Multidomain Alzheimer Preventive Trial Research Articles

Interactions Between Weight Loss and Plasma Neurodegenerative Markers for Determining Cognitive Decline Among Community-Dwelling Older Adults.

This study aimed to investigate the interaction between weight loss (WL) and plasma amyloid-β 42/40 (Aβ 42/40), neurofilament light chain (NfL), progranulin, and their association with cognitive decline over time among older adults. This 5-year observational approach included 470 participants from the Multidomain Alzheimer Preventive Trial, mean age 76.8 years (SD = 4.5), 59.4% women. WL was defined as ≥5% decrease over the first year. Biomarkers were measured at 12 months. Cognitive function was assessed yearly from 12 months onward by Mini-Mental State Examination (MMSE); Clinical Dementia Rating sum of boxes (CDR-SB); a composite score based on Category Naming Test; Digit Symbol Substitution Test; 10 MMSE orientation items (MMSEO) and free and total recall of the Free and Cued Selective Reminding test; and these tests individually. Twenty-seven participants (5.7%) presented WL. In adjusted analyses, combined WL + lower Aβ 42/40 (≤0.103, lowest quartile) was related with more pronounced 4-year cognitive decline according to CDR-SB (p < .0001) and MMSEO (p = .021), compared with non-WL + higher Aβ 42/40. WL + higher NfL (>94.55 pg/mL, highest quartile) or progranulin (>38.4 ng/mL, 3 higher quartiles) were related with higher cognitive decline according to CDR-SB, MMSE, MMSEO, and composite score (all p < .03), compared with non-WL + lower NfL or higher progranulin. Regrouping progranulin quartiles (Q1-Q3 vs Q4) revealed higher cognitive decline among the WL + lower progranulin group compared with non-WL + lower progranulin. In conclusion, 1-year WL was associated with subsequent higher 4-year cognitive decline among older adults presenting low Aβ 42/40 or high NfL. Future studies combining plasma biomarker assessments and body weight surveillance may be useful for identifying people at risk of cognitive impairment. Clinical trial number: NCT00672685.

Plasma MCP-1 and changes on cognitive function in community-dwelling older adults

BackgroundMonocyte Chemoattractant Protein-1 (MCP-1), a glial-derived chemokine, mediates neuroinflammation and may regulate memory outcomes among older adults. We aimed to explore the associations of plasma MCP-1 levels (alone and in combination with β-amyloid deposition—Aβ42/40) with overall and domain-specific cognitive evolution among older adults.MethodsSecondary analyses including 1097 subjects (mean age = 75.3 years ± 4.4; 63.8% women) from the Multidomain Alzheimer Preventive Trial (MAPT). MCP-1 (higher is worse) and Aβ42/40 (lower is worse) were measured in plasma collected at year 1. MCP-1 in continuous and as a dichotomy (values in the highest quartile (MCP-1+)) were used, as well as a dichotomy of Aβ42/40. Outcomes were measured annually over 4 years and included the following: cognitive composite z-score (CCS), the Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) sum of boxes (overall cognitive function); composite executive function z-score, composite attention z-score, Free and Cued Selective Reminding Test (FCSRT - memory).ResultsPlasma MCP-1 as a continuous variable was associated with the worsening of episodic memory over 4 years of follow-up, specifically in measures of free and cued delayed recall. MCP-1+ was associated with worse evolution in the CCS (4-year between-group difference: β = −0.14, 95%CI = −0.26, −0.02) and the CDR sum of boxes (2-year: β = 0.19, 95%CI = 0.06, 0.32). In domain-specific analyses, MCP-1+ was associated with declines in the FCSRT delayed recall sub-domains. In the presence of low Aβ42/40, MCP-1+ was not associated with greater declines in cognitive functions. The interaction with continuous biomarker values Aβ42/40× MCP-1 × time was significant in models with CDR sum of boxes and FCSRT DTR as dependent variables.ConclusionsBaseline plasma MCP-1 levels were associated with longitudinal declines in overall cognitive and episodic memory performance in older adults over a 4-year follow-up. How plasma MCP-1 interacts with Aβ42/40 to determine cognitive decline at different stages of cognitive decline/dementia should be clarified by further research. The MCP-1 association on cognitive decline was strongest in those with amyloid plaques, as measured by blood plasma Aβ42/40.

