Predicting sojourn times across dementia disease stages, institutionalization, and mortality.

INTRODUCTION: Inferring the timeline from mild cognitive impairment (MCI) to severe dementia is pivotal for patients, clinicians, and researchers. Literature is sparse and often contains few patients. We aim to determine the time spent in MCI, mild-, moderate-, severe dementia, and institutionalization until death. METHODS: Multistate modeling with Cox regression was used to obtain the sojourn time. Covariates were age at baseline, sex, amyloid status, and Alzheimer's disease (AD) or other dementia diagnosis. The sample included a register (SveDem) and memory clinics (Amsterdam Dementia Cohort and Memento). RESULTS: Using 80,543 patients, the sojourn time from clinically identified MCI to death across all patient groups ranged from 6.20 (95% confidence interval [CI]: 5.57-6.98) to 10.08 (8.94-12.18) years. DISCUSSION: Generally, sojourn time was inversely associated with older age at baseline, males, and AD diagnosis. The results provide key estimates for researchers and clinicians to estimate prognosis.

Cerebral Metabolic Signature of Chronic Benzodiazepine Use in Nondemented Older Adults: An FDG-PET Study in the MEMENTO Cohort.

OBJECTIVE: We sought to examine the association between chronic Benzodiazepine (BZD) use and brain metabolism obtained from 2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) in the MEMENTO clinical cohort of nondemented older adults with an isolated memory complaint or mild cognitive impairment at baseline. METHODS: Our analysis focused on 3 levels: (1) the global mean brain standardized uptake value (SUVR), (2) the Alzheimer's disease (AD)-specific regions of interest (ROIs), and (3) the ratio of total SUVR on the brain and different anatomical ROIs. Cerebral metabolism was obtained from 2-deoxy-2-fluoro-D-glucose-FDG-PET and compared between chronic BZD users and nonusers using multiple linear regressions adjusted for age, sex, education, APOE ε 4 copy number, cognitive and neuropsychiatric assessments, history of major depressive episodes and antidepressant use. RESULTS: We found that the SUVR was significantly higher in chronic BZD users (n = 192) than in nonusers (n = 1,122) in the whole brain (beta = 0.03; p = 0.038) and in the right amygdala (beta = 0.32; p = 0.012). Trends were observed for the half-lives of BZDs (short- and long-acting BZDs) (p = 0.051) and Z-drug hypnotic treatments (p = 0.060) on the SUVR of the right amygdala. We found no significant association in the other ROIs. CONCLUSION: Our study is the first to find a greater global metabolism in chronic BZD users and a specific greater metabolism in the right amygdala. Because the acute administration of BZDs tends to reduce brain metabolism, these findings may correspond to a compensatory mechanism while the brain adapts with global metabolism upregulation, with a specific focus on the right amygdala.

Physical activity, biomarkers of brain pathologies and dementia risk: Results from the Memento clinical cohort.

INTRODUCTION: This study aims to examine whether physical activity moderates the association between biomarkers of brain pathologies and dementia risk. METHODS: From the Memento cohort, we analyzed 1044 patients with mild cognitive impairment, aged 60 and older. Self-reported physical activity was assessed using the International Physical Activity Questionnaire. Biomarkers of brain pathologies comprised medial temporal lobe atrophy (MTA), white matter lesions, and plasma amyloid beta (Aß)42/40 and phosphorylated tau181. Association between physical activity and risk of developing dementia over 5 years of follow-up, and interactions with biomarkers of brain pathologies were tested. RESULTS: Physical activity moderated the association between MTA and plasma Aß42/40 level and increased dementia risk. Compared to participants with low physical activity, associations of both MTA and plasma Aß42/40 on dementia risk were attenuated in participants with high physical activity. DISCUSSION: Although reverse causality cannot be excluded, this work suggests that physical activity may contribute to cognitive reserve. HIGHLIGHTS: Physical activity is an interesting modifiable target for dementia prevention. Physical activity may moderate the impact of brain pathology on dementia risk. Medial temporal lobe atrophy and plasma amyloid beta 42/40 ratio were associated with increased dementia risk especially in those with low level of physical activity.

