Fatigue in Alzheimer's disease: biological basis and clinical management-a narrative review.

BACKGROUND: Fatigue is a common symptom in neurodegenerative diseases and is associated with decreased cognitive performances. A full knowledge of the causes and physiopathological pathways leading to fatigue in Alzheimer's disease could help treating this symptom and obtain positive effects on cognitive functions. OBJECTIVES: To provide an overview of the clinical conditions and the biological mechanisms leading to fatigue in Alzheimer's disease patients. To review the recent advances on fatigue management and describe the landscape of future possibilities. METHODS: We performed a narrative review including all type of studies (e.g. cross-sectional and longitudinal analysis, reviews, clinical trials). RESULTS: We found very few studies considering the symptom fatigue in Alzheimer's disease patients. Populations, designs, and objectives varied across studies rendering comparability across studies difficult to perform. Results from cross-sectional and longitudinal analysis suggest that the amyloid cascade may be involved in the pathogenesis of fatigue and that fatigue may be a prodromal manifestation of Alzheimer's disease. Fatigue and neurodegeneration of Alzheimer's disease could share common brain signatures (i.e. hippocampal atrophy and periventricular leukoaraiosis). Some mechanisms of aging (i.e. inflammation, mitochondrial dysfunction, telomere shortening) may be proposed to play a common underlying role in Alzheimer's disease neurodegeneration and muscle fatigability. Considering treatments, donepezil has been found to reduce cognitive fatigue in a 6-week randomized controlled study. Fatigue is frequently reported as an adverse event in patients treated by anti-amyloid agents in clinical trials. CONCLUSION: The literature is actually inconclusive about the main causes of fatigue in Alzheimer's disease individuals and its potential treatments. Further research is needed to disentangle the role of several components such as comorbidities, depressive symptoms, iatrogenic factors, physical decline and neurodegeneration itself. Given the clinical relevance of this symptom, it seems to be important to systematically assess fatigue by validated tools in Alzheimer's disease clinical trials.

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

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

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.

OBJECTIVES: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. METHODS: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. RESULTS: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. CONCLUSIONS: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.

Potentially modifiable factors associated with agitation and aggression in Alzheimer's disease: results of the ICTUS study.

OBJECTIVES: To study potentially modifiable factors associated with the severity of agitation or aggression (A/A) symptoms among Alzheimer's disease (AD) patients. DESIGN: Data from the Impact of Cholinergic Treatment Use (ICTUS) study, European longitudinal prospective observational study. SETTING: Community dwelling outpatients included in 29 European memory clinics. PARTICIPANTS: 1375 participants with probable AD (Mini-Mental State Examination score of 10-26) with an informal caregiver. MEASUREMENTS: At baseline and twice yearly over the two-year follow-up, patients underwent comprehensive clinical and neuropsychological assessments: sociodemographic data, cognitive status, functional impairment, and assessment of neuropsychiatric symptoms based on Neuro-Psychiatric Inventory (NPI). The ZARIT scale assessed the caregiver's burden. The variable of interest was the severity of the item of A/A of the NPI. To study factors associated to the severity of A/A symptoms six months later, a multivariate mixed regression model was used. RESULTS: Frequency of A/A symptom varied from 30% to 34% at each visit. Two factors were found to be independently associated with the severity of A/A: (1) the presence of affective disorder (anxiety, depression, and/or irritability) that increased the severity of the A/A by 0.89 point (coefficient:0.89; 95% Confidence Interval (CI) = [0.48,1.30], p < 0.001), and (2) a severe caregiver burden that increased the severity of the A/A by 1.08 point (coefficient:1.08; 95% CI = [0.69,1.47], p < 0.001). CONCLUSION: Research should evaluate whether the identification and treatment of an affective disorder along with the evaluation and optimal management of the caregiver would have a positive impact on the course of A/A in mild to moderate AD patients.

Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype.

INTRODUCTION: We estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration. METHODS: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration. RESULTS: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE ε4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage. DISCUSSION: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design.

European Prevention of Alzheimer's Dementia Registry: Recruitment and prescreening approach for a longitudinal cohort and prevention trials.

INTRODUCTION: It is a challenge to find participants for Alzheimer's disease (AD) prevention trials within a short period of time. The European Prevention of Alzheimer's Dementia Registry (EPAD) aims to facilitate recruitment by preselecting subjects from ongoing cohort studies. This article introduces this novel approach. METHODS: A virtual registry, with access to risk factors and biomarkers for AD through minimal data sets of ongoing cohort studies, was set up. RESULTS: To date, ten cohorts have been included in the EPAD. Around 2500 participants have been selected, using variables associated with the risk for AD. Of these, 15% were already recruited in the EPAD longitudinal cohort study, which serves as a trial readiness cohort. DISCUSSION: This study demonstrates that a virtual registry can be used for the preselection of participants for AD studies.