Validation of the Integrated Care for Older People Screening Tool: Focus on the Chair Rise Test to Assess Locomotion

The Integrated Care for Older People (ICOPE) is a function- and person-centered healthcare pathway developed by the World Health Organization (WHO). ICOPE's first step (Step 1) consists of screening for impairments in the intrinsic capacity (IC) domains (namely sensorial, cognition, nutrition, psychological, and locomotion). For instance, the ICOPE Step1 tool suggests a cut-point of 14 seconds for five-repetition chair rise time as a marker of impaired locomotion. Given the lack of validation of this tool in the literature, we aimed to validate the ICOPE screening tool concerning incident health outcomes, focusing on the locomotion assessment. First, we analyzed the five-domain screening tool's ability to identify older adults (OA) at higher risk of incident outcomes (frailty, disability, dementia) using longitudinal data from the Multidomain Alzheimer Preventive Trial (MAPT). For the locomotion assessment (chair rise test), we derived and cross-validated age-specific cut points from two population-based cohorts using ROC (receiver operating characteristic) analysis. We further verified those cut points among OA real-life users of the health system and clinical trial participants. In conclusion, the ICOPE Step 1 screening tool was able to identify OA at higher risk of incident frailty, disability, and dementia. New chair-rise-time cut points for age groups 70-79 years old and 80 years and older were valid in populations from different settings. The ICOPE Step 1 tool provides a practical and integrative way of screening older adults for impairments in IC and detecting those at higher risk of functional decline.

Interactions Between Plasma Amyloid and Aging Markers to Determine Clinically Meaningful Cognitive Decline

Older adults’ experiences with memory problems may be an important indicator of current and future well-being; however, these experiences and their impacts are poorly characterized, particularly in those with co-occurring affective symptoms. The purpose of this mixed-methods study was to examine how the experience of memory problems influences emotional well-being in older adults without dementia, and whether this differs based on cognitive status and current depressive symptoms or anxiety symptoms. A convergent parallel mixed methods design was used in which quantitative and qualitative data were collected simultaneously, analyzed separately, and then integrated to determine how participants’ experiences differed. Community-dwelling older adults (n=49, Mage = 74.5, 63% female) without severe cognitive impairment completed study questionnaires and two individual, semi-structured interviews. Five themes were identified that described the influence of memory problems on emotional well-being: Evoking Emotions, Fearing Future, Undermining Self, Normalizing Problems, and Adjusting Thinking. The extent to which memory problems impacted emotional well-being depended on multiple factors including current affective symptoms (primarily anxiety), characteristics of the experience (such as judgments of its importance), as well as personal experience with dementia. Notably, there were no thematic differences in the emotional impact of memory problems between older adults with normal cognition and those with evidence of mild cognitive impairment. Our findings suggest that thorough assessment of reports of memory problems, regardless of cognitive testing outcomes, should consider co-occurring subsyndromal affective disorders as well as older adults’ evaluations of how memory problems influence their daily lives and well-being.

Interactions Between Plasma Amyloid and Aging Markers to Determine Clinically Meaningful Cognitive Decline

Background: Brain amyloidosis is a well-known pathological hallmark of Alzheimer’s disease (AD) and can be early identified by measuring plasma amyloid-β (Aβ) status. Growing evidence implicates the biological mechanisms of aging, including chronic inflammation, mitochondrial dysfunction and neurodegeneration, in AD pathogenesis. This study aims to investigate the interactions between plasma Aβ status and aging markers on clinically meaningful cognitive decline. Methods: This secondary analysis from Multidomain Alzheimer Preventive Trial (MAPT) enrolled 401 community-dwelling older adults (mean age ± SD: 76.7 ± 4.6 years) who had clinical dementia rating (CDR) scale as 0 or 0.5, and who had their plasma biomarkers measured: amyloidosis: Aβ42/40 ratio; inflammatory: tumor necrosis factor receptor type 1 (TNFR-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), C-reactive protein (CRP); mitochondrial dysfunction: growth differentiation factor 15 (GDF-15); neurodegeneration: neurofilament light chain (NfL). Cognitive decline was determined by diagnosed dementia and worsening CDR status. Cox regression and moderation modeling were applied to examine the interrelationships between biomarkers and risk of cognitive decline. Results: Among 401 participants, 43.9% were cognitive normal (CDR=0) and 56.1% were mild cognitive impairment (CDR=0.5) initially. After 3.3 ± 1.1 years of follow-up, 7.0% of population evolved dementia and 34.2% had worsening CDR status. GDF-15 and NfL presented prospective associations with incident dementia. However, risk of dementia associated with plasma Aβ did not change after considering the serum level of GDF-15 and NfL. Conclusion: The markers of mitochondrial dysfunction and neurodegeneration did not partially explain the associations between plasma Aβ status and cognitive decline in older adults.

