA was n = 1 595; sample sizes for external validation were: MAPT n = 1 573 and Frailty day-hospital n = 2 434. The Cox models for incident disability in MAPT had a mean follow-up of 58.6 months. RESULTS: Cutoffs obtained were 14 second (ages 70-79) and 16 second (ages 80+). Those cutoffs identified older adults at higher odds of incident ADL disability odds ratio (OR) = 1.72 (95% confidence interval [CI] 1.06; 2.78) for ages 70-79 and odds ratio (OR) = 2.27 (95% CI 1.07; 4.80) in those aged 80+. Being a slow chair stander according to the cut points was associated with ADL disability in cross-sectional and longitudinal measures. CONCLUSIONS: Fourteen- and 16-second cut points for the CST are suitable to identify people at higher risk of functional decline among older adults in Mexico and Toledo, Spain. Adjusting the cut point from 14 to 16 second generally improved the psychometric properties of the test. The validation of these cutoffs can facilitate the screening for limited mobility and the implementation of the Integrated Care for Older People program.

Associations of erythrocyte omega-3 fatty acids with cognition, brain imaging and biomarkers in the Alzheimer's disease neuroimaging initiative: cross-sectional and longitudinal retrospective analyses.

BACKGROUND: The association between omega-3 (ω-3) PUFAs and cognition, brain imaging and biomarkers is still not fully established. OBJECTIVES: The aim was to analyze the cross-sectional and retrospective longitudinal associations between erythrocyte ω-3 index and cognition, brain imaging, and biomarkers among older adults. METHODS: A total of 832 Alzheimer's Disease Neuroimaging Initiative 3 (ADNI-3) participants, with a mean (SD) age of 74.0 (7.9) y, 50.8% female, 55.9% cognitively normal, 32.7% with mild cognitive impairment, and 11.4% with Alzheimer disease (AD) were included. A low ω-3 index (%EPA + %DHA) was defined as the lowest quartile (≤3.70%). Cognitive tests [composite score, AD Assessment Scale Cognitive (ADAS-Cog), Wechsler Memory Scale (WMS), Trail Making Test, Category Fluency, Mini-Mental State Examination, Montreal Cognitive Assessment] and brain variables [hippocampal volume, white matter hyperintensities (WMHs), positron emission tomography (PET) amyloid-ß (Aß) and tau] were considered as outcomes in regression models. RESULTS: Low ω-3 index was not associated with cognition, hippocampal, and WMH volume or brain Aß and tau after adjustment for demographics, ApoEε4, cardiovascular disease, BMI, and total intracranial volume in the cross-sectional analysis. In the retrospective analysis, low ω-3 index was associated with greater Aß accumulation (adjusted ß = 0.02; 95% CI: 0.01, 0.03; P = 0.003). The composite cognitive score did not differ between groups; however, low ω-3 index was significantly associated with greater WMS-delayed recall cognitive decline (adjusted ß = -1.18; 95% CI: -2.16, -0.19; P = 0.019), but unexpectedly lower total ADAS-Cog cognitive decline. Low ω-3 index was cross-sectionally associated with lower WMS performance (adjusted ß = -1.81, SE = 0.73, P = 0.014) and higher tau accumulation among ApoE ε4 carriers. CONCLUSIONS: Longitudinally, low ω-3 index was associated with greater Aß accumulation and WMS cognitive decline but unexpectedly with lower total ADAS-Cog cognitive decline. Although no associations were cross-sectionally found in the whole population, low ω-3 index was associated with lower WMS cognition and higher tau accumulation among ApoE ε4 carriers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is registered at clinicaltrials.gov as NCT00106899.

Implementation of the WHO integrated care for older people (ICOPE) programme in clinical practice: a prospective study.