Association of APOE ε4 with cerebral gray matter volumes in non-demented older adults: The MEMENTO cohort study.

Data on 2,045 non-demented individuals with memory complaints were drawn from the Memento cohort study to examine the association between Apolipoprotein E ε4 allele (APOE4) and regional brain gray matter volumes. Linear regression was used to examine the association of APOE4 and measures of regional gray matter volumes in cross-sectional analysis and change therein using longitudinal analyses based on two brain MRI performed at baseline and at two-year follow-up. Overall, in analyses adjusted for age, sex, and intracranial volume, the presence of APOE4 was associated with lower total gray matter volume at baseline and with a higher atrophy rate over the follow-up. The hippocampus and entorhinal cortex were the two gray matter regions most associated with APOE4. Further adjustment for cardiovascular risk factors had little impact on these associations. There was an interaction between age, APOE4 status and total brain volume atrophy rate, with evidence of an earlier age at onset of atrophy in hippocampal volume in APOE4 carriers compared to non-carriers. Those results are in accordance with the role of medial temporal structures in the greater risk of dementia observed in people carrying the APOE4 allele.

Personalized prediction of progression in pre-dementia patients based on individual biomarker profile: A development and validation study.

INTRODUCTION: The prognosis of patients at the pre-dementia stage is difficult to define. The aim of this study is to develop and validate a biomarker-based continuous model for predicting the individual cognitive level at any future moment. In addition to personalized prognosis, such a model could reduce trial sample size requirements by allowing inclusion of a homogenous patient population. METHODS: Disease-progression modeling of longitudinal cognitive scores of pre-dementia patients (baseline Clinical Dementia Rating ≤ 0.5) was used to derive a biomarker profile that was predictive of patient's cognitive progression along the dementia continuum. The biomarker profile model was developed and validated in the MEMENTO cohort and externally validated in the Alzheimer's Disease Neuroimaging Initiative. RESULTS: Of nine candidate biomarkers in the development analysis, three cerebrospinal fluid and two magnetic resonance imaging measures were selected to form the final biomarker profile. The model-based prognosis of individual future cognitive deficit was shown to significantly improve when incorporating biomarker information on top of cognition and demographic data. In trial power calculations, adjusting the primary analysis for the baseline biomarker profile reduced sample size requirements by ≈10%. Compared to conventional cognitive cut-offs, inclusion criteria based on biomarker-profile cut-offs resulted in up to 28% reduced sample size requirements due to increased homogeneity in progression patterns. DISCUSSION: The biomarker profile allows prediction of personalized trajectories of future cognitive progression. This enables accurate personalized prognosis in clinical care and better selection of patient populations for clinical trials. A web-based application for prediction of patients' future cognitive progression is available online.

Clinical relevance of brain atrophy subtypes categorization in memory clinics.

INTRODUCTION: The clinical relevance of brain atrophy subtypes categorization in non-demented persons without a priori knowledge regarding their amyloid status or clinical presentation is unknown. METHODS: A total of 2083 outpatients with either subjective cognitive complaint or mild cognitive impairment at study entry were followed during 4 years (MEMENTO cohort). Atrophy subtypes were defined using baseline magnetic resonance imaging (MRI) and previously described algorithms. RESULTS: Typical/diffuse atrophy was associated with faster cognitive decline and the highest risk of developing dementia and Alzheimer's disease (AD) over time, both in the whole analytic sample and in amyloid-positive participants. Hippocampal-sparing and limbic-predominant atrophy were also associated with incident dementia, with faster cognitive decline in the limbic predominant atrophy group. Lewy body dementia was more frequent in the hippocampal-sparing and minimal/no atrophy groups. DISCUSSION: Atrophy subtypes categorization predicted different subsequent patterns of cognitive decline and rates of conversion to distinct etiologies of dementia in persons attending memory clinics.

Health Risk Behaviors and Self-Esteem Among College Students: Systematic Review of Quantitative Studies.

