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BACKGROUND: The mechanisms linking mild behavioral impairment (MBI) and Alzheimer's disease (AD) have been insufficiently explored, with conflicting results regarding tau protein and few data on other metabolic markers. We aimed to evaluate the longitudinal association of the MBI domains and a spectrum of plasma biomarkers. METHODS: Our study is a secondary analysis of data from NOLAN. The longitudinal association of the MBI domains with plasma biomarkers, including pTau181, was tested using adjusted linear mixed‐effects models. RESULTS: The sample comprised 359 participants (60% female, mean age: 78.3, standard deviation: 0.3 years). After 1 year, the MBI domain of abnormal perception was associated with steeper increases in plasma pTau181. Abnormal perception, decreased motivation, and impulse dyscontrol were associated with homocysteine or insulin dysregulation. DISCUSSION: Apart from the association with plasma pTau181, our results suggest that MBI might also represent metabolic dysregulation, probably contributing to dementia transition among older adults with subjective cognitive decline or mild cognitive impairment. Highlights: Mild behavioral impairment (MBI) psychosis was associated with steeper increases in plasma p.pTau could be a pharmacological target to treat agitation and psychosis symptoms.MBI domains were linked to metabolic dysregulation involving insulin and homocysteine. [ABSTRACT FROM AUTHOR]

• Baseline resting concentrations in adenosine triphosphatase inhibitory factor 1 (IF1) were positively associated with physical activity (PA) levels in older adults. • About 37.7% of this relationship was statistically mediated by the concentrations in apolipoprotein A-I. • Higher baseline IF1 concentrations predicted faster decline in PA levels over the subsequent 2 years. • Our findings support previous studies identifying IF1 as potential exerkine. Adenosine triphosphatase inhibitory factor 1 (IF1) is a key protein involved in energy metabolism. IF1 has been linked to various age-related diseases, although its relationship with physical activity (PA) remains unclear. Additionally, the apolipoprotein A-I (apoA-I), a PA-modulated lipoprotein, could play a role in this relationship because it shares a binding site with IF1 on the cell-surface ATP synthase. We examined here the associations between chronic PA and plasma IF1 concentrations among older adults, and we investigated whether apoA-I mediated these associations. In the present work, 1096 healthy adults (63.8% females) aged 70 years and over who were involved in the Multidomain Alzheimer Prevention Trial study were included. IF1 plasma concentrations (square root of ng/mL) were measured at the 1-year visit of the Multidomain Alzheimer Prevention Trial, while PA levels (square root of metabolic equivalent task min/week) were assessed using questionnaires administered each year from baseline to the 3-year visit. Multiple linear regressions were performed to investigate the associations between the first-year mean PA levels and IF1 concentrations. Mediation analyses were conducted to examine whether apoA-I mediated these associations. Mixed-effect linear regressions were carried out to investigate whether the 1-year visit IF1 concentrations predicted subsequent changes in PA. Multiple linear regressions indicated that first-year mean PA levels were positively associated with IF1 concentrations (B = 0.021; SE = 0.010; p = 0.043). Mediation analyses revealed that about 37.7% of this relationship was mediated by apoA-I (B ab = 0.008; SE = 0.004; p = 0.023). Longitudinal investigations demonstrated that higher concentrations of IF1 at the 1-year visit predicted a faster decline in PA levels over the subsequent 2 years (time × IF1: B = –0.148; SE = 0.066; p = 0.025). This study demonstrates that regular PA is associated with plasma IF1 concentrations, and it suggests that apoA-I partly mediates this association. Additionally, this study finds that baseline concentrations of IF1 can predict future changes in PA. However, further research is needed to fully understand the mechanisms underlying these observations. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: The prevention of symptomatic Alzheimer's disease (AD) is a major endeavor currently in the field, with the prevalence of subjects on the AD continuum (i.e. presence of amyloid‐β [Aβ] pathology) being much higher than previously estimated. However, the extent to which Aβ pathology and its interaction with common risk factors in the aging population relates to disease progression is still limited. The AMYPAD Prognostic and Natural History Study (PNHS) aims to evaluate the value of amyloid‐PET for predicting AD‐related disease progression. Method: A total of 1423 non‐demented subjects were included from the AMYPAD‐PNHS pan‐European cohort (17 sites across 10 Parent Cohorts), for who a baseline [18F]flutemetamol or [18F]florbetaben amyloid‐PET scans that passed quality control was available (Table‐1). Amyloid burden was assessed using the Centiloid (CL) method (whole cerebellum reference region). Independent linear mixed‐effect models were used to assess the predictive value of continuous CL, and its interaction with time, across cognitive domains: mini‐mental state examination (MMSE), memory, attention, language fluency, visuospatial, and executive functions. Years from baseline, age, sex, years of education, cognitive dementia rating (CDR), and APOE‐ε4 were used as independent variables. Clinical follow‐up was 3.4 ± 1.8 years (up to ±10 years) on average. Result: At baseline, 90% of the subjects were classified as cognitively unimpaired (CDR = 0). Based on CL, most subjects were categorized as amyloid‐negative (59%, 0±9CL), followed by grey‐zone (24%, 25±11CL), and amyloid‐positive (17%, 82±21CL). Baseline CL and its interaction with time were predictive of MMSE scores, memory, attention, and language fluency. Baseline CL, but not its interaction with time, was predictive of executive function. Finally, the interaction of baseline CL with time, but not its main effect, was predictive of visuospatial functioning (Figure‐1). Age and sex were significant contributors to nearly all models. Conclusion: Higher baseline CL was associated with lower cognitive performance in all explored domains, suggesting that emerging cerebral amyloid accumulation in non‐demented individuals is predictive of overall cognitive function. Also, higher CL values were predictive of decline across cognitive domains, except for executive function. Further analysis is ongoing, including different confounding factors, longitudinal PET outcomes, and other biomarkers of the disease. [ABSTRACT FROM AUTHOR]