BACKGROUND: The INSPIRE integrated care for older people (ICOPE)-CARE programme is a public health programme implementing the ICOPE health-care pathway in clinical practice. The primary objective of this study was to describe the large-scale implementation and feasibility of the INSPIRE ICOPE-CARE guidelines in clinical practice. The secondary aims were to describe the characteristics of patients who were identified as positive for abnormalities in intrinsic capacity (ie, locomotion, cognition, psychology, vitality, hearing, and vision) during step 1, and to describe the prevalence of these positive screenings. METHODS: In this prospective study, we evaluated a real-life population of users of primary care services in the Occitania region (France). Participants who were aged 60 years and older and lived in a community were eligible for inclusion in our study. Individuals aged ≥60 years were screened (step 1) by health-care providers or through self-assessments using digital tools (the ICOPE MONITOR app and the ICOPEBOT conversational robot). Our implementation strategy involved raising awareness among health-care professionals about the WHO ICOPE programme, training professionals in the ICOPE-CARE guidelines, and developing a digital infrastructure (ie, digital tools, a database, and a remote ICOPE monitoring platform). The feasibility of implementing the INSPIRE ICOPE-CARE guidelines was determined by the anticipated inclusion of ≥10 000 participants, and having a follow-up rate of over 50%. FINDINGS: Between Jan 1, 2020, and November 18, 2021, 10 903 older people (mean age 76·0, SD 10·5 years; 6627 [60·8%] of whom were women) had a baseline step 1 screening done, and 5185 (70·4%) of 7367 eligible participants had a 6-month follow-up of step 1 screening. 10 285 (94·3%) participants had a positive intrinsic capacity result during screening at baseline. 958 (9·3%) participants were evaluated with step 2 (in-depth assessments). Positive intrinsic capacity was confirmed in 865 (90·3%) participants. Most recommendations in step 3 (care plan) were related to locomotion, vitality, and cognition. INTERPRETATION: The high number of participants included in our study, as well as the high rates of follow-up, provides evidence to suggest that the large-scale implementation of ICOPE in clinical practice is feasible. The very high prevalence of positive screening for impaired intrinsic capacity during step 1, as well as the high rates of confirmed deficits in intrinsic capacity during step 2, suggest that the INSPIRE ICOPE-CARE programme is able to target individuals who are at increased risk for functional loss and disability. FUNDING: Occitania Regional Health Agency, Region Occitanie and Pyrénées-Méditerranée, European Regional Development Fund, and The Interreg Program V-A Spain-France-Andorra.

Clinically meaningful change for the chair stand test: monitoring mobility in integrated care for older people.

BACKGROUND: Clinically meaningful changes in the five-repetition chair stand test are essential for monitoring mobility in integrated care for older people. Recommendations for the clinically meaningful change of the chair stand test are not well known. Our study aimed to estimate the absolute and relative clinically meaningful changes for older adults' five-repetition chair stand test. METHODS: We applied distribution-based and anchor-based methods in addition to receiver operator characteristics analyses to a population-based study of community-dwelling adults (SAGE Mexico study, n = 897) to derive the clinically meaningful change in the chair stand test. We used three self-reported clinical anchors: moving around, vigorous activities, and walking 1 km. Our primary outcome was the incidence of disability for basic activities of daily living (ADL). Secondly, we examined our estimates of clinically meaningful change in a clinical trial population of healthy volunteers (MAPT, France, study n = 1575) concerning the risk of incident ADL disability. RESULTS: The age of SAGE Mexico participants ranged from 60 to 96 years; mean (SD) = 69.0 (6.2); 54.4% were female. Their baseline chair stand time averaged 12.1 s (SD = 3 s). Forty-eight participants (5.6%) showed incident disability over 3 years. The absolute and relative clinically meaningful change cut points found over 3 years of follow-up were 2.6 s and 27.7%, respectively. Absolute clinically meaningful change ranged from 0.5 to 4.7 s, depending on the estimation method. Relative clinically meaningful change ranged from 9.6 to 46.2%. SAGE Mexico participants with absolute and relative clinically meaningful declines (increasing 2.6 s and 27.7% from baseline time, respectively) showed an increased risk of ADL disability [aRR = 1.93; P = 0.0381; 95% CI (1.05, 3.46) and aRR = 2.27; P = 0.0157; 95% CI (1.22, 4.10)], respectively, compared with those without a clinically meaningful decline. MAPT participants [age range = 70-94; mean (SD) = 75.3 (4.4); 64.8% female; incident ADL disability over 5 years = 145(14.8%)] with a relative clinically meaningful decline (≥27.7% from baseline over 3 years) had a 74% higher risk of incident ADL disability than their counterparts [aHR = 1.74; P = 0.016; CI95% (1.11, 2.72); mean follow-up of 58 months]. CONCLUSIONS: Community-dwelling older adults with an increase of 3 s or 28% in chair stand test performance over 3 years (approximately 1 s or 10% per year) could be the target of interventions to enhance mobility and prevent incident disability.