BACKGROUND: Due to their impact on premature mortality and long-term disabilities, a better understanding of health risk behavior (HRB) determinants among college students is crucial in order to build the most appropriate prevention tools. Although self-esteem appears to be a relevant candidate, a clear picture summarizing its multiple links with HRB is lacking to guide clinicians and researchers. This study aims to provide a systematic review of the associations between health risk behavior and self-esteem among college students. METHODS: This search was performed in several databases on 02/02/17. Study eligibility criteria were original articles in peer-reviewed journals, in English; observational quantitative studies; among college students; and investigated the association between self-esteem and HRB. The PRISMA statements were complied with. RESULTS: One hundred fifteen articles were included: 46 on substance use, 35 on sexual behavior, 11 on nutritional habits, 27 on physical activity, and 5 on other HRB. Most studies reported an association between higher self-esteem and healthier behavior. For alcohol consumption and number of sexual partners, both negative and positive associations have been reported. Directionality was investigated in a few studies suggesting potential bidirectional effects. CONCLUSIONS: This review points out the need for consensus for the definition of self-esteem and HRB. There was high heterogeneity in (1) the measurement of self-esteem either in the concept measured (global vs. domain) or in the way to implement validated tools; and (2) the definition of HRB. Self-esteem seems to be a relevant target to intervene on HRB, especially alcohol abuse and physical activity. TRIAL REGISTRATION: Registration number: PROSPERO (ID = CRD42017056599).

Ultrasensitive Human Immunodeficiency Virus Type 1 Viral Load as a Marker of Treatment Choice for Simplification Strategies.

Background: Using 3 randomized Protease inhibitor (PI) monotherapy studies: Kalesolo, Dream and Monoi, we performed a pooled-analysis. Our objective was to determine in PI monotherapy and standard tritherapy: 1) distribution of ultrasensitive viral load (USVL) at week 96 (W96); 2) factors associated with virological failure (VF) at W96 and 3) factors associated with USVL<1 copy at W96. Methods: VF was defined as 2 consecutive measurements of Human Immunodeficiency Virus Type 1 RNA viral load>50 copies/mL and analysed in Intention-To-Treat. A logistic model was used to investigate which variables were predictive of a VF and Fisher test to investigate differences in USVL at W96. Results: Among 609 patients, 73% were male with median age of 44.4 years (IQR 39.8-52.1), baseline CD4/CD8 ratio was 0.8 (IQR 0.6-1.10), baseline CD4 was 564.5/mm3 (IQR 422-707) and 59% presented a baseline USVL<1 copy/mL. At W96, the proportion of USVL<1 copy/mL was significantly different between PI monotherapy and standard tritherapy in pooled-analysis (65% versus 74%; p=0.04). Overall, baseline USVL<1copy/mL, tritherapy and to be a female were associated with USVL<1 copy/mL at W96 (p<0.0001, p=0.049 and p=0.006). In PI monotherapy receiving DRV/r was associated with USVL<1 copy/mL at W96 (p=0.003). Factors associated to virological succes at W96 were higher baseline CD4 (p=0.034) and baseline USVL<1 copy/mL (p=0.0005). Conclusion: Pooled-analysis of 3 PI monotherapy trials showed better efficacy of tritherapy in terms of USVL at W96. Furthermore regarding USVL at W96, to receive LPV/r seems to be more deleterious than DRV/r. Baseline USVL impacts VF at W96 more specifically in tritherapy arm. Clinical Trials Registration: NCT00421551, NCT00946595, and NCT00140751.

Explaining the Variability of Alzheimer Disease Fluid Biomarker Concentrations in Memory Clinic Patients Without Dementia.