Background: The prevention of symptomatic Alzheimer's disease (AD) is a major endeavor currently in the field, with the prevalence of subjects on the AD continuum (i.e. presence of amyloid‐ß [Aß] pathology) being much higher than previously estimated. However, the extent to which Aß pathology and its interaction with common risk factors in the aging population relates to disease progression is still limited. The AMYPAD Prognostic and Natural History Study (PNHS) aims to evaluate the value of amyloid‐PET for predicting AD‐related disease progression. Method: A total of 1423 non‐demented subjects were included from the AMYPAD‐PNHS pan‐European cohort (17 sites across 10 Parent Cohorts), for who a baseline [18F]flutemetamol or [18F]florbetaben amyloid‐PET scans that passed quality control was available (Table‐1). Amyloid burden was assessed using the Centiloid (CL) method (whole cerebellum reference region). Independent linear mixed‐effect models were used to assess the predictive value of continuous CL, and its interaction with time, across cognitive domains: mini‐mental state examination (MMSE), memory, attention, language fluency, visuospatial, and executive functions. Years from baseline, age, sex, years of education, cognitive dementia rating (CDR), and APOE‐e4 were used as independent variables. Clinical follow‐up was 3.4 ± 1.8 years (up to ±10 years) on average. Result: At baseline, 90% of the subjects were classified as cognitively unimpaired (CDR = 0). Based on CL, most subjects were categorized as amyloid‐negative (59%, 0±9CL), followed by grey‐zone (24%, 25±11CL), and amyloid‐positive (17%, 82±21CL). Baseline CL and its interaction with time were predictive of MMSE scores, memory, attention, and language fluency. Baseline CL, but not its interaction with time, was predictive of executive function. Finally, the interaction of baseline CL with time, but not its main effect, was predictive of visuospatial functioning (Figure‐1). Age and sex were significant contributors to nearly all models. Conclusion: Higher baseline CL was associated with lower cognitive performance in all explored domains, suggesting that emerging cerebral amyloid accumulation in non‐demented individuals is predictive of overall cognitive function. Also, higher CL values were predictive of decline across cognitive domains, except for executive function. Further analysis is ongoing, including different confounding factors, longitudinal PET outcomes, and other biomarkers of the disease. [ABSTRACT FROM AUTHOR]

• Physical activity was positively associated with cortical thickness in adults aged 70 years and older. • People achieving at least 1500 metabolic equivalent task min/week of physical activity had thicker cortex in temporal areas such as the fusiform gyrus, a region often associated with Alzheimer's disease. • Physical activity was also associated with cortical thickness in the caudal–middle–frontal, medial orbitofrontal, temporal pole, entorhinal, lateral occipital, and insula regions in a dose–response manner. • Most of the associations were located in the right hemisphere. Age-related changes in brain structure may constitute the starting point for cerebral function alteration. Physical activity (PA) demonstrated favorable associations with total brain volume, but its relationship with cortical thickness (CT) remains unclear. We investigated the cross-sectional associations between PA level and CT in community-dwelling people aged 70 years and older. A total of 403 older adults aged 74.8 ± 4.0 years (mean ± SD) who underwent a baseline magnetic resonance imaging examination and who had data on PA and confounders were included. PA was assessed with a questionnaire. Participants were categorized according to PA levels. Multiple linear regressions were used to compare the brain CT (mm) of the inactive group (no PA at all) with 6 active groups (growing PA levels) in 34 regions of interest. Compared with inactive persons, people who achieved PA at a level of 1500−1999 metabolic equivalent task-min/week (i.e., about 6−7 h of brisk walking for exercise and those who achieved it at 2000−2999 metabolic equivalent task-min/week (i.e., 8−11 h of brisk walking for exercise) had higher CT in the fusiform gyrus and the temporal pole. Additionally, dose−response associations between PA and CT were found in the fusiform gyrus (B = 0.011, SE = 0.004, adj. p = 0.035), the temporal pole (B = 0.026, SE = 0.009, adj. p = 0.048), and the caudal middle frontal gyrus, the entorhinal, medial orbitofrontal, lateral occipital, and insular cortices. This study demonstrates a positive association between PA level and CT in temporal areas such as the fusiform gyrus, a brain region often associated to Alzheimer's disease in people aged 70 years and older. Future investigations focusing on PA type may help to fulfil remaining knowledge gaps in this field. Aim and population: The relationship between brain cortical thickness and physical activity levels was investigated in 403 older adults aged 74.8 ± 4.0 years (mean ± standard deviation). Adapted from Winkler et al., Neuroimage, 2009. [Display omitted] [ABSTRACT FROM AUTHOR]