Nutrition state of science and dementia prevention: recommendations of the Nutrition for Dementia Prevention Working Group.

Observational studies suggest that nutritional factors have a potential cognitive benefit. However, systematic reviews of randomised trials of dietary and nutritional supplements have reported largely null effects on cognitive outcomes and have highlighted study inconsistencies and other limitations. In this Personal View, the Nutrition for Dementia Prevention Working Group presents what we consider to be limitations in the existing nutrition clinical trials for dementia prevention. On the basis of this evidence, we propose recommendations for incorporating dietary patterns and the use of genetic, and nutrition assessment tools, biomarkers, and novel clinical trial designs to guide future trial developments. Nutrition-based research has unique challenges that could require testing both more personalised interventions in targeted risk subgroups, identified by nutritional and other biomarkers, and large-scale and pragmatic study designs for more generalisable public health interventions across diverse populations.

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.

Disparities in the participation and adherence of older adults in lifestyle-based multidomain dementia prevention and the motivational role of perceived disease risk and intervention benefits: an observational ancillary study to a randomised controlled trial.

BACKGROUND: Preventive interventions for dementia are urgently needed and must be tested in randomised controlled trials (RCTs). Selection (volunteer) bias may limit efficacy, particularly in trials testing multidomain interventions and may also be indicative of disparities in intervention uptake in real-world settings. We identified factors associated with participation and adherence in a 3-year RCT of multidomain lifestyle intervention and/or omega-3 supplementation for prevention of cognitive decline and explored reasons for (non-) participation. METHODS: Ancillary study during recruitment and follow-up of the 3-year Multidomain Alzheimer Preventive Trial (MAPT) conducted in in 13 memory centres in France and Monaco, involving 1630 community-dwelling dementia-free individuals aged ≥ 70 who were pre-screened for MAPT (1270 participated in MAPT; 360 declined to participate). RESULTS: Response rates were 76% amongst MAPT participants and 53% amongst non-participants. Older individuals (odds ratio 0.94 [95% confidence interval 0.91-0.98] and those with higher anxiety (0.61 [0.47-0.79]) were less likely to participate in the trial. Those with higher income (4.42 [2.12-9.19]) and family history (1.60 [1.10-2.32]) or greater fear (1.73 [1.30-2.29]) of dementia were more likely to participate, as were those recruited via an intermediary (e.g. pension funds, local Alzheimer's associations, University of the 3rd Age, sports clubs) (2.15 [1.45-3.20]). MAPT participants living in larger towns (0.71 [0.55-0.92]) and with higher depressive symptoms (0.94 [0.90-0.99]) were less likely to adhere to the interventions. Greater perceived social support (1.21 [1.03-1.43]) and cognitive function (1.37 [1.13-1.67]) predicted better adherence. Descriptively, the most frequent reasons for accepting and refusing to participate were, respectively, altruism and logistical constraints, but underlying motivations mainly related to (lack of) perceived benefits. CONCLUSIONS: Disparities in uptake of health interventions persist in older age. Those most at risk of dementia may not participate in or adhere to preventive interventions. Barriers to implementing lifestyle changes for dementia prevention include lack of knowledge about potential benefits, lack of support networks, and (perceived) financial costs. TRIAL REGISTRATION: NCT00672685 (ClinicalTrials.gov).