BACKGROUND AND OBJECTIVES: Patients' comorbidities can affect Alzheimer disease (AD) blood biomarker concentrations. Because a limited number of factors have been explored to date, our aim was to assess the proportion of the variance in fluid biomarker levels explained by the clinical features of AD and by a large number of non-AD-related factors. METHODS: MEMENTO enrolled 2,323 individuals with cognitive complaints or mild cognitive impairment in 26 French memory clinics. Baseline evaluation included clinical and neuropsychological assessments, brain MRI, amyloid-PET, CSF (optional), and blood sampling. Blood biomarker levels were determined using the Simoa-HDX analyzer. We performed linear regression analysis of the clinical features of AD (cognition, AD genetic risk score, and brain atrophy) to model biomarker concentrations. Next, we added covariates among routine biological tests, inflammatory markers, demographic and behavioral determinants, treatments, comorbidities, and preanalytical sample handling in final models using both stepwise selection processes and least absolute shrinkage and selection operator (LASSO). RESULTS: In total, 2,257 participants were included in the analysis (median age 71.7, 61.8% women, 55.2% with high educational levels). For blood biomarkers, the proportion of variance explained by clinical features of AD was 13.7% for neurofilaments (NfL), 11.4% for p181-tau, 3.0% for Aß-42/40, and 1.4% for total-tau. In final models accounting for non-AD-related factors, the variance was mainly explained by age, routine biological tests, inflammatory markers, and preanalytical sample handling. In CSF, the proportion of variance explained by clinical features of AD was 24.8% for NfL, 22.3% for Aß-42/40, 19.8% for total-tau, and 17.2% for p181-tau. In contrast to blood biomarkers, the largest proportion of variance was explained by cognition after adjustment for covariates. The covariates that explained the largest proportion of variance were also the most frequently selected with LASSO. The performance of blood biomarkers for predicting A+ and T+ status (PET or CSF) remained unchanged after controlling for drivers of variance. DISCUSSION: This comprehensive analysis demonstrated that the variance in AD blood biomarker concentrations was mainly explained by age, with minor contributions from cognition, brain atrophy, and genetics, conversely to CSF measures. These results challenge the use of blood biomarkers as isolated stand-alone biomarkers for AD.

Associations Between Blood-Based Biomarkers and Cognitive and Functional Trajectories Among Participants of the MEMENTO Cohort.

BACKGROUND AND OBJECTIVES: Elevated levels of Alzheimer disease (AD) blood-based biomarkers are associated with accelerated cognitive decline. However, their distinct relationships with specific cognitive and functional domains require further investigation. We aimed at estimating the associations between AD blood-based biomarkers and the trajectories of distinct cognitive and functional domains over a 5-year follow-up period. METHODS: We conducted a clinic-based prospective study using data from the MEMENTO study, a nationwide French cohort. We selected dementia-free individuals at baseline aged 60 years or older. Baseline measurements of ß-amyloid (Aß) 40 and 42, phosphorylated tau (p-tau181), and neurofilament light chain (NfL) concentrations were obtained using the Simoa HD-X analyzer. Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT), animal fluency, Trail Making Tests A and B, Short Physical Performance Battery (SPPB), and Instrumental Activities of Daily Living were administered annually for up to 5 years. We used linear mixed models, adjusted for potential confounders, to model AD biomarkers' relation with cognitive and functional decline. RESULTS: A total of 1,938 participants were included in this study, with a mean (SD) baseline age of 72.8 (6.6) years, and 62% were women. Higher baseline p-tau181 and NfL were associated with significantly faster decline in most cognitive, physical, and functional outcomes (+1 SD p-tau181: ßMMSE = -0.055, 95% CI -0.067 to -0.043, ßFCSRT = -0.034, 95% CI -0.043 to -0.025, ßfluency = -0.029, 95% CI -0.038 to -0.020, ßSPPB = -0.040, 95% CI -0.057 to -0.022, and ß4IADL = -0.115, 95% CI 0.091-0.140. +1 SD NfL: ßMMSE = -0.039, 95% CI -0.053 to -0.025, ßFCSRT = -0.022, 95% CI -0.032 to -0.012, ßfluency = -0.014, 95% CI -0.024 to -0.004, and ß4IADL = 0.077, 95% CI 0.048-0.105). A multiplicative association of p-tau181 and NfL with worsening cognitive and functional trajectories was evidenced. Lower Aß42/40 ratio was only associated with slightly faster cognitive decline in FCSRT and semantic fluency (+1 SD: ß = 0.011, 95% CI 0.002-0.020, and ß = 0.011, 95% CI 0.003-0.020, respectively). These associations were not modified by APOE ε4, sex, nor education level. DISCUSSION: In a memory clinic sample, p-tau181 and NfL, both independently and jointly, are linked to more pronounced cognitive, physical and functional declines. Blood-based biomarker measurement in AD research may provide useful insights regarding biological processes underlying cognitive, physical, and functional declines in at-risk individuals.