Hypothesis: We hypothesized that Lomecel‐B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease‐modifying via pleiotropic mechanisms of action. Key Predictions: We prospectively tested the predictions that Lomecel‐B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). Strategy and Key Results: Mild AD patient received a single infusion of low‐ or high‐dose Lomecel‐B, or placebo, in a double‐blind, randomized, phase I trial. The primary safety endpoint was met. Fluid‐based and imaging biomarkers indicated significant improvement in the Lomecel‐B arms versus placebo. The low‐dose Lomecel‐B arm showed significant improvements versus placebo on neurocognitive and other assessments. Interpretation: Our results support the safety of Lomecel‐B for AD, suggest clinical potential, and provide mechanistic insights. This early‐stage study provides important exploratory information for larger efficacy‐powered clinical trials. [ABSTRACT FROM AUTHOR]

Introduction: Blood‐based biomarkers are the next challenge for Alzheimer's disease (AD) diagnosis and prognosis. Methods: Mild cognitive impairment (MCI) participants (N = 485) of the BALTAZAR study, a large‐scale longitudinal multicenter cohort, were followed‐up for 3 years. A total of 165 of them converted to dementia (95% AD). Associations of conversion and plasma amyloid beta (Aβ)1‐42, Aβ1‐40, Aβ1‐42/Aβ1‐40 ratio were analyzed with logistic and Cox models. Results: Converters to dementia had lower level of plasma Aβ1‐42 (37.1 pg/mL [12.5] vs. 39.2 [11.1] , P value =.03) and lower Aβ1‐42/Aβ1‐40 ratio than non‐converters (0.148 [0.125] vs. 0.154 [0.076], P value =.02). MCI participants in the highest quartile of Aβ1‐42/Aβ1‐40 ratio (>0.169) had a significant lower risk of conversion (hazard ratio adjusted for age, sex, education, apolipoprotein E ε4, hippocampus atrophy = 0.52 (95% confidence interval [0.31–0.86], P value =.01). Discussion: In this large cohort of MCI subjects we identified a threshold for plasma Aβ1‐42/Aβ1‐40 ratio that may detect patients with a low risk of conversion to dementia within 3 years. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and aim: Iron deficiency is associated with increased morbidity and mortality in older adults. However, data on its prevalence and incidence among older adults is limited. The aim of this study was to investigate the prevalence and incidence of iron deficiency in European community-dwelling older adults aged ≥ 70 years. Methods: Secondary analysis of the DO-HEALTH trial, a 3-year clinical trial including 2157 community-dwelling adults aged ≥ 70 years from Austria, France, Germany, Portugal and Switzerland. Iron deficiency was defined as soluble transferrin receptor (sTfR) > 28.1 nmol/L. Prevalence and incidence rate (IR) of iron deficiency per 100 person-years were examined overall and stratified by sex, age group, and country. Sensitivity analysis for three commonly used definitions of iron deficiency (ferritin < 45 μg/L, ferritin < 30 μg/L, and sTfR–ferritin index > 1.5) were also performed. Results: Out of 2157 participants, 2141 had sTfR measured at baseline (mean age 74.9 years; 61.5% women). The prevalence of iron deficiency at baseline was 26.8%, and did not differ by sex, but by age (35.6% in age group ≥ 80, 29.3% in age group 75–79, 23.2% in age group 70–74); P < 0.0001) and country (P = 0.02), with the highest prevalence in Portugal (34.5%) and the lowest in France (24.4%). As for the other definitions of iron deficiency, the prevalence ranged from 4.2% for ferritin < 30 µg/L to 35.3% for sTfR–ferritin index > 1.5. Occurrences of iron deficiency were observed with IR per 100 person-years of 9.2 (95% CI 8.3–10.1) and did not significantly differ by sex or age group. The highest IR per 100 person-years was observed in Austria (20.8, 95% CI 16.1–26.9), the lowest in Germany (6.1, 95% CI 4.7–8.0). Regarding the other definitions of iron deficiency, the IR per 100 person-years was 4.5 (95% CI 4.0–4.9) for ferritin < 45 µg/L, 2.4 (95% CI 2.2–2.7) for ferritin < 30 µg/L, and 12.2 (95% CI 11.0–13.5) for sTfR–ferritin index > 1.5. Conclusions: Iron deficiency is frequent among relatively healthy European older adults, with people aged ≥ 80 years and residence in Austria and Portugal associated with the highest risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Key summary points: Aim: This study examined the bidirectional relationship between depressive symptoms and physical performance in community-dwelling older people with subjective memory complaints (SMCs). Findings: An independent effect of baseline physical performance on the change of depressive symptoms over time and an independent effect of baseline depressive symptoms on the change of physical performance over time were found. Message: Since depressive symptoms and physical performance had a bidirectional relationship, improvement of one may improve the other. Purpose: This study examined the bidirectional relationship between depressive symptoms and physical performance in community-dwelling older people with subjective memory complaints. Methods: 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 ± 4.4 years). 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 36 months. The bidirectional relationships of GDS with SPPB and HGS were examined using mixed-effect regression analysis. Results: 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). Conclusion: 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. Trial registration number: NCT01513252. [ABSTRACT FROM AUTHOR]

