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Background: Mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) diagnosis is based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Currently, non-invasive and inexpensive blood-based biomarkers are being investigated, such as neuronal-derived plasma exosomes (NPEs). Neuroinflammation and early vascular changes have been described in AD pathogenesis and can be traced in plasma and NPEs. However, they have not been studied in early onset MCI (EOMCI). Objective: To describe the rationale, design, and baseline characteristics of the participants from the BIOFACE cohort, a two-year observational study on EOMCI conducted at Fundació ACE. The study goal is to characterize the different phenotypes from a clinical, neuropsychological, and biomarker point of view and to investigate the CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD. Methods: Participants underwent extended neurological and neuropsychological batteries, multimodal biomarkers including brain MRI, blood, saliva, CSF, anthropometric, and neuro-ophthalmological examinations. Results: Ninety-seven patients with EOMCI were recruited. 59.8%were women. Mean age at symptom onset was 57 years; mean MMSE was 28. First degree and presenile family history of dementia was present in 60.8%and 15.5%, respectively. Depressive and anxiety disorders along with vascular risk factors were the most frequent comorbidities. 29%of participants were APOE ɛ4 carriers, and 67%showed a CSF normal ATN profile. Conclusion: BIOFACE is a two-year study of clinical, cognition, and biomarkers that will shed light on the physiopathology and the potential utility of plasma and NPEs as non-invasive early diagnostic and prognostic biomarkers in people younger than 65 years.

Introduction Innovative patient engagement models are required to identify people with prodromal and mild Alzheimer's disease who are “hidden” in their communities and not normally found in a memory clinic setting. Methods A marketing campaign and a web‐based pre‐screening tool were used to identify individuals at risk of dementia in five European countries. Harmonized clinical evaluation of these patients was performed in participating memory clinics within the MOPEAD project. Results A total of 1487 individuals completed the pre‐screening, with 547 of them found to be at risk of dementia (36.8%). Among the subset of 91 patients with a positive pre‐screening result that underwent full clinical evaluation, 49 (53.8%) were diagnosed with either mild cognitive impairment or Alzheimer's disease. Conclusion This novel web‐based pre‐screening tool showed to be a valid strategy to identify undiagnosed people with cognitive impairment.

Background: The COVID-19 pandemic has brought great disruption to health systems worldwide. This affected ongoing clinical research, particularly among those most vulnerable to the pandemic, like dementia patients. Fundació ACE is a research center and memory clinic based in Barcelona, Spain, one of the hardest-hit countries. Objective: To describe the ad-hoc strategic plan developed to cope with this crisis and to share its outcomes. Methods: We describe participants’ clinical and demographic features. Additionally, we explain our strategic plan aimed at minimizing the impact on clinical trial research activities, which included SARS-CoV-2 RT-PCR and IgG serological tests to all participants and personnel. The outcomes of the plan are described in terms of observed safety events and drop-outs during the study period. Results: A total of 130 patients were participating in 16 active clinical trials in Fundació ACE when the lockdown was established. During the confinement, we performed 1018 calls to the participants, which led to identify adverse events in 26 and COVID-19 symptoms in 6. A total of 83 patients (64%) could restart on-site visits as early as May 11, 2020. All SARS-CoV-2 RT-PCR diagnostic tests performed before on-site visits were negative and only three IgG serological tests were positive. Throughout the study period, we only observed one drop-out, due to an adverse event unrelated to COVID-19. Discussion: The plan implemented by Fundació ACE was able to preserve safety and integrity of ongoing clinical trials. We must use the lessons learned from the pandemic and design crisis-proof protocols for clinical trials.

Contains fulltext : 231797.pdf (Publisher’s version ) (Closed access) 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.

BACKGROUND: Fundacio ACE is a non-profit organization providing care based on a holistic model to persons with cognitive disorders and their families for 25 years in Barcelona, Spain. Delivering care to this vulnerable population amidst the COVID-19 pandemic has represented a major challenge to our institution. OBJECTIVE: To share our experience in adapting our model of care to the new situation to ensure continuity of care. METHODS: We detail the sequence of events and the actions taken within Fundacio ACE to swiftly adapt our face-to-face model of care to one based on telemedicine consultations. We characterize individuals under follow-up by the Memory Unit from 2017 to 2019 and compare the number of weekly visits in 2020 performed before and after the lockdown was imposed. RESULTS: The total number of individuals being actively followed by Fundacio ACE Memory Unit grew from 6,928 in 2017 to 8,147 in 2019. Among those newly diagnosed in 2019, most patients had mild cognitive impairment or mild dementia (42% and 25%, respectively). Weekly visits dropped by 60% following the suspension of face-to-face activity. However, by April 24 we were able to perform 78% of the visits we averaged in the weeks before confinement began. DISCUSSION: We have shown that Fundacio ACE model of care has been able to successfully adapt to a health and social critical situation as COVID-19 pandemic. Overall, we were able to guarantee the continuity of care while preserving the safety of patients, families, and professionals. We also seized the opportunity to improve our model of care.

INTRODUCTION Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common cause of dementia. It has a complex pathophysiology that is not yet completely understood, where multiple central, systemic, and environmental factors play a key role in disease progression. Understanding the multifactorial nature of AD is paramount to formulate new therapies. AREAS COVERED The authors reviewed the role of the amyloid-β-binding, antioxidant, and immunomodulatory properties of albumin in AD and the use of therapeutic plasma exchange (PE) in neurology. The results from the Alzheimer Management By Albumin Replacement (AMBAR) trial that combined the use of PE with albumin replacement in patients with mild-to-moderate AD, are also analyzed. EXPERT OPINION Findings from the AMBAR study provide encouraging results in the treatment of AD with PE and albumin replacement, especially in patients at the moderate stage of the disease, who showed less cognitive decline from baseline compared with placebo in most of the variables analyzed. Further research is warranted to ascertain the possible mechanisms of action underlying these results. Different cohorts of patients that may also benefit from this treatment, such as those with mild cognitive impairment or other types of dementia, could also be the target of additional studies.

Background Recent research on mild cognitive impairment (MCI) has primarily focused on searching for measures to prevent or delay the progression of MCI to dementia. Physical exercise has shown to be effective in the prevention of age-related cognitive decline in elderly adults with MCI. However, the most effective type and dose of exercise for the improvement of cognition are yet to be determined. Objective To compare the cognitive effects of choreographed exercise (Choreography group) with a multimodal physical therapy program (Physical Therapy group) in elderly adults with amnestic MCI, a population with an increased risk of developing dementia. Methods We conducted a randomized clinical trial with two parallel groups under allocation concealment and assessor blinding. Participants were allocated into Choreography or Physical Therapy group and performed exercises twice per week in 60-minute sessions during 12 weeks. Results Thirty-six participants with amnestic MCI, ages 65 to 85, were assessed at baseline and after 12 weeks of intervention, by comprehensive validated neuropsychological and physical assessments. A Repeated measures General Lineal Model showed statistically significant differences in cognitive and physical outcomes. Both groups significantly improved in visual delayed recall. The Choreography group exhibited significantly more benefits on verbal recognition memory than the Physical Therapy group. Conclusion Greater cognitive benefits were achieved in the choreographic intervention than in the multimodal physical therapy, mainly in those functions more related to the risk of conversion to dementia. Additional studies are needed to confirm whether the observed effects are related to delayed onset of Alzheimer's disease in elderly adults with amnestic MCI.