Orthostatic hypertension is associated with lower plasma Aβ42/Aβ40 ratio: The Multidomain Alzheimer Preventive Trial (MAPT)

AbstractBackgroundOrthostatic hypertension (OHYPER), an emerging hemodynamic cardiovascular risk factor, is associated with cardiovascular events and mortality. Recent findings indicated that it could be an important risk factor for cognitive decline and dementia, including Alzheimer’s disease (AD). We aimed to assess the association between OHYPER and low plasma Aβ42/Aβ40 ratio, a surrogate biomarker for brain amyloidosis, associated with greater risk of mild cognitive impairment (MCI) and AD.MethodWe included 483 non‐demented community‐dwelling participants aged ≥ 70 years from the Multidomain Alzheimer Preventive Trial (MAPT). OHYPER was assessed at baseline and defined as an increase of at least 20 mmHg in systolic blood pressure (BP) and/or 10 mmHg in diastolic BP after standing. Plasma Aβ42 and Aβ40 were measured at 12 months, using an immunoprecipitation and liquid chromatography‐mass spectrometry assay. Low plasma Aβ42/Aβ40 ratio was defined as ≤ 0.107. Logistic regression models were used to assess the association between OHYPER and low plasma Aβ42/Aβ40 ratio.ResultOf 483 participants (mean age 76 years, 59% female), 113 (23.6%) had OHYPER and 161 (33.3%) low plasma Aβ42/Aβ40 ratio. OHYPER was associated with low plasma Aβ42/Aβ40 ratio (OR = 1.58, 95% CI [1.02‐2.44]) in unadjusted models. Adjustment for age, sex, education, MAPT randomization group, lying BP, antihypertensive drug use, MCI, and presence of 1 or 2 ApoE ε4 alleles did not change the results (OR = 1.67, 95% CI [1.02‐2.72]). Sensitivity analyses using the 25th percentile of plasma Aβ42/Aβ40 ratio (≤ 0.103) as an alternative cutoff and long‐term OHYPER (at least two‐thirds of visits over 12 months) reported consistent findings.ConclusionOHYPER was associated with lower plasma Aβ42/Aβ40 ratio in community‐dwelling older adults, even after accounting for potential confounders. Monitoring OHYPER may have clinical utility for identifying patients who are at risk for cognitive decline, AD or in the preclinical stages of the disease.

When is more better? Modeling the effect of dose on the efficacy of the MAPT multidomain intervention as a function of individual characteristics

AbstractBackgroundDose is a critical factor examined in pharmacological treatment. However, little is known about the optimal dosage for non‐pharmacological multidomain interventions as well as the function that relates dose to improvement. These gaps have been assessed in this present study in interaction with individual characteristics, which may moderate the effect of dose. Magnification models predict that healthier individuals will benefit more from prolonged practice, whereas reserve models predict that training will reduce cognitive disadvantage.MethodThe data from the Multidomain Alzheimer Preventive Trial (MAPT) was used to determine the relationship between cognitive training dose and cognition, and its interaction with sex, age, education, entry criteria, CAIDE risk score, frailty and Apoe4 status. The MAPT is a three‐year randomized controlled trial, which includes cognitive training, physical activity, nutrition and omega‐3 polyunsaturated fatty acids in at‐risk individuals. The number of hours of cognitive training attended (max.=28) was used as a measure of dose in the 749 participants randomized to the multidomain intervention.ResultFirst, polynomial regression analysis modelled cognitive performance over time on memory, verbal fluency and composite cognitive score. Mixed model analyses measured the effect of dose on expected scores, and interaction with individual factors were assessed. A cubic function explained the relationship between dose and performance indicating benefits up to 12‐14 training hours followed by a plateau. Interactions were found with individual characteristics. Older participants and those with a higher CAIDE score reached their plateau more rapidly. Individuals with lower education and frail individuals benefited more from increased exposure.ConclusionA non‐linear dose‐response function indicates that more is not necessarily better. Here, the optimal dose was found to be 12‐14 hours of training, about half of what was potentially available to participants. A magnification effect is found for age and vascular risk factors as younger and healthier participants show larger benefit. However, a reserve effect is found in frail or less educated participants as they benefitted more from additional training experience than their more privileged counterparts.