Screening for intrinsic capacity impairments as markers of increased risk of frailty and disability in the context of integrated care for older people: Secondary analysis of MAPT.

AIM: This longitudinal secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT) aimed to test whether the Integrated Care for Older People (ICOPE) Step 1 screening tool is able to identify people at risk of developing frailty and disability in basic (ADL) and instrumental (IADL) activities of daily living among community-dwelling older adults. PARTICIPANTS AND SETTING: Seven hundred and fifty-nine (n = 759) non-demented participants of the MAPT aged 70-89 years were assessed in memory clinics in France between 2008 and 2013. METHODS: We measured six intrinsic capacity (IC) impairments, adapted from the ICOPE screening tool. We used Cox models to estimate the adjusted hazard ratios of incident frailty and IADL/ADL disability. Incident frailty was defined by Fried's phenotype, and incident disability was measured according to Lawton and Katz for IADLs and ADLs. RESULTS: Limited mobility (HR= 2.97, 95%CI= 1.85-4.76), depressive symptoms (HR= 2.07, 95%CI= 1.03-4.19), and visual impairment (HR= 1.70, 95%CI 1.01-2.86) were associated with a higher incidence of frailty over 5 years. Each additional IC condition demonstrated a positive association with a higher risk of incident frailty, IADL, ADL disability, with risk increased by 47%, 27%, and 23% over 5 years, respectively. CONCLUSION: Screening for IC impairments identifies older adults at higher risk of incident frailty and incident IADL/ADL disability. It is relevant to screen for these impairments together because the risk of frailty and disability increases with each additional one. ClinicalTrials.gov identifier: NCT00672685.

What day is today? Cognitive capacity and the risk of incident dementia in the context of integrated care for older people (ICOPE Step 1).

Based on clinical observations, our objective was to test if the older adults who failed to recall the name of the weekday, or had a higher number of mistakes in the word recall were at higher risk of mild cognitive impairment (MCI) or dementia. Longitudinal data of the Multidomain Alzheimer Preventive Trial (MAPT) was used to retrospectively measure the cognitive capacity according to the ICOPE Step 1 tool. Incident dementia was assessed by two multidisciplinary committees independent from each other. MCI was defined as Clinical Dementia Rating scale CDR = 0.5. Failure to recall the name of the weekday had a three-fold risk of incident dementia in the next 5 years (HRa = 3.11, 95%CI: 1.18-8.17). Having two or three mistakes in the word recall carried a higher risk of incident dementia, (HRa for two mistakes = 3.50, 95% CI: 1.49-8.26; HRa for three mistakes = 4.28, 95% CI: 1.60-11.46), but not MCI. People with impaired cognitive capacity according to the ICOPE Step 1 tool deserve further assessment and a closer follow-up.

The impact of a multi-domain intervention on cerebral glucose metabolism: analysis from the randomized ancillary FDG PET MAPT trial.