Emerging digital tools have the potential to enable a new generation of qualitative and quantitative assessment of cognitive performance. Moreover, the ubiquity of consumer electronics, such as smartphones and tablets, can be harnessed to support large-scale self-assessed cognitive screening with benefit to healthcare systems and consumers. A wide variety of apps, wearables, and new digital technologies are either available or in development for the detection of mild cognitive impairment (MCI), a risk factor for dementia. Two categories of novel methodologies may be considered: passive technologies (which monitor a user’s behavior without active user input) and interactive assessments (which require active user input). Such examinations can be self-administered, supervised by a caregiver, or conducted by an informant at home or outside of a clinical setting. These direct-to-consumer tools have the potential to sidestep barriers associated with cognitive evaluation in primary care, thus improving access to cognitive assessments. Although direct-to-consumer cognitive assessment is associated with its own barriers, including test validation, user experience, and technological concerns, it is conceivable that these issues can be addressed so that a large-scale, self-assessed cognitive evaluation that would represent an initial cognitive screen may be feasible in the future.

BackgroundTo facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer’s disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers.MethodsWe included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification.ResultsEighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779–0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden’s cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913–0.100).ConclusionsPlasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer’s disease.

Background Alzheimer disease (AD) is a progressive neurodegenerative disorder affecting the elderly with a prevalence of 7.1% in women and 3.3% in men. Sex-related patterns have been reported in prognosis, biomarker status, and risk factors. Despite this, the interaction of sex has received limited attention, with AD trials persistently recruiting lower numbers of women than the population distribution and a lack of information on the sex-disaggregated effects of anti-dementia therapies. This is the first study aiming to identify the role of sex in the selection for screening in AD clinical trials. Methods This cross-sectional study provides a comprehensive analysis of screening eligibility according to a set of pre-selection criteria currently applied at Fundació ACE memory clinic for a more efficient trial screening process. A cohort of 6667 women and 2926 men diagnosed with AD dementia (55%) or mild cognitive impairment (45%) was analyzed. We also assessed the frequencies of men and women effectively screened for trial enrolment over a period of 10 years. Additionally, data from AddNeuroMed study was used to explore trends in eligibility based on the education criteria. Results Women showed a significantly lower chance of being eligible for screening than men (OR = 1.26; p < 0.01). This imbalance was confirmed by a lower frequency of women screened for enrolment compared to the study population (63.0% vs. 69.5%). Education was revealed as the key criterion contributing to this unbalance, with men showing over twice the chance of being screened compared with women (OR = 2.25, p < 0.01). Education-based differences were greater in earlier born patients, but the gap narrowed and achieved balance with increasing year of birth. This observation was replicated using data from other European populations included in AddNeuroMed study. Comorbidity was the most limiting criterion with sex differences in frequencies and significant discrimination against the selection of men (OR = 0.86, p < 0.01). Conclusions The large number of low-educated elderly women with AD demands for a sex-focused approach in clinical research. New assessment tools insensitive to education level should be developed to enable a proportional representation of women. Although this gender education gap is mostly inexistent in developed countries, economic or cultural factors may lead to different scenarios in other regions. Overlooking the impact of sex may lead to a handicap in AD research with a direct adverse impact on women’s health.

Background A low amount and extent of Aβ deposition at early stages of Alzheimer’s disease (AD) may limit the use of previously developed pathology-proven composite SUVR cutoffs. This study aims to characterize the population with earliest abnormal Aβ accumulation using 18F-florbetaben PET. Quantitative thresholds for the early (SUVRearly) and established (SUVRestab) Aβ deposition were developed, and the topography of early Aβ deposition was assessed. Subsequently, Aβ accumulation over time, progression from mild cognitive impairment (MCI) to AD dementia, and tau deposition were assessed in subjects with early and established Aβ deposition. Methods The study population consisted of 686 subjects (n = 287 (cognitively normal healthy controls), n = 166 (subjects with subjective cognitive decline (SCD)), n = 129 (subjects with MCI), and n = 101 (subjects with AD dementia)). Three categories in the Aβ-deposition continuum were defined based on the developed SUVR cutoffs: Aβ-negative subjects, subjects with early Aβ deposition (“gray zone”), and subjects with established Aβ pathology. Results SUVR using the whole cerebellum as the reference region and centiloid (CL) cutoffs for early and established amyloid pathology were 1.10 (13.5 CL) and 1.24 (35.7 CL), respectively. Cingulate cortices and precuneus, frontal, and inferior lateral temporal cortices were the regions showing the initial pathological tracer retention. Subjects in the “gray zone” or with established Aβ pathology accumulated more amyloid over time than Aβ-negative subjects. After a 4-year clinical follow-up, none of the Aβ-negative or the gray zone subjects progressed to AD dementia while 91% of the MCI subjects with established Aβ pathology progressed. Tau deposition was infrequent in those subjects without established Aβ pathology. Conclusions This study supports the utility of using two cutoffs for amyloid PET abnormality defining a “gray zone”: a lower cutoff of 13.5 CL indicating emerging Aβ pathology and a higher cutoff of 35.7 CL where amyloid burden levels correspond to established neuropathology findings. These cutoffs define a subset of subjects characterized by pre-AD dementia levels of amyloid burden that precede other biomarkers such as tau deposition or clinical symptoms and accelerated amyloid accumulation. The determination of different amyloid loads, particularly low amyloid levels, is useful in determining who will eventually progress to dementia. Quantitation of amyloid provides a sensitive measure in these low-load cases and may help to identify a group of subjects most likely to benefit from intervention. Trial registration Data used in this manuscript belong to clinical trials registered in ClinicalTrials.gov (NCT00928304, NCT00750282, NCT01138111, NCT02854033) and EudraCT (2014-000798-38).

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER) Altres ajuts: Generalitat de Catalunya. Programa CERCA Altres ajuts: Instituto de Salud Carlos III (CIBERSAM i CIBERNED) Altres ajuts: Fundació "La Caixa" Altres ajuts: Grífols SA (GR@ACE project) Neuropsychiatric symptoms (NPS) have been recently addressed as risk factors of conversion to Alzheimer's disease (AD) and other dementia types in patients diagnosed with Mild Cognitive Impairment (MCI). Our aim was to determine profiles based on the prominent NPS in MCI patients and to explore the predictive value of these profiles on conversion to specific types of dementia. A total of 2137 MCI patients monitored in a memory clinic were included in the study. Four NPS profiles emerged (classes), which were defined by preeminent symptoms: Irritability, Apathy, Anxiety/Depression and Asymptomatic. Irritability and Apathy were predictors of conversion to dementia (HR = 1.43 and 1.56, respectively). Anxiety/depression class showed no risk effect of conversion when compared to Asymptomatic class. Irritability class appeared as the most discriminant neuropsychiatric condition to identify non-AD converters (i.e., frontotemporal dementia, vascular dementia, Parkinson's disease and dementia with Lewy Bodies). The findings revealed that consistent subgroups of MCI patients could be identified among comorbid basal NPS. The preeminent NPS showed to behave differentially on conversion to dementia, beyond AD. Therefore, NPS should be used as early diagnosis facilitators, and should also guide clinicians to detect patients with different illness trajectories in the progression of MCI.