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

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

An Analysis of the Public Financial Support Eligibility Rule for French Dependent Elders with Alzheimer's Disease.

BACKGROUND: It is crucial to define health policies that target patients with the highest needs. In France, public financial support is provided to dependent patients: it can be used to finance informal care time and nonmedical care use. Eligibility for public subsidies and reimbursement of costs is associated with a specific tool: the autonomie gérontologie groupes iso-ressources (AGGIR) scale score. OBJECTIVE: Our objective was to explore whether patients with Alzheimer's disease who are eligible for public financial support have greater needs than do noneligible patients. METHODS: Using data from the Dépendance des patients atteints de la maladie d'Alzheimer en France study, we calculated nonmedical care expenditures (in €) using microcosting methods and informal care time demand (hours/month) using the Resource Use in Dementia questionnaire. We measured the burden associated with informal care provision with Zarit Burden Interview. We used a modified two-part model to explore the correlation between public financial support eligibility and these three variables. RESULTS: We find evidence of higher informal care use, higher informal caregivers' burden, and higher care expenditures when patients have an AGGIR scale score corresponding to public financial support eligibility. CONCLUSIONS: The AGGIR scale is useful to target patients with the highest costs and needs. Given our results, public subsidies could be used to further sustain informal caregivers networks by financing programs dedicated to lowering informal caregivers' burden.

Donepezil decreases annual rate of hippocampal atrophy in suspected prodromal Alzheimer's disease.

INTRODUCTION: The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD). METHODS: A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method. RESULTS: Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups. DISCUSSION: A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo.

Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design.

ABSTRACT Background: The management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer's disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD. Methods: We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013. Results: We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. Of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of "clinically significant A/A." There was considerable heterogeneity in study design. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials. Conclusions: This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.

[Immunotherapies in Alzheimer's disease: state of the art and potential use in the elderly]. / Immunothérapie passive dans la maladie d'Alzheimer : état des lieux et applicabilité en population gériatrique.

The recent positive results of phase III clinical trials evaluating the efficacy of anti-amyloid antibodies in Alzheimer's disease may give hope for an approbation in clinical practice soon. Indeed, lecanemab showed cognitive efficacy but also on functional status, quality of life and caregiver burden in the phase III CLARITY study. Aducanumab has already received marketing authorization in the United States in 2021 for the treatment of Alzheimer's disease. However, these clinical trials include mostly young participants without significant comorbidities who are not fully representative of the real elderly population. It is therefore necessary to examine the potential use of these treatments in routine care in the elderly population and to identify potential barriers to their use. The presence of cerebral microbleeds and anticoagulation, two frequent conditions in the elderly, could limit the use of anti-amyloid immunotherapy in the geriatric population. In this population, another limitation would be the unusually long diagnosis delays given that the anti-amyloid therapies target the earliest stages of the disease. However, the results of the phase III trials and in particular the subgroup analyses seem indicate a superior cognitive efficacy in elderly subjects, especially those over 75. European recommendations on the future use of these treatments are therefore awaited to clarify this situation, which will probably require a precise analysis of the benefit-risk balance. Age alone cannot be a contraindication to the administration of these treatments.

Different Trajectories of Apathy and Depression Among Subjective Cognitive Impairment Individuals with or without Conversion to Dementia: Results from the Memento Cohort in France.

BACKGROUND: Apathy and depression are two early behavioral symptoms in Alzheimer's disease (AD) and related disorders that often occur prior to the onset of cognitive decline and memory disturbances. Both have been associated with an increased risk of conversion to dementia, with a distinct neuropathology. OBJECTIVE: The assessment of the trajectories of apathy and depression and their independent impact on dementia conversion. METHODS: Apathy and Depression were measured using the Neuropsychiatric Inventory for caregiver (NPI) and clinician (NPI-C), among the nondemented individuals reporting subjective cognitive decline (SCD) at baseline. They were followed up over a 60-month period. Some converted to dementia, according to the methodology carried out by the French Memento Cohort. RESULTS: Among individuals with SCD (n = 2,323), the levels of apathy and depression were low and did not evolve significantly over the 60-month period, despite a trend in apathy increasing as of month 24. Regarding SCD individuals who converted to dementia within the 60-month period (n = 27), the prevalence of depression remained globally steady, while the levels of apathy increased over time. CONCLUSION: Apathy and depression have different trajectories among individuals with SCD and apathy alone is more likely-compared to depression-to be associated with conversion to dementia.