Introduction: The 2017 European Union‐North American Clinical Trials in Alzheimer's Disease Task Force recommended development of clinician‐rated primary outcome measures for Alzheimer's disease (AD) agitation trials, incorporating International Psychogeriatric Association (IPA) criteria. Methods: In a modified Delphi process, Cohen‐Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory‐Clinician (NPI‐C) items were mapped to IPA agitation domains generating novel instruments, CMAI‐IPA and NPI‐C‐IPA. Validation in the Agitation and Aggression AD Cohort (A3C) assessed minimal clinically important differences (MCIDs), change sensitivity, and predictive validity. Results: MCID was –17 (odds ratio [OR] = 14.9, 95% confidence interval [CI] = 6.8–32.6) for CMAI; –5 (OR = 9.3, 95% CI = 4.0–21.2) for CMAI‐IPA; –3 (OR = 11.9, 95% CI = 4.1–34.8) for NPI‐C‐A+A; and –5 (OR = 7.8, 95% CI = 3.4–17.9) for NPI‐C‐IPA at 3 months. Areas under the curve suggested no scale better predicted global clinician ratings. Sensitivity to change for all measures was high. Conclusion: Internal consistency and reliability analyses demonstrated better accuracy for the NPI‐C‐IPA than for the CMAI‐IPA and can be used for agitation clinical trial inclusion, and for response to intervention. [ABSTRACT FROM AUTHOR]

Introduction: This study investigated the diagnostic and disease‐monitoring potential of plasma biomarkers in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia and cognitively unimpaired (CU) individuals. Methods: Plasma was analyzed using Simoa assays from 99 CU, 107 MCI, and 103 AD dementia participants. Results: Phosphorylated‐tau181 (P‐tau181), neurofilament light, amyloid‐β (Aβ42/40), Total‐tau and Glial fibrillary acidic protein were altered in AD dementia but P‐tau181 significantly outperformed all biomarkers in differentiating AD dementia from CU (area under the curve [AUC] = 0.91). P‐tau181 was increased in MCI converters compared to non‐converters. Higher P‐tau181 was associated with steeper cognitive decline and gray matter loss in temporal regions. Longitudinal change of P‐tau181 was strongly associated with gray matter loss in the full sample and with Aβ measures in CU individuals. Discussion: P‐tau181 detected AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss. These findings highlight the potential value of plasma P‐tau181 as a non‐invasive and cost‐effective diagnostic and prognostic biomarker in AD. [ABSTRACT FROM AUTHOR]

Background: Chronic fatigue is a common symptom in older adults. Although some studies have attempted to identify the neuronal correlates of fatigue associated with chronic diseases, the scientific evidence is scarce regarding fatigue in older people not suffering from a specific disease. Aims: To gather available evidence of neuroimaging studies investigating the associations between fatigue and brain health in older adults out of the context of a specific disease, and to identify potential brain structures associated with this symptom. Methods: Studies considering exclusively patients with a specific disease and/or studies focusing on physiological mechanisms of acute fatigue induced by the realization of cognitive and physical tasks were excluded. Results: Very few studies on the associations of fatigue with neuroimaging markers are currently available. Fatigue was associated with reduced hippocampus volumes and with hippocampal amyloid deposition. Regarding the association between fatigue and the circuit of basal ganglia, putamen and thalamus were associated with physical fatigability, whereas amygdala and thalamus with mental fatigability. Very limited evidence about white matter integrity found that healthy individuals with high levels of fatigue had a greater total volume of leukoaraiosis. Conclusion: This review suggests that hippocampus damage and potentially loss of function in basal ganglia networks could play a role on chronic fatigue during aging. Further studies are needed to assess the associations of fatigue with white matter alterations. [ABSTRACT FROM AUTHOR]