International audience; Introduction: A previous phase 2b study supported the use of the 5-HT6 receptor antagonist intepirdine as adjunctive therapy to donepezil for Alzheimer's disease (AD) dementia. A phase 3 study, MINDSET, was performed to test this hypothesis. Methods: MINDSET was a global, double-blind, randomized, placebo-controlled trial in 1315 mild-to-moderate AD dementia patients on stable donepezil. Patients received 35 mg/day intepirdine or placebo for 24 weeks. The co-primary endpoints were change from baseline to week 24 on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). Results: There were no statistically significant differences between intepirdine and placebo groups (adjusted mean [95% confidence interval]) on the co-primary endpoints ADAS-Cog (−0.36 [−0.95, 0.22], P = 0.2249) and ADCS-ADL (−0.09 [−0.90, This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

To date, very few studies have been focused on the impact of the convergence of neuropsychiatric symptoms (NPS) and APOE ε4 on the conversion to dementia in patients with Mild Cognitive Impairment patients (MCI), and none has been based in a clinical setting. The objective of the study is to determine the predictive value of additive and multiplicative interactions of NPS and APOE ε4 status on the prediction of incident dementia among MCI patients monitored in a Memory Clinic. 1512 patients (aged 60 and older) with prevalent MCI were followed for a mean of 2 years. Neuropsychiatric symptoms were assessed at baseline using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models were calculated. Additive interactions for depression, apathy, anxiety, agitation, appetite, or irritability and a positive ε4 carrier status were obtained, significantly increasing the hazard ratios of incident dementia (HR range 1.3-2.03). Synergistic interactions between NPS and APOE ε4 are identified among MCI patients when predicting incident dementia. The combination of the behavioral status and the genetic trait could be considered a useful strategy to identify the most vulnerable MCI patients to dementia conversion in a Memory Clinic.

BACKGROUND: The Clinical Dementia Rating–Sum of Boxes (CDR-SB) has been proposed as a primary outcome for use in prodromal AD trials. However, the psychometric properties of this, and of other commonly used measures, have not been well-established in this patient population. OBJECTIVE: To describe the psychometric properties of commonly used efficacy measures in a clinical trial of prodromal AD. SETTING: Data were gathered as part of a two-year clinical trial. PARTICIPANTS: Patients had biomarker confirmed prodromal AD. MEASUREMENTS: Clinical Dementia Rating (CDR), Functional Activities Questionnaire (FAQ), Alzheimer’s Disease Assessment Scale – Cognition Subscale 11 and 13 (ADAS-Cog), Mini Mental State Exam (MMSE), and Free and Cued Selective Reminding Test (FCSRT-IR [words]). Assessments were conducted at least every 24 weeks. RESULTS: For the CDR-SB, test-retest reliability was good (intra-class correlation coefficient [ICC]=0.83); internal consistency was 0.65 at baseline but above 0.8 at later assessments. Relationships between the CDR-SB and other measures were as expected (higher correlations with more closely related constructs), and the CDR-SB differentiated between patients with different severities of dementia (-2.9 points difference between CDR-Global Score 0.5 and 1, P

Increasing life expectancy has led to an aging population, which has consequently increased the prevalence of dementia. Alzheimer's disease (AD), the most common form of dementia worldwide, is estimated to make up 50--80% of all cases. AD cases are expected to reach 131 million by 2050, and this increasing prevalence will critically burden economies and health systems in the next decades. There is currently no treatment that can stop or reverse disease progression. In addition, the late diagnosis of AD constitutes a major obstacle to effective disease management. Therefore, improved diagnostic tools and new treatments for AD are urgently needed. In this review, we investigate and describe both well-established and recently discovered AD biomarkers that could potentially be used to detect AD at early stages and allow the monitoring of disease progression. Proteins such as NfL, MMPs, p-tau217, YKL-40, SNAP-25, VCAM-1, and Ng BACE are some of the most promising biomarkers because of their successful use as diagnostic tools. In addition, we explore the most recent molecular strategies for an AD therapeutic approach and nanomedicine-based technologies, used to both target drugs to the brain and serve as devices for tracking disease progression diagnostic biomarkers. State-of-the-art nanoparticles, such as polymeric, lipid, and metal-based, are being widely investigated for their potential to improve the effectiveness of both conventional drugs and novel compounds for treating AD. The most recent studies on these nanodevices are deeply explained and discussed in this review., Authors acknowledge the support of the Instituto de Salud Carlos III (ISCIII) Accion Estrategica en Salud, integrated in the Spanish National R+D+I Plan and financed by ISCIII Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER "Una manera de hacer Europa") grant PI17/01474 awarded to Merce Boada and grant PI19/00335 awarded to Marta Marquie; Spanish Ministry of Economy and Competitiveness (SAF201784283-R); Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED, CB06/05/0024); Portuguese Science and Technology Foundation (FCT) for the strategic fund (UIDB/04469/2020) and European Regional Development Funds., info:eu-repo/semantics/publishedVersion

Introduction: General practitioners (GPs) play a key role in early identification of dementia, yet diagnosis is often missed or delayed in primary care. As part of the multinational Models of Patient Engagement for Alzheimer’s Disease project, we assess GPs’ attitude toward early and pre-dementia diagnosis of AD and explore barriers to early diagnosis. Methods: Our survey covered general attitude toward early diagnosis, diagnostic procedures, resources, and opinion on present and future treatment options across five European countries. Results: In total 343 GPs completed the survey; 74% of GPs indicated that an early diagnosis is valuable. There were country-specific differences in GPs’ perceptions of reimbursement and time available for the patient. If a drug were available to slow down the progression of AD, 59% of the GPs would change their implementation of early diagnosis. Discussion: Our findings provide insight into GPs’ attitudes by exploring differences in perception and management of early diagnosis. (Less)

Background: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. Methods: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. Results: We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. Conclusions: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

To date, very few studies have been focused on the impact of the convergence of neuropsychiatric symptoms (NPS) and APOE ε4 on the conversion to dementia in patients with Mild Cognitive Impairment patients (MCI), and none has been based in a clinical setting. The objective of the study is to determine the predictive value of additive and multiplicative interactions of NPS and APOE ε4 status on the prediction of incident dementia among MCI patients monitored in a Memory Clinic. 1512 patients (aged 60 and older) with prevalent MCI were followed for a mean of 2 years. Neuropsychiatric symptoms were assessed at baseline using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models were calculated. Additive interactions for depression, apathy, anxiety, agitation, appetite, or irritability and a positive ε4 carrier status were obtained, significantly increasing the hazard ratios of incident dementia (HR range 1.3–2.03). Synergistic interactions between NPS and APOE ε4 are identified among MCI patients when predicting incident dementia. The combination of the behavioral status and the genetic trait could be considered a useful strategy to identify the most vulnerable MCI patients to dementia conversion in a Memory Clinic.

We present the clinical and neuropathological findings of a patient with early onset Alzheimer's dementia (AD), heterozygous carrier of the rare Apolipoprotein E Christchurch (APOEch) variant. The patient did not harbor any pathogenic mutation in known Mendelian genes related to AD or other neurodegenerative disorders. A sibling of this patient, also carrying the APOEch variant, developed AD at the age of 66 years old. Our data suggest a possible deleterious effect of this variant, which contrast with the protective role that has been previously shown in a subject homozygous for the APOEch with he Paisa PSEN1 mutation.