Contribution of Global Amyloid-PET Imaging for Predicting Future Cognition in the MEMENTO Cohort.

BACKGROUND AND OBJECTIVES: Global amyloid-PET is associated with cognition and cognitive decline, but most research on this association does not account for past cognitive information. We assessed the prognostic benefit of amyloid-PET measures for future cognition when prior cognitive assessments are available, evaluating the added value of amyloid measures beyond information on multiple past cognitive assessments. METHODS: The French MEMENTO cohort (a cohort of outpatients from French research memory centers to improve knowledge on Alzheimer disease and related disorders) includes older outpatients with incipient cognitive changes, but no dementia diagnosis at inclusion. Global amyloid burden was assessed using positron emission tomography (amyloid-PET) for a subset of participants; semiannual cognitive testing was subsequently performed. We predicted mini-mental state examination (MMSE) scores using demographic characteristics (age, sex, marital status, and education) alone or in combination with information on prior cognitive measures. The added value of amyloid burden as a predictor in these models was evaluated with percent reduction of the mean squared error (MSE). All models were conducted separately for evaluating the added value of dichotomous amyloid positivity status compared with a continuous amyloid-standardized uptake-value ratio. RESULTS: Our analytic sample comprised 510 individuals who underwent amyloid-PET scans with at least 4 MMSE assessments. The mean age at the PET scan was 71.6 (standard deviation 7.4) years; 60.7% were female. The median follow-up was 4.6 years (interquartile range: 0.9 years). Adding amyloid burden when adjusting for only demographic characteristics reduced the MSE of predictions by 5.08% (95% CI 0.97%-10.86%) and 12.64% (95% CI 3.35%-25.28%) for binary and continuous amyloid, respectively. If the model included 1 past MMSE measure, the MSE improvement was 3.51% (95% CI 1.01%-7.28%) when adding binary amyloid and 8.83% (95% CI 2.63%-16.37%) when adding continuous amyloid. Improvements in model fit were smaller with the addition of amyloid burden when more than 1 past cognitive assessment was included. For all models incorporating past cognitive assessments, differences in predictions amounted to a fraction of 1 MMSE point on average. DISCUSSION: In a clinical setting, global amyloid burden did not appreciably improve cognitive predictions when past cognitive assessments were available. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02164643.

Prediction of dementia risk from multimodal repeated measures: The added value of brain MRI biomarkers.

Abstract: The utility of brain magnetic resonance imaging (MRI) for predicting dementia is debated. We evaluated the added value of repeated brain MRI, including atrophy and cerebral small vessel disease markers, for dementia prediction. We conducted a landmark competing risk analysis in 1716 participants of the French population-based Three-City Study to predict the 5-year risk of dementia using repeated measures of 41 predictors till year 4 of follow-up. Brain MRI markers improved significantly the individual prediction of dementia after accounting for demographics, health measures, and repeated measures of cognition and functional dependency (area under the ROC curve [95% CI] improved from 0.80 [0.79 to 0.82] to 0.83 [0.81 to 0.84]). Nonetheless, accounting for the change over time through repeated MRIs had little impact on predictive abilities. These results highlight the importance of multimodal analysis to evaluate the added predictive abilities of repeated brain MRI for dementia and offer new insights into the predictive performances of various MRI markers. Highlights: We evaluated whether repeated brain volumes and cSVD markers improve dementia prediction.The 5-year prediction of dementia is slightly improved when considering brain MRI markers.Measures of hippocampus volume are the main MRI predictors of dementia.Adjusted on cognition, repeated MRI has poor added value over single MRI for dementia prediction.We utilized a longitudinal analysis that considers error-and-missing-prone predictors, and competing death.

Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia.

Importance: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. Objective: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases. Design, Setting, and Participants: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022. Exposures: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations. Main Outcomes and Measures: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses. Results: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke. Conclusions: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.

What Tools Can We Use to Screen for Fall Risk in Older Patients with Mild Cognitive Impairment? Findings from the MEMENTO Cohort.

OBJECTIVES: Identifying risk factors for falls can improve outcomes in older patients without cognitive decline. Yet this has not been demonstrated in older people with mild cognitive impairment (MCI). We therefore sought to better identify risk factors for falls in this particular group. DESIGN: The analysis was conducted on the MEMENTO cohort, which is a large, French, prospective cohort. SETTING AND PARTICIPANTS: We included older people (>65 years old) with MCI (defined from neuropsychological scores) and a Short Physical Performance Battery (SPPB) score at baseline. METHODS: Fallers were defined as participants having fallen at least once during the study's 2-year follow-up period. We compared clinical, neuropsychological, and biological data at baseline in fallers vs nonfallers. Additional analyses were performed on the following subgroups: women, men, people aged ≥75 years. RESULTS: Of the 1416 people included in our study, 194 (13.5%) fell at least once. A bivariate analysis showed that fallers were older, predominantly women, less independent in activities of daily living, and more apathetic. Fallers performed less well in executive function, balance, and gait tests. In a multivariable analysis, only age, gender, the number of limitations in instrumental activities of daily living, and living alone were significantly associated with falls. In a multivariable analysis of the subgroup of oldest patients and of the subgroup of men, executive function was significantly worse in fallers than in nonfallers. CONCLUSION AND IMPLICATIONS: Our results demonstrate that easily attainable risk factors can be used to identify individuals with MCI with a higher risk of falls and for whom prevention could be beneficial. Future studies are needed to further evaluate the role of mild executive dysfunction in certain subgroups, such as men and oldest patients.

Health-related quality of life in subjective cognitive decline and mild cognitive impairment: a longitudinal cohort analysis.

BACKGROUND: Health-related quality of life (HR-QoL) is an important outcome for patients and crucial for demonstrating the value of new treatments. Health utility estimates in subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are limited, especially in biomarker-confirmed populations. Besides, little is known about the longitudinal HR-QoL trajectory. This study aims to provide health utility estimates for SCD and MCI and investigate the QoL trajectory along the disease continuum. METHODS: Longitudinal data from 919 SCD and 1336 MCI patients from the MEMENTO cohort were included. SCD was defined as clinical dementia rating (CDR) = 0, and MCI as CDR = 0.5. HR-QoL was measured using the EQ-5D-3L patient-reported instrument. Linear mixed-effect models (LMM) were used to assess the longitudinal change in HR-QoL and identify predictors of these changes. RESULTS: Baseline health utilities were 0.84 ± 0.16 and 0.81 ± 0.18, and visual analogue scale (VAS) were 75.8 ± 14.82 and 70.26 ± 15.77 in SCD and MCI. In amyloid-confirmed cases, health utilities were 0.85 ± 0.14 and 0.86 ± 0.12 in amyloid-negative and amyloid-positive SCD, and 0.83 ± 0.17 and 0.84 ± 0.16 in amyloid-negative and amyloid-positive MCI. LMM revealed an annual decline in health utility of - 0.015 (SE = 0.006) and - 0.09 (SE = 0.04) in moderate and severe dementia (P < 0.05). There was a negative association between clinical stage and VAS where individuals with MCI, mild, moderate, and severe dementia were on average 1.695 (SE = 0.274), 4.401 (SE = 0.676), 4.999 (SE = 0.8), and 15.386 (SE = 3.142) VAS points lower than individuals with SCD (P < 0.001). Older age, female sex, higher body mass index, diabetes, cardiovascular history, depression, and functional impairment were associated with poor HR-QoL. Amyloid positivity was associated with an annual decline of - 0.011 (SE = 0.004, P < 0.05) health utility over time. CONCLUSIONS: Health utility estimates from this study can be used in economic evaluations of interventions targeting SCD and MCI. Health utility declines over time in moderate and severe dementia, and VAS declines with advancing clinical stages. Amyloid-positive patients show a faster decline in health utility indicating the importance of considering biomarker status in HR-QoL assessments. Future research is needed to confirm the longitudinal relationship between amyloid status and HR-QoL and to examine the level at which depression and IADL contribute to HR-QoL decline in AD.