BACKGROUND: The Multidomain Alzheimer Preventive Trial (MAPT) was designed to assess the efficacy of omega-3 fatty acid supplementation, multidomain intervention (MI), or a combination of both on cognition. Although the MAPT study was negative, an effect of MI in maintaining cognitive functions compared to placebo group was showed in positive amyloid subjects. A FDG PET study (MAPT-NI) was implemented to test the impact of MI on brain glucose metabolism. METHODS: MAPT-NI was a randomized, controlled parallel-group single-center study, exploring the effect of MI on brain glucose metabolism. Participants were non-demented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. Participants were randomly assigned (1:1) to "MI group" or "No MI group." The MI consisted of group sessions focusing on 3 domains: cognitive stimulation, physical activity, nutrition, and a preventive consultation. [18F]FDG PET scans were performed at baseline, 6 months, and 12 months, and cerebral magnetic resonance imaging scans at baseline. The primary objective was to evaluate the MI effect on brain glucose metabolism assessed by [18F]FDG PET imaging at 6 months. The primary outcome was the quantification of regional metabolism rate for glucose in cerebral regions involved early in Alzheimer disease by relative semi-quantitative SUVr (FDG-based AD biomarker). An exploratory voxel-wise analysis was performed to assess the effect of MI on brain glucose metabolism without anatomical hypothesis. RESULTS: The intention-to-treat population included 67 subjects (34 in the MI group and 33 in the No MI group. No significant MI effect was observed on primary outcome at 6 months. In the exploratory voxel-wise analysis, we observed a difference in favor of MI group on the change of cerebral glucose metabolism in limbic lobe (right hippocampus, right posterior cingulate, left posterior parahippocampal gyrus) at 6 months. CONCLUSIONS: MI failed to show an effect on metabolism in FDG-based AD biomarker, but exploratory analysis suggested positive effect on limbic system metabolism. This finding could suggest a delay effect of MI on AD progression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT01513252 .

Multidomain intervention and/or omega-3 in nondemented elderly subjects according to amyloid status.

INTRODUCTION: The Multidomain Alzheimer Preventive Trial (MAPT) assessed the efficacy of omega-3 fatty acid supplementation, a multidomain intervention (MI), or a combination of both on cognition. Impact according to cerebral amyloid status was evaluated by PET scan. METHODS: Participants were nondemented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. The primary outcome was a change from baseline in 36 months measured with a cognitive composite Z score. RESULTS: No effect was observed on cognition in the negative amyloid group (n = 167). In the positive amyloid group (n = 102), we observed a difference of 0.708 and 0.471 in the cognitive composite score between the MI plus omega-3 fatty acid group, the MI alone group, and the placebo group, respectively. DISCUSSION: MI alone or in combination with omega-3 fatty acids was associated with improved primary cognitive outcome in subjects with positive amyloid status. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01513252.

Effect of Long-Term Omega 3 Polyunsaturated Fatty Acid Supplementation with or without Multidomain Lifestyle Intervention on Muscle Strength in Older Adults: Secondary Analysis of the Multidomain Alzheimer Preventive Trial (MAPT).

BACKGROUND: The benefits of long-term omega 3 polyunsaturated fatty acid (ω3-PUFA) supplementation on muscle strength in older adults remains to be investigated. OBJECTIVES: We assessed the effect of ω3-PUFA supplementation and a multidomain (physical activity, cognitive training, and nutritional advice), alone or in combination, compared with placebo, on muscle strength. We also hypothesized that ω3-PUFA supplementation resulted in additional benefit in participants with a low docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) erythrocyte level at baseline and high adherence to the multidomain intervention sessions. DESIGN: We performed secondary analyses of the Multidomain Alzheimer Preventive Trial (MAPT), a 3-year, multicenter, randomized, placebo-controlled trial with four parallel groups. Participants were non-demented, aged 70 years or older. They were recruited in 13 memory clinics in France and Monaco between 30 May 2008 and 24 February 2011. Participants were randomly assigned to either ω3-PUFA alone (two capsules a day providing a total daily dose of 800 mg DHA and 225 mg EPA), ω3-PUFA plus the multidomain intervention (43 group sessions integrating advice for physical activity (PA), and nutrition, cognitive training, and three preventive consultations), the multidomain intervention plus placebo, or placebo alone. Our primary outcome was the change from baseline to 36 months of the muscle strength assessed with the repeated chair stand test and handgrip strength. RESULTS: A total of 1680 participants (75.34 years ± 4.42) were randomized. In the modified intention-to-treat population (n = 1679), no significant differences at 3-year follow-up were observed in the repeated chair stand test score between any of the three intervention groups and the placebo group. The between-group differences compared with placebo were -0.05388 (-0.6800 to 0.5723; Standard Error, SE = 0.3192; p = 0.8660) for the ω3-PUFA group, -0.3936 (-1.0217 to 0.2345; SE = 0.3180; p = 0.2192) for the multidomain intervention plus placebo group, and -0.6017 (-1.2255 to 0.02222; SE = 0.2092; p = 0.3202) for the combined intervention group. No significant effect was also found for the handgrip strength. Sensitivity analyses performed among participants with low (DHA+EPA) erythrocyte level at baseline (first quartile vs. others) or highly adherent participants (≥75% of the multidomain intervention sessions) revealed similar results. CONCLUSION: Low dose ω3-PUFA supplementation, either alone or in combination with a multidomain lifestyle intervention comprising physical activity counselling, had no significant effects on muscle strength over 3 years in elderly people.