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide and has had unprecedented effects in healthcare systems, economies and society. COVID-19 clinical presentation primarily affects the respiratory system causing bilateral pneumonia, but it is increasingly being recognized as a systemic disease, with neurologic manifestations reported in patients with mild symptoms but, most frequently, in those in a severe condition. Elderly individuals are at high risk of developing severe forms of COVID-19 due to factors associated with aging and a higher prevalence of medical comorbidities and, therefore, they are more vulnerable to possible lasting neuropsychiatric and cognitive impairments. Several reports have described insomnia, depressed mood, anxiety, post-traumatic stress disorder and cognitive impairment in a proportion of patients after discharge from the hospital. The potential mechanisms underlying these symptoms are not fully understood but are probably multifactorial, involving direct neurotrophic effect of SARS-CoV-2, consequences of long intensive care unit stays, the use of mechanical ventilation and sedative drugs, brain hypoxia, systemic inflammation, secondary effects of medications used to treat COVID-19 and dysfunction of peripheral organs. Chronic diseases such as dementia are a particular concern not only because they are associated with higher rates of hospitalization and mortality but also because COVID-19 further exacerbates the vulnerability of those with cognitive impairment. In patients with dementia, COVID-19 frequently has an atypical presentation with mental status changes complicating the early identification of cases. COVID-19 has had a dramatical impact in long-term care facilities, where rates of infection and mortality have been very high. Community measures implemented to slow the spread of the virus have forced to social distancing and cancelation of cognitive stimulation programs, which may have contributed to generate loneliness, behavioral symptoms and worsening of cognition in patients with dementia. COVID-19 has impacted the functioning of Memory Clinics, research programs and clinical trials in the Alzheimer’s field, triggering the implementation of telemedicine. COVID-19 survivors should be periodically evaluated with comprehensive cognitive and neuropsychiatric assessments, and specific mental health and cognitive rehabilitation programs should be provided for those suffering long-term cognitive and psychiatric sequelae.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD+P). AD+P affects ∼50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD-P). Although the estimated heritability of AD+P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5,445 AD+P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p=1.26×10−8) and one spanning the 3’-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p=3.24×10−8), had genome-wide significant associations with AD+P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD+P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD+P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

Introduction: Although the Diabetes Specific Dementia Risk Score (DSDRS) was proposed for predicting risk of dementia at 10 years, its usefulness as a screening tool is unknown. For this purpose, the European consortium MOPEAD included the DSDRS within the specific strategy for screening of cognitive impairment in type 2 diabetes (T2D) patients attended in a third-level hospital. Material and Methods: T2D patients &gt, 65 years, without known cognitive impairment, attended in a third-level hospital, were evaluated. As per MOPEAD protocol, patients with MMSE &le, 27 or DSDRS &ge, 7 were referred to the memory clinic for complete neuropsychological assessment. Results: 112 T2D patients were recruited. A total of 82 fulfilled the criteria for referral to the memory unit (43 of them declined referral: 48.8% for associated comorbidities, 37.2% lack of interest, 13.95% lack of social support). At the Fundaci&oacute, ACE&rsquo, s Memory Clinic, 34 cases (87.2%) of mild cognitive impairment (MCI) and 3 cases (7.7%) of dementia were diagnosed. The predictive value of DSDRS &ge, 7 as a screening tool of cognitive impairment was AUROC = 0.739, p 0.024, CI 95% (0.609&ndash, 0.825). Conclusions: We found a high prevalence of unknown cognitive impairment in TD2 patients who attended a third-level hospital. The DSDRS was found to be a useful screening tool. The presence of associated comorbidities was the main factor of declining referral.

Disease-modifying pharmacotherapies for Alzheimer’s Disease (AD) are currently in late-stage clinical development; once approved, new healthcare infrastructures and services, including primary healthcare, will be necessary to accommodate a huge demand for early and large-scale detection of AD. The increasing global accessibility of digital consumer electronics has opened up new prospects for early diagnosis and management of mild cognitive impairment (MCI) with particular regard to AD. This new wave of innovation has spurred research in both academia and industry, aimed at developing and validating a new “digital generation” of tools for the assessment of the cognitive performance. In light of this paradigm shift, an international working group (the Global Advisory Group on Future MCI Care Pathways) convened to elaborate on how digital tools may be optimally integrated in screening-diagnostic pathways of AD The working group developed consensus perspectives on new algorithms for large-scale screening, detection, and diagnosis of individuals with MCI within primary medical care delivery. In addition, the expert panel addressed operational aspects concerning the implementation of unsupervised at-home testing of cognitive performance. The ultimate intent of the working group’s consensus perspectives is to provide guidance to developers of cognitive tests and tools to facilitate the transition toward globally accessible cognitive screening aimed at the early detection, diagnosis, and management of MCI due to AD.

Background Lysophosphatidic acids (LPAs) are bioactive signaling phospholipids that have been implicated in Alzheimer’s disease (AD). It is largely unknown whether LPAs are associated with AD pathology and progression from mild cognitive impairment (MCI) to AD. Methods The current study was performed on cerebrospinal fluid (CSF) and plasma samples of 182 MCI patients from two independent cohorts. We profiled LPA-derived metabolites using liquid chromatography-mass spectrometry. We evaluated the association of LPAs with CSF biomarkers of AD, Aβ-42, p-tau, and total tau levels overall and stratified by APOE genotype and with MCI to AD progression. Results Five LPAs (C16:0, C16:1, C22:4, C22:6, and isomer-LPA C22:5) showed significant positive association with CSF biomarkers of AD, Aβ-42, p-tau, and total tau, while LPA C14:0 and C20:1 associated only with Aβ-42 and alkyl-LPA C18:1, and LPA C20:1 associated with tau pathology biomarkers. Association of cyclic-LPA C16:0 and two LPAs (C20:4, C22:4) with Aβ-42 levels was found only in APOE ε4 carriers. Furthermore, LPA C16:0 and C16:1 also showed association with MCI to AD dementia progression, but results did not replicate in an independent cohort. Conclusions Our findings provide evidence that LPAs may contribute to early AD pathogenesis. Future studies are needed to determine whether LPAs play a role in upstream of AD pathology or are downstream markers of neurodegeneration.

International audience; Mild cognitive impairment (MCI) is significantly misdiagnosed in the primary care setting due to multi-dimensional frictions and barriers associated with evaluating individuals’ cognitive performance. To move toward large-scale cognitive screening, a global panel of clinicians and cognitive neuroscientists convened to elaborate on current challenges that hamper widespread cognitive performance assessment. This report summarizes a conceptual framework and provides guidance to clinical researchers and test developers and suppliers to inform ongoing refinement of cognitive evaluation. This perspective builds upon a previous article in this series, which outlined the rationale for and potentially against efforts to promote widespread detection of MCI. This working group acknowledges that cognitive screening by default is not recommended and proposes large-scale evaluation of individuals with a concern or interest in their cognitive performance. Such a strategy can increase the likelihood to timely and effective identification and management of MCI. The rising global incidence of AD demands innovation that will help alleviate the burden to healthcare systems when coupled with the potentially near-term approval of disease-modifying therapies. Additionally, we argue that adequate infrastructure, equipment, and resources urgently should be integrated in the primary care setting to optimize the patient journey and accommodate widespread cognitive evaluation.

Background: Easily accessible biomarkers are needed for the early identification of individuals at risk of developing Alzheimer’s disease (AD) in large population screening strategies. Objectives: This study evaluated the potential of plasma β-amyloid (Aβ) biomarkers in identifying early stages of AD and predicting cognitive decline over the following two years. Design: Total plasma Aβ42/40 ratio (TP42/40) was determined in 83 cognitively normal individuals (CN) and 145 subjects with amnestic mild cognitive impairment (a-MCI) stratified by an FDG-PET AD-risk pattern. Results: Significant lower TP42/40 ratio was found in a-MCI patients compared to CN. Moreover, a-MCIs with a high-risk FDG-PET pattern for AD showed even lower plasma ratio levels. Low TP42/40 at baseline increased the risk of progression to dementia by 70%. Furthermore, TP42/40 was inversely associated with neocortical amyloid deposition (measured with PiB-PET) and was concordant with the AD biomarker profile in cerebrospinal fluid (CSF). Conclusions: TP42/40 demonstrated value in the identification of individuals suffering a-MCI, in the prediction of progression to dementia, and in the detection of underlying AD pathology revealed by FDG-PET, Amyloid-PET and CSF biomarkers, being, thus, consistently associated with all the well-established indicators of AD.