Background: Understanding the role of amyloid imaging in the earliest stages of Alzheimer's Disease (AD) becomes increasingly relevant for secondary prevention. In this context, the AMYPAD Prognostic and Natural History Study (PNHS) is an open‐label, prospective, multi‐centre cohort study (http://amypad.eu/) to determine the value of quantitative amyloid PET imaging in determining AD dementia risk. The study aims at enrolling 2000 non‐demented individuals from several European cohorts, with a focus on those with emerging amyloid pathology. Method: As of January 31th 2020, 438 participants have consented into AMYPAD PNHS across 15 active sites. Of those, 347 are from EPAD LCS, 9 from ALFA+ and 82 from EMIF‐AD (Figure 1). To date, 329 subjects have been scanned with [18F]flutemetamol or [18F]florbetaben, and 108 PET scans have been analyzed with IXICO's LEAP pipeline. The primary variable is the Centiloid value (CL) using the whole cerebellum as reference region. Scans were categorized as negative (CL<12); gray‐zone (1250) for amyloid burden, and associations between CL values and age, CDR and RBANS were assessed. Result: Site activation is almost complete, with two remaining sites to be activated by February 2020. In addition to current recruitment sources, two additional cohorts (FACEHBI and FPACK) have started recruitment, and at least one more is expected in February. Current AMYPAD PNHS participants have a mean age of 67.08 ± 7.71 years and 59% of them are female. The distribution of CL values ranged from ‐12.75 to 141.79 (Figure 2), and showed a positive association with age (p<0.001) as expected, with similar behavior for the each radiotracer (Figure 3). Forty‐five scans (42%) were classified as negative, 40 (37%) gray‐zone, and 23 (21%) positive. Within EPAD LCS participants, increasing amyloid burden was related to lower global scores on RBANS (ANOVA, F=3.6, p<0.05), and CDR=0.5 was most frequently observed in the gray‐zone (9.5%) and positive (12.0%) groups compared to amyloid‐negative subjects (2.1%). Conclusion: The AMYPAD Prognostic and Natural History Study is currently ongoing and a total of 17 sites will be actively recruiting by February 2020. Preliminary quantitative results indicate that the trial is effectively recruiting the intended target population. [ABSTRACT FROM AUTHOR]

Difficulties with meal-related activities (preparing meals and food shopping) may influence food intake, and contribute to nutritional risk among elderly people. All known studies on this topic had a cross-sectional design, thereby no causal relationships could be derived. We aim to investigate if difficulties with meal-related activities can contribute to subsequent weight loss in community-dwelling older people. We used data of older subjects from the MAPT Study (n = 1531, median age = 74 years, 64% women), who provided prospective data on weight every 6 months and cognitive, physical condition, and functional capacities every year during a 3-year period. Difficulties preparing meals and shopping were evaluated each year with the Alzheimer's Disease Cooperative Study-Activities of Daily Living Prevention Instrument (ADCS ADL-PI) Scale. The risk of losing weight (≥5% or ≥ 3 kg in the following year) was estimated using a time-dependent Cox regression model. During the 3-year follow-up, a total of 851 subjects experienced at least a 5% or 3 kg weight loss. Two hundred thirty-seven subjects declared having difficulties with meal preparation at least once, and 133 declared having difficulties shopping. Subjects reporting any meal-related difficulties were older (p < 0.001), had more depressive symptoms (p < 0.001), and a lower physical function (p < 0.001) compared to those without difficulties. They also had a lower cognitive score (preparing meals: p < 0.001; shopping: p = 0.005) and a lower body mass index (preparing meals: p = 0.005; shopping: p = 0.023) at the end of the study. Meal-related activities were not associated with weight loss in unadjusted analysis and after adjustment for sex, age, depression, physical and cognitive status. Difficulties preparing meals and shopping had no effect on weight loss in community-dwelling older people, despite their association with advanced age, functional decline, and depressive symptoms. [ABSTRACT FROM AUTHOR]

Introduction: The APECS and AMARANTH trials showed that beta‐secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported. Methods: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double‐blind, placebo‐controlled, parallel‐group, 104‐week clinical trials conducted by different sponsors. Measures included the 3‐Domain Composite Cognition Score (CCS‐3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding. Results: Verubecestat showed worsening on the CCS‐3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency. Discussion: In both studies, many measures showed treatment‐associated cognitive worsening, whereas verbal fluency tasks showed improvement. [ABSTRACT FROM AUTHOR]

Empirical evidence suggests that a fair proportion of dementia cases are preventable, that some preventive actions can be taken immediately, and others may soon be implemented. Primary prevention may target cognitively normal persons with modifiable risk factors through lifestyle and multiple domain interventions (including general cardiovascular health). While the effect on individuals may be modest, it might have a large societal impact by decreasing overall dementia incidence by up to 35%. Secondary prevention will target cognitively normal persons at high risk of dementia due to Alzheimer's disease pathology with future anti‐amyloid, anti‐tau, or other drugs. This approach is likely to have major benefits to both individuals and society. Memory clinics will need structural and functional changes to adapt to novel technologies and increased patients' demands, and brand‐new services may need to be developed with specific skills on risk profiling, risk communication, and personalized risk reduction plans. [ABSTRACT FROM AUTHOR]