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.

Lifestyle multidomain intervention, omega-3 supplementation, or both for reducing the risk of developing clinically relevant depressive symptoms in older adults with memory complaints? Secondary analysis from the MAPT trial.

BACKGROUND: We tested the associations of a lifestyle multidomain intervention (MI), omega-3 supplementation (O3) or their combination with the change of clinically meaningful depressive symptoms in older adults. METHODS: Secondary analysis of the 3-year Multidomain Alzheimer Preventive Trial (MAPT), in which 1679 people, ≥70 years with memory complaints were randomized into: MI, O3, MI + O3, or placebo. MI was composed of nutritional and physical activity counselling and cognitive training. O3 supplementation corresponded to a daily dose of 1000 mg of omega-3. Discrete-time cox regressions were performed for each outcome. Three binary variables of incidence of depressive symptoms were created from the 15-item geriatric depression scale (GDS-15): minimum clinically meaningful depressive symptoms (≥2-point increase in GDS-15), moderate depressive symptoms (GDS-15 ≥ 5), and severe depressive symptoms (GDS-15 ≥ 10) DS. RESULTS: Discrete-time cox proportional hazards have found no associations for all of the analysis. The incidence of severe depressive symptoms across groups were, respectively: 1.1, 2.4, 2.3 and 2.5 per 100 person year for MI + O3, for O3, for MI, for placebo. There was a trend for a decreased risk of developing severe DS compared to placebo in the MI + O3 group (p = 0.085 after adjustment). CONCLUSIONS: To conclude, we did not find any association of a lifestyle multidomain intervention with the onset of clinically depressive symptoms in older adults with memory complaints. A study with a more intensive multidomain intervention might bring further insights on this topic.

Effects of a 3-Year Multi-Domain Intervention with or without Omega-3 Supplementation on Cognitive Functions in Older Subjects with Increased CAIDE Dementia Scores.

Findings from recent Alzheimer's disease prevention trials have shown subjects with increased dementia score based upon mid-life cardiovascular risk factors, to benefit from multi-domain intervention strategies to some extent. The effects of such interventions on cognitive functions remains yet to be well-established. This study is a secondary analysis of the MAPT study, 1,293 older subjects (mean age 75 years) with high CAIDE score (i.e., ≥6) were classified according to the four intervention groups: 1) multi-domain intervention plus placebo, 2) isolated supplementation with Omega-3 polyunsaturated fatty acid (n-3 PUFA), 3) combination of the two interventions, and 4) placebo alone. Linear mixed-model repeated-measures analyses were used to assess the cognitive changes according to various neuropsychological test scores between intervention groups compared to the placebo at 36 months from baseline. Compared to the placebo, group with multi-domain intervention in combination withn-3PUFA was found to show significant improvement in the delayed total recall test of the free and cued selective reminding test (FCSRT) (mean±standard error(SE) = 0.20±0.10) and MMSE orientation test (mean±SE = 0.15±0.06) at 36 months. Isolated multi-domain intervention group showed significant less decline in the MMSE orientation test (mean±SE = 0.12±0.06) compared to the placebo. There was significant less improvement (mean±SE = - 1.01±0.46) in the FCSRT free recall test in the n-3 PUFA intervention group compared to the placebo at 36 months. Our findings show high-risk subjects for dementia screened with CAIDE dementia score might benefit from multi-domain intervention strategies as in the MAPT study, particularly in the orientation and delayed recall domain.