Background: Sembragiline is a potent, selective, long-acting, and reversible MAO-B inhibitor developed as a potential treatment for Alzheimer’s disease (AD). Objective: To evaluate the safety, tolerability, and efficacy of sembragiline in patients with moderate AD. Methods: In this Phase II study ({"type":"clinical-trial","attrs":{"text":"NCT01677754","term_id":"NCT01677754"}}NCT01677754), 542 patients with moderate dementia (MMSE 13–20) on background acetylcholinesterase inhibitors with/without memantine were randomized (1:1:1) to sembragiline 1 mg, 5 mg, or placebo once daily orally for 52 weeks. Results: No differences between treated groups and placebo in adverse events or in study completion. The primary endpoint, change from baseline in ADAS-Cog11, was not met. At Week 52, the difference between sembragiline and placebo in ADAS-Cog11 change from baseline was – 0.15 (p = 0.865) and 0.90 (p = 0.312) for 1 and 5 mg groups, respectively. Relative to placebo at Week 52 (but not at prior assessment times), the 1 mg and 5 mg sembragiline groups showed differences in ADCS-ADL of 2.64 (p = 0.051) and 1.89 (p = 0.160), respectively. A treatment effect in neuropsychiatric symptoms (as assessed by the difference between sembragiline and placebo on BEHAVE-AD-FW) was also seen at Week 52 only: – 2.80 (p = 0.014; 1 mg) and – 2.64 (p = 0.019; 5 mg), respectively. A post hoc subgroup analysis revealed greater treatment effects on behavior and functioning in patients with more severe baseline behavioral symptoms (above the median). Conclusions: This study showed that sembragiline was well-tolerated in patients with moderate AD. The study missed its primary and secondary endpoints. Post hoc analyses suggested potential effect on neuropsychiatric symptoms and functioning in more behaviorally impaired study population at baseline.

BACKGROUND Recruitment methods can determine sample characteristics in mild cognitive impairment and Alzheimer's disease dementia, but little is known about its influence in subjective cognitive decline (SCD). OBJECTIVE To determine the influence of two types of recruitment methods in the characteristics of individuals with SCD. METHODS We select and compare clinical and neuropsychological features, and frequency of APOE ɛ4 allele of 326 subjects with SCD from two cohorts: Open House Initiative (OHI) versus Memory Unit (MU). A logistic regression analysis (LRA), using gender and years of education as covariates, was used to examine the neuropsychological variables. RESULTS The OHI sample were mostly women (75.9% versus 64.5%, p

Highlights • CSF Amyloid- β is related to medial temporal and posterior brain atrophy in Lewy body dementia. • CSF p-Tau is associated with posterior brain atrophy in Lewy body dementia. • CSF AD-related biomarkers are not related to atrophy in the frontal lobes., Background Alzheimer’s disease (AD)-related pathology is frequently found in patients with dementia with Lewy bodies (DLB). However, it is unknown how amyloid-β and tau-related pathologies influence neurodegeneration in DLB. Understanding the mechanisms underlying brain atrophy in DLB can improve our knowledge about disease progression, differential diagnosis, drug development and testing of anti-amyloid and anti-tau therapies in DLB. Objectives We aimed at investigating the combined effect of CSF amyloid-β42, phosphorylated tau and total tau on regional brain atrophy in DLB in the European DLB (E-DLB) cohort. Methods 86 probable DLB patients from the E-DLB cohort with CSF and MRI data were included. Random forest was used to analyze the association of CSF biomarkers (predictors) with visual rating scales for medial temporal lobe atrophy (MTA), posterior atrophy (PA) and global cortical atrophy scale-frontal subscale (GCA-F) (outcomes), including age, sex, education and disease duration as extra predictors. Results DLB patients with abnormal MTA scores had abnormal CSF Aβ42, shorter disease duration and older age. DLB patients with abnormal PA scores had abnormal levels of CSF Aβ42 and p-tau, older age, lower education and shorter disease duration. Abnormal GCA-F scores were associated with lower education, male sex, and older age, but not with any AD-related CSF biomarker. Conclusions This study shows preliminary data on the potential combined effect of amyloid-β and tau-related pathologies on the integrity of posterior brain cortices in DLB patients, whereas only amyloid-β seems to be related to MTA. Future availability of α-synuclein biomarkers will help us to understand the effect of α-synuclein and AD-related pathologies on brain integrity in DLB.

Background The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. Methods and findings This case–control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44–96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44–94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1–5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4–31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65–70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. Conclusions In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65–70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level., In a case-control study using cerebrospinal fluid biomarkers, Hana Saddiki and colleagues investigate how age is related to the association between Apolipoprotein E genotype and Alzheimer's disease, among individuals with and without Alzheimer's disease in Europe and the US., Author summary Why was this study done? The ε4 allele of apolipoprotein E (APOE) gene (APOE4) and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The recent development of diagnostic criteria based on biomarkers that reflect brain β-amyloid and tau lesions (β-amyloid deposition, pathologic tau, neurodegeneration [A/T/N] classification]) increases homogeneity in diagnosed cases. The strength of association of AD with risk factors can be better determined using biomarker-based AD compared with AD diagnosis based only on clinical criteria because the latter are known to lack specificity as a result of difficulties in ruling out other causes of dementia. What did the researchers do and find? We compared the overall and age-specific association between APOE4 and AD using a case–control study that included 1,593 AD cases from memory clinics with positive cerebrospinal fluid biomarkers and 11,723 dementia-free controls drawn from two longitudinal cohort studies. The use of a large number of cases and controls allows assessment of whether the association between APOE4 and AD is dependent on age. Compared with controls, patients with AD were more likely to carry one APOE4 (odds ratio [OR] = 4.6) or two APOE4 (OR = 25.3). This association was significantly modified by age, with the strongest association seen between 65 and 70 years of age and weaker associations at the two tails of the age distribution. What do these findings mean? Incorporating biomarkers for diagnosis of AD identified an association with APOE4 that is apparently greater than has been previously reported using clinical diagnosis of the disease. The impact of APOE4 on the risk of AD was strongest between the 65 and 70 years of age, earlier than the mean age at diagnosis in this study, which was 72.8 years.

Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aβ). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease.We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function.The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group.Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck SharpDohme; ClinicalTrials.gov number, NCT01953601.).

In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.