Understanding factors associated with the trajectory of subjective cognitive complaints in groups with similar objective cognitive trajectories.

BACKGROUND: Cognitive complaints are often regarded as an early sign of Alzheimer's disease (AD) but may also occur in several other conditions and contexts. This study examines the correlates of cognitive complaint trajectories over a 5-year period in individuals who shared similar objective cognitive trajectories. METHODS: We analyzed a subsample (n = 1748) of the MEMENTO cohort, consisting of individuals with subjective cognitive decline or mild cognitive impairment at baseline. Participants were stratified based on their latent MMSE trajectory over a 5-year period: "high and increasing," "subtle decline," and "steep decline." Within each of the three strata, we used a latent-class longitudinal approach to identify distinct trajectories of cognitive complaints. We then used multiple logistic regressions to examine the association between these complaint trajectories and several factors, including AD biomarkers (blood pTau/Aß42 ratio, cortical thickness, APOE genotype), anxiety, depression, social relationships, a comorbidity-polypharmacy score, and demographic characteristics. RESULTS: Among participants with high and increasing MMSE scores, greater baseline comorbidity-polypharmacy scores (odds ratio (OR) = 1.30, adjusted p = 0.03) were associated with higher odds of moderate and increasing cognitive complaints (as opposed to mild and decreasing complaints). Baseline depression and social relationships also showed significant associations with the complaint pattern but did not survive correction for multiple comparisons. Among participants with subtle decline in MMSE scores, greater baseline depression (OR = 1.76, adjusted p = 0.02) was associated with higher odds of moderate and increasing cognitive complaints (versus mild and decreasing). Similarly, baseline comorbidity-polypharmacy scores and pTau/Aß42 ratio exhibited significant associations, but they did not survive correction. Among participants with a steep decline in MMSE scores, greater baseline comorbidity-polypharmacy scores increased the odds of moderate complaints (versus mild, OR = 1.38, unadjusted p = 0.03, adjusted p = 0.32), but this effect did not survive correction for multiple comparisons. CONCLUSIONS: Despite similar objective cognitive trajectory, there is heterogeneity in the subjective perception of these cognitive changes. This perception was explained by both AD-related and, more robustly, non-AD-related factors. These findings deepen our understanding of the multifaceted nature of subjective cognitive complaints in individuals at risk for dementia and underscore the importance of considering a range of factors when interpreting cognitive complaints.

Forecasting individual progression trajectories in Alzheimer's disease.

The anticipation of progression of Alzheimer's disease (AD) is crucial for evaluations of secondary prevention measures thought to modify the disease trajectory. However, it is difficult to forecast the natural progression of AD, notably because several functions decline at different ages and different rates in different patients. We evaluate here AD Course Map, a statistical model predicting the progression of neuropsychological assessments and imaging biomarkers for a patient from current medical and radiological data at early disease stages. We tested the method on more than 96,000 cases, with a pool of more than 4,600 patients from four continents. We measured the accuracy of the method for selecting participants displaying a progression of clinical endpoints during a hypothetical trial. We show that enriching the population with the predicted progressors decreases the required sample size by 38% to 50%, depending on trial duration, outcome, and targeted disease stage, from asymptomatic individuals at risk of AD to subjects with early and mild AD. We show that the method introduces no biases regarding sex or geographic locations and is robust to missing data. It performs best at the earliest stages of disease and is therefore highly suitable for use in prevention trials.

Validity and Performance of Blood Biomarkers for Alzheimer Disease to Predict Dementia Risk in a Large Clinic-Based Cohort.