Potentially Inappropriate Medication Prescribing Detected by Computer Algorithm among Older Patients: Results from the MAPT Study.

(1) Background: Some medications may be dangerous for older patients. Potentially inappropriate medication prescribing (PIP) among older patients represents a significant cause of morbidity. The aim of this study was to create an algorithm to detect PIP in a geriatric database (Multidomain Alzheimer Preventive Trial (MAPT) study), and then to assess the algorithm construct validity by comparing the prevalence of PIP and associated factors with literature data. (2) Methods: An algorithm was constructed to detect PIP and was based on different explicit criteria among which the European list of potentially inappropriate medications (EU(7)-PIM), the STOPP and START version 2 tools. For construct validity assessment, logistic mixed-effects model repeated measures analyses were used to identify factors associated with PIP. (3) Results: Prevalence of PIP was 59.0% with the EU(7)-PIM list criteria, 43.2% with the STOPP criteria and 51.3% with the START criteria. Age, polypharmacy, and higher Charlson comorbidity index were associated with PIP. (4) Conclusions: Prevalence of PIP and associated factors are consistent with literature data, supporting the construct validity of our algorithm. This algorithm opens up interesting perspectives both in terms of analysis of very large databases and integration into e-prescribing or pharmaceutical validation software.

Abstract 12049: Orthostatic Hypertension is Associated With Lower Plasma aβ 42 /aβ 40 Ratio: The Multidomain Alzheimer Preventive Trial (MAPT)

Introduction: Orthostatic hypertension (OHYPER), an emerging hemodynamic cardiovascular risk factor, is associated with cardiovascular events and mortality. Recent findings indicated that it could be an important risk factor for cognitive decline and dementia, including Alzheimer’s disease (AD). Hypothesis: We aimed to assess the association between OHYPER and low plasma Aβ 42 /Aβ 40 ratio, a surrogate biomarker for brain amyloidosis. Methods: We included 483 non-demented community-dwelling participants aged ≥ 70 years from the Multidomain Alzheimer Preventive Trial (MAPT). OHYPER was assessed at baseline and defined as an increase of at least 20 mmHg in systolic blood pressure (BP) and/or 10 mmHg in diastolic BP after standing. Plasma Aβ 42 and Aβ 40 were measured at 12 months, using an immunoprecipitation and liquid chromatography-mass spectrometry assay. Low plasma Aβ 42 /Aβ 40 ratio was defined as ≤ 0.107. Logistic regression models were used to assess the association between OHYPER and low plasma Aβ 42 /Aβ 40 ratio. Results: Of 483 participants (mean age 76 years, 59% female), 113 (23.6%) had OHYPER and 161 (33.3%) low plasma Aβ 42 /Aβ 40 ratio. OHYPER was associated with low plasma Aβ 42 /Aβ 40 ratio (OR = 1.58, 95% CI [1.02-2.44]) in unadjusted models. Adjustment for age, sex, education, MAPT randomization group, lying BP, antihypertensive drug use, MCI, and presence of 1 or 2 ApoE ε4 alleles did not change the results (OR = 1.67, 95% CI [1.02-2.72]). Sensitivity analyses using the 25 th percentile of plasma Aβ 42 /Aβ 40 ratio (≤ 0.103) as an alternative cutoff and long-term OHYPER (at least two-thirds of visits over 12 months) reported consistent findings. Conclusions: OHYPER was associated with lower plasma Aβ 42 /Aβ 40 ratio in community-dwelling older adults, even after accounting for potential confounders. Monitoring OHYPER may have clinical utility for identifying patients who are at risk for cognitive decline, AD or in the preclinical stages of the disease.