Introduction: There is a growing interest in new therapeutic strategies for the treatment of Alzheimer disease (AD) which focus on reducing the beta-amyloid peptide (Aβ) burden in the brain by sequestering plasma Aβ, a large proportion of which is bound to albumin and other proteins. This review discusses the concepts of interaction between Aβ and albumin that have given rise to AMBAR (Alzheimer's Disease Management by Albumin Replacement) project, a new multicentre, randomised, controlled clinical trial for the treatment of AD. Development: Results from preliminary research suggest that Albutein® (therapeutic albumin, Grifols) contains no quantifiable levels of Aβ. Studies also show that Albutein® has Aβ binding capacity. On the other hand, AD entails a high level of nitro-oxidative stress associated with fibrillar aggregates of Aβ that can induce albumin modification, thus affecting its biological functions. Results from the phase ii study confirm that using therapeutic apheresis to replace endogenous albumin with Albutein® 5% is feasible and safe in patients with AD. This process resulted in mobilisation of Aβ and cognitive improvement in treated patients. The AMBAR study will test combination therapy with therapeutic apheresis and haemopheresis with the possible leverage effect of Albutein® with intravenous immunoglobulin replacement (Flebogamma® DIF). Cognitive, functional, and behavioural changes in patients with mild to moderate AD will be assessed. Conclusions: The AMBAR study represents a new therapeutic perspective for AD. Resumen: Introducción: Existe un creciente interés en las nuevas estrategias terapéuticas para la enfermedad de Alzheimer (EA) orientadas a reducir la carga de péptido β-amiloide (Aβ) en el cerebro mediante el secuestro de Aβ en el plasma, un alto porcentaje del cual se encuentra unido a albúmina y otras proteínas plasmáticas. En esta revisión, se analizan los conceptos de interacción entre Aβ y albúmina que han conducido al desarrollo del proyecto AMBAR (Alzheimer Management By Albumin Replacement), un nuevo estudio clínico multicéntrico, aleatorizado y controlado para el tratamiento de la EA. Desarrollo: Resultados de estudios de investigación básica indican que Albutein® (albúmina terapéutica, Grifols) contiene niveles no cuantificables de Aβ. Asimismo demuestran la capacidad de Albutein® de unirse a Aβ. Por otro lado, en la EA existe un elevado estrés nitro-oxidativo asociado a los agregados fibrilares de Aβ que puede inducir la modificación de la albúmina, afectando a sus funciones biológicas. Resultados del estudio en fase ii confirman que el reemplazo de la albúmina endógena con Albutein® 5% mediante aféresis terapéutica es factible y seguro en pacientes con EA, produciendo una movilización de Aβ, además de una mejoría cognitiva de los pacientes tratados. En el estudio AMBAR se ensayará el uso combinado de aféresis terapéutica y hemoféresis con el posible efecto potenciador de Albutein® con reposición de inmunoglobulina por vía intravenosa (Flebogamma® DIF). Se evaluarán los cambios cognitivos, funcionales y conductuales en pacientes con EA leve o moderada. Conclusiones: El estudio AMBAR representa una nueva perspectiva terapéutica ante la EA. Keywords: Albumin, Alzheimer disease, Haemapheresis, Intravenous immunoglobulin, Beta amyloid peptide, Plasmapheresis, Palabras clave: Albúmina, Enfermedad de Alzheimer, Hemoféresis, Inmunoglobulina intravenosa, Péptido betaamiloide, Plasmaféresis

IntroductionAlzheimer's disease pathologies are common in dementia with Lewy bodies, but their clinical relevance is not clear. CSF biomarkers amyloid beta 1‐42, total tau, and tau phosphorylated at threonine 181 reflect Alzheimer's disease neuropathology antemortem. In PD, low CSF amyloid beta 1‐42 predict long‐term cognitive decline, but little is known about these biomarkers as predictors for cognitive decline in Lewy body dementia. The aim of this study was to assess whether Alzheimer's disease CSF biomarkers predict cognitive decline in Lewy body dementia.MethodsFrom a large European dementia with Lewy bodies multicenter study, we analyzed baseline Alzheimer's disease CSF biomarkers and serial MMSE (baseline and 1‐ and 2‐year follow‐up) in 100 patients with Lewy body dementia. Linear mixed‐effects analyses, adjusted for sex, age, baseline MMSE, and education, were performed to model the association between CSF biomarkers and rate of cognitive decline measured with MMSE. An Alzheimer's disease CSF profile was defined as pathological amyloid beta 1‐42 plus pathological total tau or phosphorylated tau.ResultsThe Alzheimer's disease CSF profile, and pathological levels of amyloid beta 1‐42, were associated with a more rapid decline in MMSE (2.2 [P < 0.05] and 2.9 points difference [P< 0.01], respectively). Higher total tau values showed a trend toward association without statistical significance (2.0 points difference; P = 0.064), whereas phosphorylated tau was not associated with decline.ConclusionsReduced levels of CSF amyloid beta 1‐42 were associated with more rapid cognitive decline in Lewy body dementia patients. Future prospective studies should include larger samples, centralized CSF analyses, longer follow‐up, and biomarker‐pathology correlation.

Aims To explore whether type 2 diabetes (T2D) is a risk factor for dementia conversion in patients with mild cognitive impairment (MCI). Methods A longitudinal nested case–control study in which 101 T2D patients and 101 non-diabetic patients with MCI matched by age and gender were included. Results The dementia conversion rate was 57.4% in T2D patients vs. 42.6% in non-diabetic subjects (p = 0.02). T2D and APOE e4 allele were independent risk factors for developing dementia. Conclusion T2D is an independent risk factor for dementia conversion in MCI patients. This finding has significant clinical implications.

BackgroundGenetics plays a major role in Alzheimer’s Disease (AD). To date, 40 genes associated with AD have been identified, although most remain undiscovered. Clinical, neuropathological and genetic variability might impact genetic discoveries and complicate dissection of the biological pathways underlying AD.MethodsGR@ACE is a genome-wide study of dementia and its clinical endophenotypes that encompasses 4,120 cases and 3,289 controls from Spain. GR@ACE phenotypes were defined according to AD’s clinical certainty and the presence of vascular co-morbidity. To explore whether clinical endophenotypes reflect variation in underlying biological pathways, we first assessed the impact of known AD loci across endophenotypes to generate three loci categories. Next, we incorporated gene co-expression data and conducted pathway analysis on each category. To assess the impact of heterogeneity in the GWAS findings, the GR@ACE series were meta-analyzed with: 1) genotype-level data from dbGaP (N=21,235); and 2) summary statistics from IGAP Stages I and II (n=61,571 and n=81,455 respectively).FindingsWe classified known AD loci in three categories, which might reflect the disease clinical heterogeneity, from vascular and mixed forms to pure AD pathology. Immune system pathways were detected in all categories. Intriguingly, vascular processes were only detected as a causal mechanism in probable AD. A meta-analysis of GR@ACE with additional GWAS datasets revealed theANKRD31-rs4704171signal in theHMGCRgenomic region. We confirmed NDUFAF6-rs10098778 andSCIMP-rs7225151, which were previously detected by IGAP, to be suggestive signals. We also confirmed CD33-rs3865444 to be genome-wide significant.InterpretationThe regulation of vasculature is a prominent causal component of probable AD. In that context, cerebral amyloid angiopathy, the unique identified link between the vascular and amyloid hypotheses, deserves further investigation. The GR@ACE meta-analysis revealed novel AD genetic signals. GWAS results are strongly driven by the presence of clinical heterogeneity in the AD series.FundingGrifols SA, Fundación bancaria “La Caixa”, Fundació ACE and ISCIII (Instituto de Salud Carlos III).