BACKGROUND AND OBJECTIVE: Blood biomarkers for Alzheimer disease (AD) have consistently proven to be associated with CSF or PET biomarkers and effectively discriminate AD from other neurodegenerative diseases. Our aim was to test their utility in clinical practice, from a multicentric unselected prospective cohort where patients presented with a large spectrum of cognitive deficits or complaints. METHODS: The MEMENTO cohort enrolled 2,323 outpatients with subjective cognitive complaint (SCC) or mild cognitive impairment (MCI) consulting in 26 French memory clinics. Participants had neuropsychological assessments, MRI, and blood sampling at baseline. CSF sampling and amyloid PET were optional. Baseline blood Aß42/40 ratio, total tau, p181-tau, and neurofilament light chain (NfL) were measured using a Simoa HD-X analyzer. An expert committee validated incident dementia cases during a 5-year follow-up period. RESULTS: Overall, 2,277 individuals had at least 1 baseline blood biomarker available (n = 357 for CSF subsample, n = 649 for PET subsample), among whom 257 were diagnosed with clinical AD/mixed dementia during follow-up. All blood biomarkers but total tau were mildly correlated with their equivalence in the CSF (r = 0.33 to 0.46, p < 0.0001) and were associated with amyloid-PET status (p < 0.0001). Blood p181-tau was the best blood biomarker to identify amyloid-PET positivity (area under the curve = 0.74 [95% CI = 0.69; 0.79]). Higher blood and CSF p181-tau and NfL concentrations were associated with accelerated time to AD dementia onset with similar incidence rates, whereas blood Aß42/40 was less efficient than CSF Aß42/40. Blood p181-tau alone was the best blood predictor of 5-year AD/mixed dementia risk (c-index = 0.73 [95% CI = 0.69; 0.77]); its accuracy was higher in patients with clinical dementia rating (CDR) = 0 (c-index = 0.83 [95% CI = 0.69; 0.97]) than in patients with CDR = 0.5 (c-index = 0.70 [95% CI = 0.66; 0.74]). A "clinical" reference model (combining demographics and neuropsychological assessment) predicted AD/mixed dementia risk with a c-index = 0.88 [95% CI = 0.86-0.91] and performance increased to 0.90 [95% CI = 0.88; 0.92] when adding blood p181-tau + Aß42/40. A "research" reference model (clinical model + apolipoprotein E genotype and AD signature on MRI) had a c-index = 0.91 [95% CI = 0.89-0.93] increasing to 0.92 [95% CI = 0.90; 0.93] when adding blood p181-tau + Aß42/40. Chronic kidney disease and vascular comorbidities did not affect predictive performances. DISCUSSION: In a clinic-based cohort of patients with SCC or MCI, blood biomarkers may be good hallmarks of underlying pathology but add little to 5-year dementia risk prediction models including traditional predictors.

Complexities of cerebral small vessel disease, blood pressure, and dementia relationship: new insights from genetics.

Importance: There is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear. Objective: To disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia. Design Setting and Participants: This study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022. Exposures: Genetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke. Main outcomes and measures: The summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (ADmeta, n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses. Results: In the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of ADmeta (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and ADmeta, with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke. Conclusion: These findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.

The Multidimensional Nature of Research Ethics: Letters Issued by a French Research Ethics Committee Included Similar Proportions of Ethical and Scientific Queries.

Debate is ongoing concerning the activities and functioning of Research Ethics Committees (REC), especially a possible science-or-ethics dichotomy in research ethics review. We retrospectively analyzed 145 letters issued by a French REC over 18 months. All queries were classified in three levels: qualification (definition of the problem), category (aggregation of broader topics) and finally fields (ethical, scientific, or administrative). Overall, 971 queries were identified, of which 407 (42%), 379 (39%), and 135 (14%) were deemed ethical, scientific, and administrative queries, respectively. The most frequent concern was about participants' information. The main influencing factor was the profession of the reporting readers-scientific queries were more frequently raised by a methodologist, whereas ethical queries were more frequently raised by an ethicist. These results indicate that research ethics review is a multidimensional task that should be considered a collaborative effort.