Sarcopenia, defined as the loss of muscle mass and function, is a widely prevalent and severe condition in older adults. Since 2016, it is recognized as a disease. Strength exercise training and nutritional support are the frontline treatment of sarcopenia, with no drug currently approved for this indication. However, new therapeutic options are emerging. In this review, we evidenced that only very few trials have focused on sarcopenia/sarcopenic patients. Most drug trials were performed in different clinical older populations (e.g., men with hypogonadism, post-menopausal women at risk for osteoporosis), and their efficacy were tested separately on the components of sarcopenia (muscle mass, muscle strength and physical performances). Results from trials testing the effects of Testosterone, Selective Androgen Receptor Modulators (SARMs), Estrogen, Dehydroepiandrosterone (DHEA), Insulin-like Growth Factor-1 (IGF-1), Growth Hormone (GH), GH Secretagogue (GHS), drug targeting Myostatin and Activin receptor pathway, Vitamin D, Angiotensin Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs), or β-blockers, were compiled. Although some drugs have been effective in improving muscle mass and/or strength, this was not translated into clinically relevant improvements on physical performance. Finally, some promising molecules investigated in on-going clinical trials and in pre-clinical phase were summarized, including apelin and irisin. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To investigate ready-meal consumption trends in older French people, its association with overall diet quality and obesity. Design: Cross-sectional analysis Setting: Multidomain Alzheimer Preventive Trial (MAPT), France Subjects: 421 MAPT participants (mean age 76.8 years) who filled a food frequency questionnaire. Results: The frequency of ready-meal consumption was low, with nearly 90% of participants declaring consuming ≤ 1 ready-meal per week. Compared to non- and low-consumers (≤ 1 ready-meal/week), regular consumers (≥ 2 ready-meals/week) were older (p < 0.01), more often frail and pre-frail (p 0.04), with impaired cognition (p = 0.02) and functional status (p = 0.02), with more depressive symptoms (p = 0.03) and more difficulties with preparing meals (p = 0.01). Results from multivariate analyses showed that regular ready-meal consumption was not associated with obesity (p = 0.26) and diet quality (p = 0.37). Conclusions: In our sample, few older people declared consumption of 2 or more ready-meals per week, this consumption was not associated with a higher prevalence of obesity or a lower diet quality, despite the fact that these subject were older, with a lower physical and cognitive status. These findings suggest that, for these people with difficulties in meal preparation, convenience foods consumed occasionally could help to maintain diet quality and weight status. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Key summary points: Aim: To determine the proportion of non-conforming antidepressant prescriptions among nursing home residents and identify the associated institutional and demographic factors. Findings: Despite the practice guidelines, non-conforming antidepressant prescribing is still of significant concern in nursing homes, in over one-third of the residents. Institutional factors, such as simple drug prescribing actions and accessible psychiatric care, are associated with better antidepressant conformance and should be taken into account in further research. Message: A "quality process" by the nursing home might optimize antidepressant prescribing for residents. Purpose: Depression is diagnosed in approximately 40% of the nursing home (NH) residents, but the pertinence of the high use of antidepressants is often criticized. We aimed at determining the proportion of non-conforming antidepressant prescriptions among NH residents and the associated institutional and demographic factors. Methods: Cross-sectional study of 2651 residents in 175 French NH participating in the IQUARE study (Impact of a QUAlity process on the development of practices and the functional decline of NH REsidents) and treated with antidepressants. Diagnosis of depression was obtained from the medical records. Antidepressant treatments were identified on the prescriptions and their conformance was analyzed in light of the international practice guidelines (i.e., indication, drug class, duplication, and monitoring). Results: A total of 1017 residents (38.4%) had a non-conforming prescription. Availability of a list of recommended medications for older patients (OR = 1.39, 95% CI [1.15; 1.68], p < 0.001) and regular intervention by a psychiatrist/psychiatric nurse in the facility (OR = 1.50, 95% CI [1.26; 1.77], p < 0.001) were associated with better antidepressant conformance. Women (OR = 0.76, 95% CI [0.61; 0.93], p < 0.05) and residents on multiple drugs (OR = 0.64, 95% CI [0.50; 0.80], p < 0.001) were at higher risk for non-conforming antidepressant prescription. A history of dementia (OR = 1.54, 95% CI [1.29; 1.84], p < 0.001), co-prescription of neuroleptics (OR = 4.23, 95% CI [2.20; 8.12], p < 0.001), and a known date of psychotropic initiation (OR = 2.58, 95% CI [2.10; 3.16], p < 0.001) were associated with better antidepressant conformance. Conclusions: Our results suggest that a "quality process" by the NH combining accessible psychiatric care in facilities, pharmacological monitoring, and prescription improvement actions might optimize antidepressant prescribing for residents. [ABSTRACT FROM AUTHOR]

Aim: To examine the added value of a geriatrician intervention in a nursing home (NH) engaged in an 18-month quality assurance exercise on the potentially inappropriate prescription of antipsychotics (PIPA), compared to straightforward nursing home audit feedback.Findings: Our study showed that the intervention, including collaborative work meetings between a geriatrician and NH staff, had no effects on PIPA. However, we found that feedback from each NH quality assurance audit had a substantial impact, reducing PIPA by more than 20% in the two study groups.Message: The involvement of the NH in a quality assurance approach and the high rate of antipsychotic prescriptions highlighted in a quality assurance audit lead to improvements in the level and quality of antipsychotic prescriptions. Purpose: To study the effect of a quality assurance approach in a nursing home, with or without the intervention of a geriatrician, on the potentially inappropriate prescription of antipsychotics (PIPA) at 18 months; and to identify the factors associated with PIPA after 18 months of intervention (T18).Methods: We used data from a multicentre individually tailored controlled trial (IQUARE study). The study population comprised residents included in the IQUARE study with at least one potentially inappropriate prescription of antipsychotics at baseline (T0) who were still in nursing home at T18 (n = 636; nursing homes = 175). The control group received individual feedback from the quality assurance audit performed at baseline. The intervention group also had at least 5 collaborative work meetings with a geriatrician over an 18-month period. We used a multilevel logistic regression model.Results: The rates of inappropriate antipsychotic drug prescribing were 66.5% and 45.2% at T0 and T18, respectively. This decrease in the rate of PIPA is significant (p < 0.001). A significant decrease was found within each group: in the intervention arm (68.1% at T0 vs. 44.6% at T18; p < 0.001) and in the control arm (65.2% at T0 vs. 45.6% at T18; p < 0.001). Multivariate analysis did not highlight any statistically significant association between living in a nursing home having received an intervention and PIPA at T18.Conclusions: Collaborative work meetings with a geriatrician does not provide significant added value to a global quality assurance approach towards PIPA. Individual feedback to each nursing home appears to have a substantial impact on decreasing PIPA. [ABSTRACT FROM AUTHOR]