Associations Between Nutritional Deficits and Physical Performance in Community-Dwelling Older Adults.

Background: Whether multiple nutritional deficiencies have a synergic effect on mobility loss remains unknown. This study aims to evaluate associations between multi-nutritional deficits and physical performance evolution among community-dwelling older adults.Methods: We included 386 participants from the Multidomain Alzheimer Preventive Trial (MAPT) (75.6 ± 4.5 years) not receiving omega-3 polyunsaturated fatty acid (PUFA) supplementation and who had available data on nutritional deficits. Baseline nutritional deficits were defined as plasma 25 hydroxyvitamin D <20 ng/ml, plasma homocysteine >14 μmol/L, or erythrocyte omega-3 PUFA index ≤ 4.87% (lower quartile). The Short Physical Performance Battery (SPPB), gait speed, and chair rise time were used to assess physical performance at baseline and after 6, 12, 24, 36, 48, and 60 months. We explored if nutrition-physical performance associations varied according to the presence of low-grade inflammation (LGI) and brain imaging indicators.Results: Within-group comparisons showed that physical function (decreased SPPB and gait speed, increased chair rise time) worsened over time, particularly in participants with ≥2 nutritional deficits; however, no between-group differences were observed when individuals without deficit and those with either 1 or ≥2 deficits were compared. Our exploratory analysis on nutritional deficit-LGI interactions showed that, among people with ≥2 deficits, chair rise time was increased over time in participants with LGI (adjusted mean difference: 3.47; 95% CI: 1.03, 5.91; p = 0.017), compared with individuals with no LGI.Conclusions: Accumulated deficits on vitamin D, homocysteine, and omega-3 PUFA were not associated with physical performance evolution in older adults, but they determined declined chair rise performance in subjects with low-grade inflammation.Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT00672685], identifier [NCT00672685].

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

BackgroundPreventive 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.MethodsAncillary 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).ResultsResponse 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.ConclusionsDisparities 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 registrationNCT00672685 (ClinicalTrials.gov)

Amyloid Burden and Depressive Symptom Trajectories in Older Adults at Risk of Developing Cognitive Decline.

Objective: Little is known about the amyloid load impact on depressive symptoms or disorders, although it can modulate the cognitive trajectory in older adults. Here, we analyzed, in individuals at risk of Alzheimer's dementia, the relationship between amyloid load and depressive symptoms changes over time.Methods: This study included ≥ 70-year-old participants from the French Multidomain Alzheimer Preventive Trial (MAPT) (May 2008 to February 2011) who underwent brain amyloid load measurement by β-amyloid-[18F] florbetapir-PET at baseline and had spontaneous memory complaints and/or limitation in 1 instrumental activity of daily living or slow walking gait (N = 264). Symptoms of depression were measured with the Geriatric Depression Scale-15 items (GDS) at baseline and 6, 12, 24, and 36 months of follow-up. Four GDS factors were determined by principal component analysis (PCA): life satisfaction, level of apathy, self-esteem, and anxiety. Amyloid positive status was defined based on the amyloid load in 6 Alzheimer's dementia-related regions. Regional amyloid load was based on 3 dimensions defined by PCA. The longitudinal links between depressive symptomatology and amyloid load (ie, cortical AV45 and amyloid load dimensions) were analyzed using linear mixed-multivariate models.Results: At baseline, 11% of participants had depressive symptoms (GDS > 5) and 34% were amyloid-positive. The global amyloid load was not associated with worsening of the total GDS score but only with the impairment of self-esteem factor during the follow-up after adjustment for age, sex, education level, and drug intake, dementia, and Mini-Mental State Examination score (β = -0.029, 95% CI [-0.052 to -0.007], P = .003). Regional amyloid load in hippocampus and bilateral caudate nucleus protected significantly from self-esteem decrease during the 3-year follow-up.Conclusions: Although amyloid load shows no impact on GDS score in subjects at risk of Alzheimer's dementia, amyloid load may influence the progression of depressive dimension (self-esteem) with different effects according to the regional burden.Trial Registration: ClinicalTrials.gov identifier: NCT00672685.