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.

The affordability of lecanemab, an amyloid-targeting therapy for Alzheimer's disease: an EADC-EC viewpoint.

Lecanemab, an anti-amyloid antibody with effects on biomarker and clinical endpoints in early Alzheimer's Disease (AD), was granted accelerated approval by the FDA in 2023 and regulatory review in Europe is ongoing. We estimate the population potentially eligible for treatment with lecanemab in the 27 EU countries to 5.4 million individuals. Treatment costs would exceed 133 billion EUR per year if the drug is priced similarly as in the United States, amounting to over half of the total pharmaceutical expenditures in the EU. This pricing would be unsustainable; the ability to pay for high-priced therapies varies substantially across countries. Pricing similarly to what has been announced for the United States may place the drug out of reach for patients in some European countries. Disparities in access to novel amyloid-targeting agents may further deepen the inequalities across Europe in health outcomes. As representatives of the European Alzheimer's Disease Consortium Executive Committee, we call for pricing policies that allow eligible patients across Europe to access important innovations, but also continued investments in research and development. Infrastructure to follow up the usage of new therapies in routine care and new payment models may be needed to address affordability and inequalities in patient access.

'Clinical trials in Alzheimer's disease': immunotherapy approaches.

Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid ß (Aß) peptide represents an important molecular target for intervention in Alzheimer's disease. Several types of Aß peptide immunotherapy for Alzheimer's disease are under investigation, direct immunization with synthetic intact Aß(42) , active immunization involving the administration of synthetic fragments of Aß peptide conjugated to a carrier protein and passive administration with monoclonal antibodies directed against Aß peptide. Pre-clinical studies showed that immunization against Aß peptide can provide protection and reversal of the pathology of Alzheimer's disease in animal models. Indeed, several adverse events have been described like meningoencephalitis with AN1792, vasogenic edema and microhemorrhages with bapineuzumab. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several Aß peptide immunotherapy approaches are under investigation but also against tau pathology.

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

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

Development and Validation of a Model to Identify Alzheimer's Disease and Related Syndromes in Administrative Data.

BACKGROUND: Administrative data are used in the field of Alzheimer's Disease and Related Syndromes (ADRS), however their performance to identify ADRS is unknown. OBJECTIVE: i) To develop and validate a model to identify ADRS prevalent cases in French administrative data (SNDS), ii) to identify factors associated with false negatives. METHODS: Retrospective cohort of subjects ≥ 65 years, living in South-Western France, who attended a memory clinic between April and December 2013. Gold standard for ADRS diagnosis was the memory clinic specialized diagnosis. Memory clinics' data were matched to administrative data (drug reimbursements, diagnoses during hospitalizations, registration with costly chronic conditions). Prediction models were developed for 1-year and 3-year periods of administrative data using multivariable logistic regression models. Overall model performance, discrimination, and calibration were estimated and corrected for optimism by resampling. Youden index was used to define ADRS positivity and to estimate sensitivity, specificity, positive predictive and negative probabilities. Factors associated with false negatives were identified using multivariable logistic regressions. RESULTS: 3360 subjects were studied, 52% diagnosed with ADRS by memory clinics. Prediction model based on age, all-cause hospitalization, registration with ADRS as a chronic condition, number of anti-dementia drugs, mention of ADRS during hospitalizations had good discriminative performance (c-statistic: 0.814, sensitivity: 76.0%, specificity: 74.2% for 2013 data). 419 false negatives (24.0%) were younger, had more often ADRS types other than Alzheimer's disease, moderate forms of ADRS, recent diagnosis, and suffered from other comorbidities than true positives. CONCLUSION: Administrative data presented acceptable performance for detecting ADRS. External validation studies should be encouraged.

Kidney Function and Cognitive Decline in Older Adults: Examining the Role of Neurodegeneration.