Background: Studies have demonstrated changes in activities of daily living after an exercise intervention in people with dementia (PWD) living in nursing homes (NH). However, some discrepancies are shown during follow-up.Aims: Our objective was to measure activities of daily living (ADL) performance during a 6-month observational follow-up after a 6-month exercise or social activity intervention in PWD living in NH.Methods: After cluster randomisation, 91 PWD living in NH performed a 6-month structured exercise intervention (n = 44) or a social activity intervention (n = 47). After the intervention, 85 PWD were assessed for post-intervention follow-up. Instrumental and basic activities of daily living (IADL, ADL) were measured at 6-month observational follow-up after the intervention using the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory for Severe Alzheimer's Disease (ADCS-ADL-sev) scale (scores ranging from 0 to 51, higher is better).Results: Compared to participants in the social activity, those who participated to the exercise intervention had a significant decrease of their ADCS-ADL-sev score (between-group adjusted mean difference: 4.6 points, p = 0.001) with IADL having the most decrease (2.8 points, p = 0.004).Discussion: Unexpectedly, exercisers declined sharply in the performance of ADLs and IADLs, whereas participants in the social intervention group maintained their levels. The potential mechanisms to explain these findings remain still to be elucidated. [ABSTRACT FROM AUTHOR]

Background: While the last two decades have seen important advances in the in vivo detection of Alzheimer's disease (AD) pathology (i.e. β‐amyloid [Aβ] and Tau) using biomarkers (PET‐ and CSF‐based), the global use of these measures is quite limited due to high costs, insufficient availability and their invasive nature. Interest in blood‐based biomarkers for AD is growing due their greater accessibility and lower cost. We here aimed to investigate the relationship between ultrasensitive plasma‐based measures for AD and both cross‐sectional and longitudinal brain atrophy. Methods: We evaluated cross‐sectional plasma samples for 307 participants (100 cognitively unimpaired (CU) elderly, and 207 cognitively impaired (CI; 101 with mild cognitive impairment (MCI) and 106 AD) from the European multicentre AddNeuroMed cohort. Single molecule array (Simoa) assays were performed for NfL, T‐tau, Aβ42, Aβ40 and GFAp. P‐tau181 was measured using an in‐house Simoa assay. Associations with longitudinal MRI (baseline, 3‐months, 12‐months) were performed using linear mixed models (adjusted for age, sex, education, APOE ε4 status, and interval between plasma and MRI). Three predefined MRI markers were selected: hippocampal volume (adjusted for intracranial volume), cortical thickness within a temporal meta‐ROI encompassing regions susceptible to AD (mean thickness in the bilateral entorhinal, inferior/middle temporal, and fusiform cortices) and whole‐brain cortical thickness. Results: Cross‐sectionally, P‐tau181 and whole‐brain cortical thickness were the only significant association for CU. In CI subjects, Aβ42/Aβ40 and P‐tau181 were significantly associated with hippocampal volume and temporal meta‐ROI/whole‐brain cortical thickness (Table 1). Longitudinally, increased baseline P‐tau181 was associated with all three MRI measures in both CU and CI subjects (Table 1). Low Aβ42/Aβ40 was also associated with all three MRI measures, though only in CI subjects. Further analyses will associate these plasma measures at the voxel level. Conclusion: These results suggest that plasma‐based measurements of Aβ42/Aβ40 and P‐tau181 are associated with cross‐sectional atrophy levels and, more importantly, can predict brain atrophy over time, both in patients with AD and in CU elderly individuals. These findings add to a growing number of studies suggesting that these markers hold great promise, both as diagnostic tools as well as in research and clinical trials. [ABSTRACT FROM AUTHOR]