ATENCIÓ: la correcció està també al DDD, cal relacionar??? https://ddd.uab.cat/record/226203 Altres ajuts: The following studies and consortia have contributed to this manuscript. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe): This study/publication is part of the German Research Network on Dementia (KND), the German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe), and the Health Service Research Initiative (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+; AgeQualiDe)) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, 01GY1322G). Alfredo Ramirez was partly supported by the ADAPTED consortium: Alzheimer's disease Apolipoprotein Pathology for Treatment Elucidation and Development, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. Brain compendium: This work was funded by the UK Medical Research Council (13044). P.F.C. is a Wellcome Trust principal Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.Clinical AD, Sweden: We would like to thank UCL Genomics for performing the genotyping analyses. Danish data: The studies behind the Danish long-lived cases received funding from The National Program for Research Infrastructure 2007 (grant no. 09-063256), the Danish Agency for Science Technology and Innovation, the Velux Foundation, the US National Institute of Health (P01 AG08761), the Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research (grant no. 11-107308), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the CERA Foundation (Lyon), the AXA Research Fund, Paris, and The Health Foundation (Helsefonden), Copenhagen, Denmark. The GOYA study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth Cohort which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Fundació ACE (FACE): We would like to thank patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). Agustín Ruiz has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED Grant No. 115975 and by grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- "Una manera de Hacer Europa"), by Fundación bancaria "La Caixa" and Grifols SA (GR@ACE project). Genetics of Healthy Ageing Study (GEHA - NL): The work described in this paper was funded mainly by the EU GEHA Project contract no. LSHM-CT-2004-503-270. Gothenburg Birth Cohort (GBC) Studies: We would like to thank UCL Genomics for performing the genotyping analyses. The studies were supported by The Stena Foundation, The Swedish Research Council (2015-02830, 2013-8717), The Swedish Research Council for Health, Working Life and Wellfare (2013-1202, 2005-0762, 2008-1210, 2013-2300, 2013-2496, 2013-0475), The Brain Foundation, Sahlgrenska University Hospital (ALF), The Alzheimer's Association (IIRG-03-6168), The Alzheimer's Association Zenith Award (ZEN-01-3151), Eivind och Elsa K:son Sylvans Stiftelse, The Swedish Alzheimer Foundation. International FTD-Genomics Consortium (IFGC): International FTD-Genomics Consortium (IFGC): The authors thank the IFGC for providing relevant data to support the analyses presented in this manuscript. Further acknowledgments for IFGC (https://ifgcsite.wordpress.com/), e.g. full members list and affiliations, are found in the online supplementary files. IPDGC (​The International Parkinson Disease Genomics Consortium): We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgements and funding http://pdgenetics.org/partners. Kompetenznetz Multiple Sklerose (KKNMS): This work was supported by the German Ministry for Education and Research (BMBF) as part of the "German Competence Network Multiple Sclerosis" (KKNMS) (grant nos. 01GI0916 and 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). TA was supported by the BMBF through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J). BH was supported by the EU Horizon 2020 project MultipleMS.Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. Leiden Longevity Study: This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (Grant 050-060-810), all in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and by Unilever Colworth.Maria Carolina Dalmasso: Georg Forster Research Award (Alexander von Humboldt Foundation). Mayo Clinic AD, DLB, PD, PSP: We thank the patients and their families for their participation, without whom these studies would not have been possible. Funding for this work was supported by National Institute on Aging [RF AG051504 to NET.; U01 AG046139 to NET]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET; P50 NS072187]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information and Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to OAR). The PD program at the Mayo Clinic Florida is also supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and The Sol Goldman Charitable Trust. Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP The online version of this article (10.1007/s00401-019-02026-8) contains supplementary material, which is available to authorized users.

Background: We investigated the global and age-specific association between Apolipoprotein E (APOE) genotype and Alzheimer's disease (AD) in a large multicentric case-control study, using cerebrospinal fluid (CSF) biomarkers-based diagnostic criteria for AD. Methods: In this case-control design, data on 1,599 Caucasian AD cases with abnormal values of CSF biomarkers came from 9 European memory clinics and the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. AD cases were compared to 11,724 dementia-free controls, drawn from two longitudinal cohort studies (Whitehall II and 3-City). Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were reported, overall and by 5-year age categories. Findings. 63*4% of CSF biomarker-defined AD patients and 22*6% of population controls carried at least one APOE e4 allele; respective percentages for APOE e4 homozygotes were 16*7% and 1*4%. Compared to none4 carriers, heterozygous e4 carriers had a 4*6 (95% confidence interval: 4*1 - 5*2) and e4/e4 homozygotes a 25*4 (20*5 - 31*3) higher OR of AD. This association was strongly modified by age (p for interaction < 0*001). The PAF associated with carrying at least one e4 allele was greatest in the 65-70 age group (69*7%), and weaker before 55 years (14*2%) and after 85 years (22*6%). There was some evidence of a stronger effect of APOE on AD risk in women. Interpretation: Incorporating biomarkers for diagnosis of AD led to a stronger association with APOE e4 than previously reported, perhaps due to better diagnostic accuracy. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE e4 at the population level. Funding Statement: US National Institutes of Health, Fondation Plan Alzheimer. Declaration of Interests: ASM is supported by NIH/NIA R01AG056477. IZ is supported by the Robert-Koch-Institute through funds of Federal Ministry of Health (grant no. 1369-341) and DZNE (German Center for Neurodegenerative Diseases). KB reports consulting fees from Fujirebio Europe, IBL International, Roche Diagnostics. HZ is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. MB has been a consultant for Araclon, Avid, Bayer, Elan, Grifols, Janssen/Pfizer, Lilly, Neuroptix, Nutricia, Roche, Sanofi, and Servier. All other authors declare no competing interests. Ethics Approval Statement: Ethical clearance was obtained by the institutional review boards of all participating sites (European memory centers and ADNI Study sites) and all participants provided written, informed consent.

Altres ajuts: This work was supported by grants from , Fundació La Marató TV3 (TV3-2014-3610), CIBERNED (CB06/05/0042 and PI2017/01) to JRA. DSW was supported by the Fundació La Marató TV3. JCS is a recipient of a Ph.D. Fellowship from the Ministerio de Ciencia, Innovación y Universidades. CF is a recipient of a Ph.D. Fellowship from the Department of Biochemistry and Molecular Biology of the Universitat Autònoma de Barcelona. Several evidences suggest that failure of synaptic function occurs at preclinical stages of Alzheimer's disease (AD) preceding neuronal loss and the classical AD pathological hallmarks. Nowadays, there is an urgent need to identify reliable biomarkers that could be obtained with non-invasive methods to improve AD diagnosis at early stages. Here, we have examined plasma levels of a group of miRNAs related to synaptic proteins in a cohort composed of cognitive healthy controls (HC), mild cognitive impairment (MCI) and AD subjects. Plasma and brain levels of miRNAs were analysed in two different cohorts including 38 HC, 26 MCI, 56 AD dementia patients and 27 frontotemporal dementia (FTD) patients. D'Agostino and Pearson and Shapiro-Wilk tests were used to evaluate data normality. miRNA levels between groups were compared using a two-sided nonparametric Mann-Whitney test and sensitivity and specificity was determined by receiver operating characteristic curve analysis. Significant upregulation of miR-92a-3p, miR-181c-5p and miR-210-3p was found in the plasma of both MCI and AD subjects. MCI patients that progress to AD showed higher plasma levels of these miRNAs. By contrast, no changes in miR-92a-3p, miR-181c-5p or miR-210-3p levels were observed in plasma obtained from a cohort of FTD. Our study shows that plasma miR-92a-3p, miR-181c-5p and miR-210-3p constitute a specific molecular signature potentially useful as a potential biomarker for AD. The online version of this article (10.1186/s13195-019-0501-4) contains supplementary material, which is available to authorized users.