BACKGROUND/OBJECTIVES: Cognitive decline associated with impaired kidney function might involve neurodegeneration. Our objectives were to evaluate the longitudinal association between kidney function and cognitive decline in older adults and to assess the involvement of cortical beta-amyloid and hippocampal atrophy (features of Alzheimer's disease (AD)) in this association. DESIGN: Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial (MAPT). SETTINGS: Thirteen memory centers (France and Monaco, 2008-2016). PARTICIPANTS: A total of 1,334 community-dwellers >70 years old without dementia at baseline. MEASUREMENTS: We estimated glomerular filtration rate (eGFR) from serum creatinine using CKD-Epi equation. Cognition was assessed at baseline, 6, 12, 24, 36, 48, and 60 months using a composite Z-score designed for MAPT. The Clinical Dementia Rating (CDR) score was used to assess cognition and functional independence. We examined the association between eGFR and (1) evolution of the composite cognitive Z-score using mixed-effect models and (2) progression on CDR using Cox models and mixed-effect models. Adjustments were made for age, sex, education, ApoE genotype, cardiovascular risk factors and disease, hippocampal volume (measured with magnetic resonance), and cortical beta-amyloid (measured with positron emission tomography). RESULTS: Median (IQR) eGFR was 73(60-84) mL/min/1.73 m2 . Two hundred sixty-nine participants experienced progression on CDR score during follow-up. eGFR<60 was significantly associated with progression on CDR score (adjusted hazard ratio (aHR) = 1.35, 95% CI 1.01-1.80) and with both the cognitive and functional independence components of CDR, but not with the evolution of the composite cognitive Z-score (adjusted ß-coefficient -0.004, 95% CI -0.014; 0.006). Associations were not modified after further adjustment for beta-amyloid (subsample: n = 252) and hippocampal volume (subsample: n = 270). CONCLUSIONS: We did not find a mild to moderate renal insufficiency to be associated with brain imaging features of AD, and our results do not support the involvement of AD mechanisms in the incidence of cognitive impairment and functional decline associated with chronic kidney disease.

Diabetes Mellitus and Cognition: Pathway Analysis in the MEMENTO Cohort.

OBJECTIVE: To assess the role of biomarkers of Alzheimer disease (AD), neurodegeneration, and small vessel disease (SVD) as mediators in the association between diabetes mellitus and cognition. METHODS: The study sample was derived from MEMENTO, a cohort of French adults recruited in memory clinics and screened for either isolated subjective cognitive complaints or mild cognitive impairment. Diabetes was defined based on blood glucose assessment, use of antidiabetic agent, or self-report. We used structural equation modeling to assess whether latent variables of AD pathology (PET mean amyloid uptake, Aß42/Aß40 ratio, and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) mediate the association between diabetes and a latent variable of cognition (5 neuropsychological tests), adjusting for potential confounders. RESULTS: There were 254 (11.1%) participants with diabetes among 2,288 participants (median age 71.6 years; 61.8% women). The association between diabetes and lower cognition was significantly mediated by higher neurodegeneration (standardized indirect effect: -0.061, 95% confidence interval: -0.089, -0.032), but not mediated by SVD and AD markers. Results were similar when considering latent variables of memory or executive functioning. CONCLUSION: In a large clinical cohort in the elderly, diabetes is associated with lower cognition through neurodegeneration, independently of SVD and AD biomarkers.

Gait and balance impairments in Alzheimer disease patients.

OBJECTIVE: To describe the characteristics and associated factors of Alzheimer disease (AD) patients with balance and gait impairments. METHODS: Balance and gait impairments were assessed in 380 AD patients using the Tinetti test. RESULTS: A total of 120 (31.5%) patients had an abnormal Tinetti test, 96 (25.2%) had balance impairments, and 72 (18.9%) patients presented gait impairments. Global Tinetti score was associated with age [odds ratio (OR), 1.09; 95% confidence interval (CI), 1.05-1.14], Mini-Mental State Examination (MMSE) score (OR, 0.94; 95% CI, 0.90-0.99), activities of daily living (ADL) score (OR, 0.62; 95% CI, 0.47-0.83), and being man (OR, 0.44; 95% CI, 0.25-0.78). Balance impairment was associated with age (OR, 1.11; 95% CI, 1.05-1.17), ADL score (OR, 0.60; 95% CI, 0.43-0.84), and being female (OR, 0.19; 95% CI, 0.08-0.49). Gait impairment was associated with age (OR, 1.09; 95% CI, 1.03-1.15), MMSE score (OR, 0.92; 95% CI, 0.87-0.98), ADL score (OR, 0.63; 95% CI, 0.46-0.87), body mass index (OR, 1.10; 95% CI, 1.01-1.18), presence of comorbidities (OR, 2.13; 95% CI, 1.14-3.96), and the Cornell score (OR, 2.97; 95% CI, 1.12-7.89). CONCLUSIONS: AD patients are frequently concerned with balance and gait impairments. These impairments were associated to factors related to the severity of the disease (low MMSE and low ADL); nonmodifiable factors such as age or sex; and modifiable factors such as depression, obesity, and presence of comorbidities.