Effects of multidomain lifestyle intervention, omega-3 supplementation or their combination on physical activity levels in older adults: secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT) randomised controlled trial.

Background/objectives: to investigate the effects of a 3-year multidomain lifestyle intervention, omega-3 supplementation or both on physical activity (PA) in older adults with subjective memory complaints. Design/settings/subjects: the Multidomain Alzheimer Preventive Trial was a 3-year randomised controlled trial that enroled 1,680 community-dwelling adults aged 70 years or over, with subjective memory complaints. Participants were randomised to omega-3 supplementation (total daily dose of 800 mg docosahexanoic acid and up to 225 mg eicosapentanoic acid), multidomain intervention (nutritional and exercise counselling and cognitive training), omega-3 plus multidomain intervention or placebo with usual care. Methods: PA was assessed using a self-reported questionnaire. From this, global moderate-to-vigorous PA, leisure-time PA, non-leisure-time PA and light PA were measured in metabolic equivalent tasks-minutes per week (MET-min/week). Results: in the multidomain groups, participants significantly increased their moderate-to-vigorous and leisure-time PA at 6 months (≥300 MET-min/week for both in the multidomain groups; P ≤ 0.002) before returning to baseline by the end of the trial. Activity in the placebo/usual care and omega-3/usual care groups declined overtime. Between-group differences remained significant for both multidomain groups for leisure-time physical activity at 2- and 3-year follow-ups. Compared to placebo/usual care, interventions had no significant effects on non-leisure-time PA and light PA. Omega-3 supplementation alone had no effects on PA. Conclusions: a multidomain intervention focused on cognitive training, and nutritional and PA counselling increased PA in the short-term and limited its decline in the long-term among older adults with memory complaints. ClinicalTrials.gov-Registration number: NCT0067268.

Memory Complaints and Cognitive Decline: Data from the GUIDAGE Study1.

BACKGROUND: Subjective cognitive decline (SCD) may be a very early symptom of Alzheimer's disease (AD) and may be associated with a cognitive decline in a cognitively normal population. The McNair and Kahn Scale was used to assess memory complaints in the GuidAge study. OBJECTIVE: Our objectives were to examine if the McNair and Kahn Scale can predict cognitive decline and to screen which (if any) of the question(s) of this scale would better predict this cognitive decline. METHODS: The GuidAge study was a phase III, multicenter, randomized, double blind, placebo-controlled study. Individuals aged 70 years and older, without cognitive impairment (Clinical Dementia Rate (CDR = 0)) at baseline who had spontaneously reported SCD were included in this study. The 20-item version of the McNair and Kahn Scale was used to assess SCD and a standardized neuropsychological assessment was used to assess the cognitive status. RESULTS: 1,307 patients with SCD and with CDR = 0 at baseline were included. During the 5 years of follow-up, 519 patients showed cognitive decline. Incidence of aggravation score of CDR was 13.40% person years (95% CI [12.24-14.56]). Results showed a significant relationship between the McNair and Kahn Scale score and decline in cognitive performance (HR 1.012; 95% CI [1.002-1.021]; p = 0.0156). Among the 20 items, 5 were statistically significant to predict cognitive decline after adjustment. CONCLUSION: SCD is a promising indicator of memory impairment. Our study found that using the McNair and Kahn scale can predict cognitive decline. A 5-item version of this scale could be used to screen patients in clinical practice and in clinical research.

Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial.