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

AimThis 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 settingSeven 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. MethodsWe 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. ResultsLimited 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. ConclusionScreening 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

Neuroimaging correlates of persistent fatigue in older adults: A secondary analysis from the Multidomain Alzheimer Preventive Trial (MAPT) trial

Objectives Fatigue has been suggested as a marker of biological aging. It seems plausible that this symptom might be associated with changes in brain health. The objective of this study was to examine the associations between persistent fatigue and neuroimaging correlates in a non-disease-specific population of community-dwelling older adults. Methods We performed a cross-sectional analysis using data from The Multidomain Alzheimer Preventive Trial (MAPT). We included 458 subjects. Persistent fatigue was defined as meeting exhaustion criterion of Fried frailty phenotype in two consecutive clinical visits six months apart between study baseline and one year. Brain imaging correlates, assessed by magnetic resonance imaging (MRI), were the outcomes. The associations between persistent fatigue and brain correlates were explored using mixed model linear regressions with random effect at the center level. Results The mean age of the participants was 74.8 ± 4 years old, and 63% of the subjects were women. Forty-seven participants (10%) exhibited a persistent fatigue profile. People with persistent fatigue were older compared to subjects without persistent fatigue (76.2 years ± 4.3 vs.74.7 ± 3.9 p = 0.009). Persistent fatigue was associated with higher white matter hyperintensity volume in the fully adjusted analysis. We did not find any cross-sectional association between persistent fatigue and sub-cortical volumes and global and regional cortical thickness. Conclusion Persistent fatigue was cross-sectionnally associated with higher white matter hyperintensity volume in older adults. Further longitudinal studies, using an assessment tool specifically designed and validated for measuring fatigue, are needed to confirm our findings.

Bidirectional relationship between depressive symptoms and physical performance in community-dwelling older people with subjective memory complaints.

This study examined the bidirectional relationship between depressive symptoms and physical performance in community-dwelling older people with subjective memory complaints. Secondary analyses using data from the Multidomain Alzheimer Preventive Trial (MAPT) study were performed. The participants were 1679 subjects (female, 64.8%; mean age, 75.3 ± 4.4years). The outcome measures were depressive symptoms assessed by the 15-item Geriatric Depression Scale (GDS) and physical performance assessed by the Short Physical Performance Battery (SPPB) and handgrip strength (HGS). All measurements were performed at baseline and at 6, 12, 24, and 36months. The bidirectional relationships of GDS with SPPB and HGS were examined using mixed-effect regression analysis. Baseline physical performance was significantly associated with a decreased GDS score (SPPB score: β = - 0.210, 95% confidence interval [CI], - 0.283 to - 0.137; HGS: β = - 0.038, 95% CI - 0.056 to - 0.019). The baseline GDS score was significantly associated with decreased physical performance (SPPB score: β = - 0.082, 95% CI - 0.107 to - 0.056; HGS: β = - 0.261, 95% CI - 0.370 to - 0.152). Since depressive symptoms and physical performance had a bidirectional relationship, prevention or improvement of decreased physical performance could play a role in reducing depressive symptoms, and addressing depressive symptoms may play a role in improving physical performance. NCT01513252.

Five-Year Lower Extremity Function is Associated with White Matter Abnormality in Older Adults.

To explore associations between changes of lower extremity function (LEF) parameters over a 5-year period and diffusion tensor imaging (DTI) parameters of white matter tracts among community-dwelling older adults. A secondary analysis on image and physical function data collected from the Multidomain Alzheimer's Preventive Trial (MAPT). 208 older adults (aged 75 ± 4 years, with spontaneous memory complaint or limited instrumental daily living activity or slow gait speed, 60% female) of the MAPT-magnetic resonance imaging (MRI) ancillary study. The time interval between a participant's enrolment and MRI scan was on average 110 ± 97 days. Forty-eight white matter tracts (WMTs) were measured. LEF parameters (measured after the MRI scan) were assessed as the short physical performance battery (SPPB) score, gait speed, and chair stands time over a 5-year period. Mixed-effects models were performed to explore the associations between baseline DTI values and the progression of LEF parameters. Bonferroni correction was applied for multiple comparison correction. The progression of LEF was associated with 35 baseline DTI parameters from 24 WMTs. Higher baseline DTI parameter values were related to more decreases in SPPB score and gait speed, and greater increases in chair stands time. Bilateral uncinate fasciculus was associated with all LEF parameters. Other WMTs in cingulum, cerebral and cerebellar peduncle, internal capsule, and corpus callosum also showed close connections with LEF changes. Our findings show that DTI parameters of some WMTs are associated with the 5-year decline in LEF, suggesting that alterations in WMT integrity (evaluated by DTI parameters) might be used to explore potential causes of impaired mobility in older adults when no clear explanations can be found.