Background: The association between ω‐3 polyunsaturated fatty acids and cognition, brain imaging and biomarkers is still not fully established. We aimed to analyze the cross‐sectional and retrospective longitudinal associations between erythrocyte ω‐3 index and cognition, brain imaging and biomarkers among older adults. Method: 832 participants from the Alzheimer's Disease Neuroimaging Initiative 3, mean (SD) age 74.0 (7.9) years, 50.8% female, 55.9% cognitively normal, 32.7% with mild cognitive impairment and 11.4% with Alzheimer's disease (AD) were included. Low ω‐3 index (% eicosapentaenoic acid EPA + % docosahexaenoic acid DHA) was defined as the lowest quartile (≤3.70%). Cognitive tests (composite score; AD Assessment Scale cognitive (ADAS‐Cog) subscale; Wechsler Memory Scale (WMS); Trail Making Test A and B; Category fluency; Mini Mental State Examination; Montreal Cognitive Assessment; Clinical Dementia Rating) and brain variables (hippocampal volume, white matter hyperintensities (WMH), PET amyloid‐β and Tau) were considered as outcomes in regression models. Result: Low ω‐3 index was not associated with cognition, hippocampal and WMH volume, brain Aβ and Tau after adjustment for age, education, ApoE ε4, cardiovascular disease, BMI and total intracranial volume in the cross‐sectional analysis. In the retrospective analysis, low ω‐3 index was associated with greater Aβ accumulation over time. The composite cognitive score did not differ between groups; however, low ω‐3 index was associated with greater cognitive decline on the WMS‐Delayed recall but unexpectedly lower cognitive decline on the total ADAS‐Cog. Low ω‐3 index was cross‐sectionally associated with lower performance on WMS tests and higher Tau accumulation among ApoE ε4 carriers. Conclusion: Longitudinally, low ω‐3 index was associated with greater Aβ accumulation over time and cognitive decline on the WMS but unexpectedly with lower cognitive decline on the total ADAS‐Cog. Low ω‐3 index was associated with lower cognition on the WMS and higher Tau accumulation among ApoE ε4 carriers in the cross‐sectional analysis. [ABSTRACT FROM AUTHOR]

Background: Aducanumab is a human monoclonal antibody selective for aggregated forms of amyloid beta approved in the United States by the Food and Drug Administration (FDA) for the treatment of Alzheimer's disease on June 7, 2021 under the accelerated approval pathway, which requires a randomized‐controlled trial with an appropriate control to verify the clinical benefit of aducanumab. On March 25, 2022 the sponsor submitted the final protocol for this trial, named ENVISION, to the FDA. Method: ENVISION (NCT05310071) is a multicenter, randomized, double‐blind, placebo‐controlled, parallel group study in participants with mild cognitive impairment due to Alzheimer's disease (Stage 3) and mild Alzheimer's disease dementia (Stage 4), designed to verify the clinical efficacy and safety of aducanumab. Key enrollment criteria include MMSE score of 22‐30, age 60‐85, CDR‐G of 0.5 or 1.0, regardless of ApoE ε4 status. Participants will be randomized, to receive aducanumab or placebo in a 2:1 ratio and will be titrated to 10 mg/kg aducanumab or placebo by intravenous infusion every 4 weeks for a treatment duration of 24 months. The primary objective is to assess the clinical benefit of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by change of CDR‐SB score at 18 months as compared to placebo. Key secondary endpoints include change in ADCS‐ADL‐MCI, ADAS‐Cog13, iADRS, MMSE, and NPI‐10; other secondary endpoints include change in amyloid PET and tau PET signal. Safety endpoints include incidence of ARIA events and SAEs. Exploratory endpoints include CSF and plasma biomarkers. Approximately 1512 participants will be enrolled across 220 centers globally. A racially/ethnically representative population will be included in the United States, with an enrollment goal of 18% Black/African American and LatinX/Hispanic patients. Result: ENVISION will begin in Q2 2022 and read out approximately 4 years after first patient in. Primary analysis read‐out of clinical, biomarker, and safety data will be at 18 months, with additional longer‐term data on aducanumab treatment effect up to 24 months. Conclusion: The confirmatory ENVISION trial will further explore clinical efficacy, biomarker profile, and safety of aducanumab in a racially/ethnically representative population. [ABSTRACT FROM AUTHOR]

Introduction: Diagnostic relevance of plasma amyloid β (Aβ) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aβ42 and Aβ40 in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers. Methods: One thousand forty participants (417 amnestic MCI, 122 nonamnestic MCI, and 501 AD) from the Biomarker of AmyLoïd pepTide and AlZheimer's diseAse Risk multicenter prospective study with cognition, plasma, cerebrospinal fluid (CSF), and magnetic resonance imaging assessments were included. Results: Plasma Aβ1–42 and Aβ1–40 were lower in AD (36.9 [11.7] and 263 [80] pg/mL) than in amnestic MCI (38.2 [11.9] and 269 [68] pg/mL) than in nonamnestic MCI (39.7 [10.5] and 272 [52] pg/mL), respectively (P =.01 for overall difference between groups for Aβ1–42 and P =.04 for Aβ1–40). Globally, plasma Aβ1–42 correlated with age, Mini–Mental State Examination, and APOE ε4 allele. Plasma Aβ1–42 correlated with all CSF biomarkers in MCI but only with CSF Aβ42 in AD. Discussion: Plasma Aβ was associated with cognitive status and CSF biomarkers, suggesting the interest of plasma amyloid biomarkers for diagnosis purpose. [ABSTRACT FROM AUTHOR]