BACKGROUND: No large trials have been done to investigate the efficacy of an intervention combining a specific compound and several lifestyle interventions compared with placebo for the prevention of cognitive decline. We tested the effect of omega 3 polyunsaturated fatty acid supplementation and a multidomain intervention (physical activity, cognitive training, and nutritional advice), alone or in combination, compared with placebo, on cognitive decline. METHODS: The Multidomain Alzheimer Preventive Trial was a 3-year, multicentre, randomised, placebo-controlled superiority trial with four parallel groups at 13 memory centres in France and Monaco. Participants were non-demented, aged 70 years or older, and community-dwelling, and had either relayed a spontaneous memory complaint to their physician, limitations in one instrumental activity of daily living, or slow gait speed. They were randomly assigned (1:1:1:1) to either the multidomain intervention (43 group sessions integrating cognitive training, physical activity, and nutrition, and three preventive consultations) plus omega 3 polyunsaturated fatty acids (ie, two capsules a day providing a total daily dose of 800 mg docosahexaenoic acid and 225 mg eicosapentaenoic acid), the multidomain intervention plus placebo, omega 3 polyunsaturated fatty acids alone, or placebo alone. A computer-generated randomisation procedure was used to stratify patients by centre. All participants and study staff were blinded to polyunsaturated fatty acid or placebo assignment, but were unblinded to the multidomain intervention component. Assessment of cognitive outcomes was done by independent neuropsychologists blinded to group assignment. The primary outcome was change from baseline to 36 months on a composite Z score combining four cognitive tests (free and total recall of the Free and Cued Selective Reminding test, ten Mini-Mental State Examination orientation items, Digit Symbol Substitution Test, and Category Naming Test) in the modified intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT00672685). FINDINGS: 1680 participants were enrolled and randomly allocated between May 30, 2008, and Feb 24, 2011. In the modified intention-to-treat population (n=1525), there were no significant differences in 3-year cognitive decline between any of the three intervention groups and the placebo group. Between-group differences compared with placebo were 0·093 (95% CI 0·001 to 0·184; adjusted p=0·142) for the combined intervention group, 0·079 (-0·012 to 0·170; 0·179) for the multidomain intervention plus placebo group, and 0·011 (-0·081 to 0·103; 0·812) for the omega 3 polyunsaturated fatty acids group. 146 (36%) participants in the multidomain plus polyunsaturated fatty acids group, 142 (34%) in the multidomain plus placebo group, 134 (33%) in the polyunsaturated fatty acids group, and 133 (32%) in the placebo group had at least one serious emerging adverse event. Four treatment-related deaths were recorded (two in the multidomain plus placebo group and two in the placebo group). The interventions did not raise any safety concerns and there were no differences between groups in serious or other adverse events. INTERPRETATION: The multidomain intervention and polyunsaturated fatty acids, either alone or in combination, had no significant effects on cognitive decline over 3 years in elderly people with memory complaints. An effective multidomain intervention strategy to prevent or delay cognitive impairment and the target population remain to be determined, particularly in real-world settings. FUNDING: French Ministry of Health, Pierre Fabre Research Institute, Gerontopole, Exhonit Therapeutics, Avid Radiopharmaceuticals.

An omnibus test for several hazard alternatives in prevention randomized controlled clinical trials.

The logrank test is optimal for testing the equality of survival distributions against a proportional hazards alternative. Under a late effects alternative, it is no longer appropriate, and one may turn to Fleming-Harrington's class of weighted logrank tests instead. In some settings, such as in preventive clinical trials where the statistical analysis has to be designed before the trial begins, it can be difficult to choose a priori between the logrank and Fleming-Harrington tests. A solution to this issue is provided. A decision rule is constructed for the problem of testing the equality of two survival distributions when the expected alternative may be one of the proportional hazards and late effects. A formula for computing the necessary sample size is obtained for this decision rule. A comprehensive simulation study is conducted to assess finite sample properties of the proposed test statistic. The proposed test improves both the logrank test and Fleming-Harrington's test for late effects. Finally, the methodology is illustrated on a data set in the field of prevention of Alzheimer's disease.