The Cost-Effectiveness of Three Prevention Strategies in Alzheimer\u2019s Disease: Results from the Multidomain Alzheimer Preventive Trial (MAPT)

BackgroundTo date, no curative treatment is available for Alzheimer’s disease (AD). Therefore, efforts should focus on prevention strategies to improve the efficiency of healthcare systems.ObjectiveOur aim was to assess the cost-effectiveness of three preventive strategies for AD compared to a placebo.DesignThe Multidomain Alzheimer Preventive Trial (MAPT) study was a multicenter, randomized, placebo-controlled superiority trial with four parallel groups, including three intervention groups (one group with Multidomain Intervention (MI) plus a placebo, one group with Polyunsaturated Fatty Acids (PFA), one group with a combination of PFA and MI) and one placebo group.SettingParticipants were recruited and included in 13 memory centers in France and Monaco.ParticipantsCommunity-dwelling subject aged 70 years and older were followed during 3 years.InterventionsWe used data from the MAPT study which aims to test the efficacy of a MI along PFA, the MI plus a placebo, PFA alone, or a placebo alone.MeasurementDirect medical and non-medical costs were calculated from a payer’s perspective during the 3 years of follow-up. The base case incremental Cost-Effectiveness Ratio (ICER) represents the cost per improved cognitive Z-score point. Sensitivity analyses were performed using different interpretation of the effectiveness criteria.ResultsAnalyses were conducted on 1,525 participants. The ICER at year 3 that compares the MI + PFA and the MI alone to the placebo amounted to €21,443 and €21,543 respectively, per improved Z score point. PFA alone amounted to €111,720 per improved Z score point.ConclusionOur study shows that ICERS of PFA combined with MI and MI alone amounted to €21,443 and €21,543 respectively per improved Z score point compared to the placebo and are below the WTP of €50,000 while the ICER of PFA alone amounted to €111,720 per improved Z score point. This information may help decision makers and serve as a basis for the implementation of a lifetime decision analytic model.

The Effect of Multidomain Interventions on Global Cognition, Symptoms of Depression and Apathy \u2014 A Pooled Analysis of Two Randomized Controlled Trials

BackgroundCardiovascular risk factors and lifestyle factors are associated with an increased risk of cognitive decline and dementia in observational studies, and have been targeted by multidomain interventions.ObjectivesWe pooled individual participant data from two multi-domain intervention trials on cognitive function and symptoms of depression to increase power and facilitate subgroup analyses.DesignPooled analysis of individual participant data.SettingPrevention of Dementia by Intensive Vascular Care trial (preDIVA) and Multidomain Alzheimer Preventive Trial (MAPT).ParticipantsCommunity-dwelling individuals, free from dementia at baseline.InterventionMultidomain interventions focused on cardiovascular and lifestyle related risk factors.MeasurementsData on cognitive functioning, depressive symptoms and apathy were collected at baseline, 2 years and 3–4 years of follow-up as available per study. We analyzed crude scores with linear mixed models for overall cognitive function (Mini Mental State Examination [MMSE]), and symptoms of depression and apathy (15-item Geriatric Depression Scale). Prespecified subgroup analyses were performed for sex, educational level, baseline MMSE <26, history of hypertension, and history of stroke, myocardial infarction and/or diabetes mellitus.ResultsWe included 4162 individuals (median age 74 years, IQR 72, 76) with a median follow-up duration of 3.7 years (IQR 3.0 to 4.1 years). No differences between intervention and control groups were observed on change in cognitive functioning scores and symptoms of depression and apathy scores in the pooled study population. The MMSE declined less in the intervention groups in those with MMSE <26 at baseline (N=250; MD: 0.84; 95%CI: 0.15 to 1.54; p<0.001).ConclusionsWe found no conclusive evidence that multidomain interventions reduce the risk of global cognitive decline, symptoms of depression or apathy in a mixed older population. Our results suggest that these interventions may be more effective in those with lower baseline cognitive functioning. Extended follow-up for dementia occurrence is important to inform on the potential long-term effects of multidomain interventions.