“The authors would like to thank the Norwegian Dementia Genetics Network (DemGene), the European DLB Consortium (E-DLB), Dementia Genetics Spanish Consortium (DEGESCO) and Genomic Research at Fundacio ACE (GR@ACE) Consortium. Fundacio ACE would like to thank patients and controls who participated in this project. We are indebted to private donors for their support of Fundacio ACE research programs. Fundacio ACE collaborates with the Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The study was founded by the Research Council of Norway, Norwegian Regional Health Authorities and Norwegian Health Association and 237250/EU/JPND (APGeM). The Cohort 2 results were generated with the assistance of financial support of grants PI13/02434 and PI16/01861. Accion Estrategica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). GR@ACE project has been funded by Fundacion bancaria “La Caixa”, Grifols SA, Fundacio ACE. The funding sources did not in any way affect the results or presentation of the results.” should read: “The authors would like to thank the Norwegian Dementia Genetics Network (DemGene), the European DLB Consortium (E-DLB), Dementia Genetics Spanish Consortium (DEGESCO) and Genomic Research at Fundacio ACE (GR@ACE) Consortium. Fundacio ACE would like to thank patients and controls who participated in this project. We are indebted to private donors for their support of Fundacio ACE research programs. Fundacio ACE collaborates with the Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The study was founded by the Research Council of Norway, Norwegian Regional Health Authorities and Norwegian Health Association and 237250/EU/JPND (APGeM). The Cohort 2 results were generated with the assistance of financial support of grants PI13/02434 and PI16/01861. Accion Estrategica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). GR@ACE project has been funded by Fundacion bancaria “La Caixa”, Grifols SA, Fundacio ACE. The funding sources did not in any way affect the results or presentation of the results. This paper represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author and not necessarily those of the NIHR or the Department of Health and Social Care”.

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series., The authors would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Fundacion bancaria La Caixa, Grifols SA, Fundacio ACE, and ISCIII (Ministry of Health, Spain). They also want to thank the private sponsors who support the basic and clinical projects of our institution (Piramal AG, Laboratorios Echevarne, Araclon Biotech S.A., and Fundacio ACE). They are indebted to the Trinitat Port-Carbo legacy and her family for their support of Fundacio ACE research programs. Fundacio ACE is a participating center in the Dementia Genetics Spanish Consortium (DEGESCO). A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, and PI17/01474. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de Hacer Europa). L.M.R. is supported by Consejeria de Salud de la Junta de Andalucia (grant PI-0001/2017). Control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed after standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. The present work was performed as part of the Biochemistry, Molecular Biology, and Biomedicine doctoral program of S. MorenoGrau at Universitat Autonoma de Barcelona (Barcelona, Spain).r Data collection and sharing for this project was partially funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering, as well as through generous contributions from the following: AbbVie; the Alzheimer's Association; the Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study was coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California.; r The AddNeuroMed data are from a public-private partnership supported by EFPIA companies and SMEs as part of InnoMed (Innovative Medicines in Europe), an integrated project funded by the European Union of the Sixth Framework program priority FP6-2004-LIFESCIHEALTH-5. Clinical leads responsible for data collection are Iwona K1oszewska (Lodz), Simon Lovestone (London), Patrizia Mecocci (Perugia), Hilkka Soininen (Kuopio), Magda Tsolaki (Thessaloniki), and Bruno Vellas (Toulouse). Imaging leads are Andy Simmons (London), Lars-Olad Wahlund (Stockholm), and Christian Spenger (Zurich). Bioinformatics leads are Richard Dobson (London) and Stephen Newhouse (London).r Funding support for the Alzheimer's Disease Genetics Consortium (ADGC) was provided through the NIA Division of Neuroscience (U01-AG032984).r The Mayo Clinic Alzheimer's Disease Genetic Studies, led by Dr. Nilufer Ertekin-Taner and Dr. Steven G. Younkin at the Mayo Clinic in Jacksonville, FL, used samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimer's Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, and R01 AG003949, NINDS grant R01 NS080820, the CurePSP Foundation, and support from the Mayo Foundation.r The Neocodex-Murcia study was funded by the Fundacion Alzheimur (Murcia), the Ministerio de Educacion y Ciencia (Gobierno de Espana), Corporacion Tecnologica de Andalucia, Agencia IDEA (Consejeria de Innovacion, Junta de Andalucia), the Diabetes Research Laboratory, and the Biomedical Research Foundation. University Hospital Clinico San Carlos has been supported by CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM); CIBERDEM is an ISCIII Project.r The ROS/MAP study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984 and U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute.r The TGEN study was supported by Kronos Life Science Laboratories, the National Institute on Aging (Arizona Alzheimer's Disease Center grants P30 AG19610 and RO1 AG023193, the Mayo Clinic Alzheimer's Disease Center grant P50 AG16574, and the Intramural Research Program), the National Alzheimer's Coordinating Center (U01 AG016976), and the state of Arizona.r The authors thank the International Genomics of Alzheimer's Project (IGAP) for providing summary result data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i-Select chip was funded by the French National Foundation on Alzheimer's disease and related disorders. European Alzheimer's Disease Initiative (EADI) was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant, Inserm, Institut Pasteur de Lille, Universite de Lille 2, and the Lille University Hospital. GERAD was supported by the Medical Research Council (grant no. 503480), Alzheimer's Research UK (grant no. 503176), the Wellcome Trust (grant no. 082604/2/07/Z), and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) grant no.; 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA grant R01 AG033193 and the NIA AG081220 and AGES contract N01-AG12100, the NHLBI grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer's Association grant ADGC-10-196728.

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE ε4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p

Importance Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein–cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression. Objective To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia. Design, Setting, and Participants AMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging–Alzheimer’s Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study. Interventions Patients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo. Main Outcomes and Measures The primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale–cognitive subscale. Secondary outcomes included Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population. Results Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo. Conclusions and Relevance Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline. Trial Registration ClinicalTrials.gov identifiers:NCT02245737andNCT02783573

Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P −3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.

The role of genetic risk markers for Alzheimer's disease (AD) in mediating the neurocognitive endophenotypes (NEs) of subjects with mild cognitive impairment (MCI) has rarely been studied. The aim of the present study was to investigate the relationship between well-known AD-associated single-nucleotide polymorphisms (SNPs) and individual NEs routinely evaluated during diagnosis of MCI, AD, and other dementias. The Fundació ACE (ACE) dataset, comprising information from 1245 patients with MCI, was analyzed, including the total sample, amnestic MCI (aMCI) (n = 811), and non-amnestic MCI (naMCI) (n = 434). As probable-MCI (Pr-MCI) patients with memory impairment have a higher risk of AD, which could influence the statistical power to detect genetic associations, the MCI phenotype was also stratified into four related conditions: Pr-aMCI (n = 262), Pr-naMCI (n = 76), possible (Pss)-aMCI (n = 549), and Pss-naMCI (n = 358). Validation analyses were performed using data from the German study on Aging, Cognition, and Dementia in primary care patients (AgeCoDe), and the German Dementia Competence Network (DCN). SNP associations with NEs were calculated in PLINK using multivariate linear regression analysis adjusted for age, gender, and education. In the total MCI sample, APOE-ε4 was significantly associated with the memory function NEs 'delayed recall (DR)' (β = -0.76, p = 4.1 × 10-10), 'learning' (β = -1.35, p = 2.91 × 10-6), and 'recognition memory' (β = -0.58, p = 9.67 × 10-5); and with 'DR' in the aMCI group (β = -0.36, p = 2.96 × 10-5). These results were confirmed by validation in the AgeCoDe (n = 503) and DCN (n = 583) datasets. APOE-ε4 was also significantly associated with the NE 'learning' in individuals classified as having Pss-aMCI (β = -1.37, p = 5.82 × 10-5). Moreover, there was a near study-wide significant association between the HS3ST1 locus (rs6448799) and the 'backward digits' working memory NE (β = 0.52, p = 7.57 × 10-5) among individuals with Pr-aMCI, while the AP2A2 locus (rs10751667) was significantly associated with the language NE 'repetition' (β = -0.19, p = 5.34 × 10-6). Overall, our findings support specific associations of established AD-associated SNPs with MCI NEs.