Assessment of Plasma Amyloid-β42/40 and Cognitive Decline Among Community-Dwelling Older Adults

Plasma measurement of amyloid-β (Aβ) peptides has been associated with cognitive function, but evidence of its ability to identify cognitive decline is still scarce. To investigate the associations between plasma Aβ42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns. This multicenter cohort study used data from volunteers in the 5-year study Multidomain Alzheimer Preventive Trial (MAPT). Participants were aged 70 years or older and observed for a median (interquartile range) of 3.9 (2.0-4.0) years. Recruitment of participants started in May 2008 and ended in February 2011. Follow-up ended in April 2016. Data analysis was conducted from April to October 2020. Plasma Aβ42 and Aβ40 were measured at 12 months for 448 participants (92.8%) and at 24 months for the rest. The moment of Aβ assessment was defined as the baseline for this study. Cognitive function was assessed at 12, 24, 36, 48, and 60 months by a composite cognitive score based on 4 tests; Mini Mental State Examination (MMSE); Clinical Dementia Rating, sum of boxes; and Alzheimer Disease Cooperative Study-Activities of Daily Living. Mixed-effect linear regressions were performed. A total of 483 participants (median [IQR] age, 76.0 [73.0-80.0]; 286 [59.2%] women) were analyzed. Of them, 161 (33.3%) were classified as low plasma Aβ42/40 (≤0.107). After adjusting for age, sex, education, body mass index, Geriatric Depression Scale score, apolipoprotein E ε4 genotype, and MAPT intervention groups, low plasma Aβ42/40 was associated with more pronounced decline in composite cognitive score (adjusted between-group mean difference: -0.20, 95% CI, -0.34 to -0.07; P = .004) and decline in MMSE score (adjusted between-group mean difference: -0.59; 95% CI, -1.07 to -0.11; P = .02) during the follow-up period compared with the group with an Aβ42/40 ratio greater than 0.107. In this study, low plasma Aβ42/40 was associated with more pronounced decline in cognitive function (measured by multiple outcomes) over time. Findings suggest that plasma Aβ42/40 may be used to identify people at risk of cognitive decline, being an alternative to more complex and expensive measures, such as positron emission tomography imaging or cerebrospinal fluid measurement.

Biological and Neuroimaging Markers as Predictors of 5-Year Incident Frailty in Older Adults: A Secondary Analysis of the MAPT Study.

This study aims to investigate the predictive value of biological and neuroimaging markers to determine incident frailty among older people for a period of 5 years. We included 1394 adults aged 70 years and older from the Multidomain Alzheimer Preventive Trial, who were not frail at baseline (according to Fried's criteria) and who had at least 1 post-baseline measurement of frailty. Participants who progressed to frailty during the 5-year follow-up were categorized as "incident frailty" and those who remained non-frail were categorized as "without frailty." The differences of baseline biochemical factors (25-hydroxyvitamin D, homocysteine, omega-3 index, C-reactive protein), other biological markers (Apolipoprotein E genotypes, amyloid-β deposits), and neuroimaging data (gray matter volume, hippocampal volume, white matter hyperintensities) were compared between groups. Cox proportional hazard model was used to evaluate the associations between biomarkers and incident frailty. A total of 195 participants (14.0%) became frail over 5 years. Although 25-hydroxyvitamin D deficiency, homocysteine levels, low-grade inflammation (persistently increased C-reactive protein 3-10 mg/L), gray matter, and hippocampal volume were significantly associated with incident frailty in unadjusted models, these associations disappeared after adjustment for age, sex, and other confounders. Omega-3 index was the sole marker that presented a trend of association with incident frailty (hazard ratio: 0.92; 95% confidence interval: 0.83-1.01; p = .082). This study failed to identify biomarkers able to predict frailty incidence in community-dwelling older adults for a period of 5 years. Further longitudinal research with multiple measurements of biomarkers and frailty is needed to evaluate the long-term relationships between changes in biomarkers levels and frailty evolution.