Differential Psychological Treatment Effects in Patients With Late-Life Depression and a History of Childhood Maltreatment.

OBJECTIVE: This is the first interventional study to assess the impact of childhood maltreatment (CM) on psychological treatment outcomes in patients with late-life depression (LLD). METHODS: This is a secondary analysis of a multicenter, randomized controlled trial with 251 participants aged ≥60 years with moderate to severe depression. Participants were randomly assigned to cognitive behavioral therapy for late life depression (LLD-CBT) or to a supportive intervention (SUI). Treatment outcomes were measured by changes in the Geriatric Depression Scale (GDS). RESULTS: In the intention-to-treat sample (n = 229), both LLD-CBT (n = 115) and SUI (n = 114) significantly reduced depressive symptoms in patients with CM, with large effects at post-treatment (d = 0.95 [95% CI: 0.65 to 1.25] in LLD-CBT; d = 0.82 [95% CI: 0.52 to 1.12] in SUI). A significant treatment group*CM interaction (F(1,201.31) = 4.71; p = .031) indicated greater depressive symptom reduction in LLD-CBT compared to SUI at week 5 and post-treatment for patients without CM, but not at 6-month follow-up. Across both treatments, higher severity of the CM subtype 'physical neglect' was associated with a smaller depressive symptom reduction (F(1,207.16) = 5.37; p = .021). CONCLUSIONS: Specific and non-specific psychotherapy effectively reduced depressive symptoms in older individuals with depression and early trauma. For patients without early trauma, LLD-CBT may be preferable over SUI. Considering early trauma subtypes may contribute to develop personalized treatment approaches.

Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation.

Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (ß-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.

BPSD Patterns in Patients With Severe Neuropsychiatric Disturbances: Insight From the RECAGE Study.

OBJECTIVE: Behavioral and psychological symptoms of dementia (BPSD) profiles vary depending on etiology in patients with mild-to-moderate BPSD. It is not known if similar differences exist in patients with severe BPSD. METHODS: We analyzed data collected at baseline in 398 patients with severe BPSD (NPI ≥ 32) and defined diagnosis of dementia (Alzheimer's disease [AD] 297; frontotemporal dementia [FTD] 39; Lewy body disease/Parkinsonian dementia [LBD/PD] 31; and vascular dementia [VD] 31) included in the European multicenter cohort RECAGE. RESULTS: Mean total NPI was 52.11 (18.55). LBD/PD patients demonstrated more hallucinations, more anxiety and more delusions than patients with other dementia. FTD patients had less delusions and more disinhibition than patients with other neurodegenerative disorders. These profiles overlapped partially with those reported in the literature in patients with less severe symptoms. CONCLUSION: Patients with severe BPSD display different and specific profiles of neuropsychiatric symptoms depending on dementia etiology.

Cognitive Behavioral Therapy for Late-Life Depression (CBTlate): Results of a Multicenter, Randomized, Observer-Blinded, Controlled Trial.

INTRODUCTION: Different psychotherapeutic interventions for late-life depression (LLD) have been proposed, but their evaluation in large, multicenter trials is rare. OBJECTIVE: The present study evaluated the efficacy of a specific cognitive behavioral therapy (CBT) for LLD (LLD-CBT) in comparison with a supportive unspecific intervention (SUI), both administered in a specialist psychiatric outpatient setting. METHODS: In this randomized, controlled, parallel group trial, we recruited participants (≥60 years) with moderate to severe depression at 7 trial sites in Germany. Participants were randomly assigned to the LLD-CBT or SUI group. The primary outcome was depression severity at the end of treatment measured by change on the Geriatric Depression Scale (GDS). Secondary outcomes included change in observer-rated depression, anxiety, sleep ratings, and quality of life throughout the treatment phase and at 6-month follow-up. RESULTS: Between October 1, 2018, and November 11, 2020, we randomly assigned 251 patients to either LLD-CBT (n = 126) or SUI (n = 125), of whom 229 provided primary-outcome data. There was no significant between-group difference in the change in GDS scores at the end of treatment (estimated marginal mean difference: -1.01 [95% CI: -2.88 to 0.86]; p = 0.287). Secondary analyses showed significant improvements in several outcomes after 8 weeks and at follow-up in both treatment arms. CONCLUSIONS: Our data suggest that LLD-specific CBT and a supportive unspecific treatment both provide clinical benefit in patients with moderate to severe LLD without evidence for superiority of LLD-CBT.

Matrix metalloproteinase 10 is linked to the risk of progression to dementia of the Alzheimer's type.

Alzheimer's disease has a long asymptomatic phase that offers a substantial time window for intervention. Using this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer's disease pathology at predementia stages, thus allowing identification of patients who will most probably progress to dementia of the Alzheimer's type and benefit from specific disease-modifying therapies. Consequently, we searched for CSF proteins associated with disease progression along with the clinical disease staging. We measured the levels of 184 proteins in CSF samples from 556 subjective cognitive decline and mild cognitive impairment patients from three independent memory clinic longitudinal studies (Spanish ACE, n = 410; German DCN, n = 93; German Mannheim, n = 53). We evaluated the association between protein levels and clinical stage, and the effect of protein levels on the progression from mild cognitive impairment to dementia of the Alzheimer's type. Mild cognitive impairment subjects with increased CSF level of matrix metalloproteinase 10 (MMP-10) showed a higher probability of progressing to dementia of the Alzheimer's type and a faster cognitive decline. CSF MMP-10 increased the prediction accuracy of CSF amyloid-ß 42 (Aß42), phospho-tau 181 (P-tau181) and total tau (T-tau) for conversion to dementia of the Alzheimer's type. Including MMP-10 to the [A/T/(N)] scheme improved considerably the prognostic value in mild cognitive impairment patients with abnormal Aß42, but normal P-tau181 and T-tau, and in mild cognitive impairment patients with abnormal Aß42, P-tau181 and T-tau. MMP-10 was correlated with age in subjects with normal Aß42, P-tau181 and T-tau levels. Our findings support the use of CSF MMP-10 as a prognostic marker for dementia of the Alzheimer's type and its inclusion in the [A/T/(N)] scheme to incorporate pathologic aspects beyond amyloid and tau. CSF level of MMP-10 may reflect ageing and neuroinflammation.

Global estimates on the number of persons across the Alzheimer's disease continuum.

INTRODUCTION: Global estimates on numbers of persons in early stages of Alzheimer's disease (AD), including prodromal and preclinical, are lacking, yet are needed to inform policy decisions on preventive measures and planning for future therapies targeting AD pathology. METHODS: We synthesized the literature on prevalence across the AD continuum and derived a model estimating the number of persons, stratified by 5-year age groups, sex, and disease stage (AD dementia, prodromal AD, and preclinical AD). RESULTS: The global number of persons with AD dementia, prodromal AD, and preclinical AD were estimated at 32, 69, and 315 million, respectively. Together they constituted 416 million across the AD continuum, or 22% of all persons aged 50 and above. DISCUSSION: Considering predementia stages, the number of persons with AD is much larger than conveyed in available literature. Our estimates are uncertain, especially for predementia stages in low- and middle-income regions where biomarker studies are missing.

Feasibility of a standard cognitive assessment in European academic memory clinics.

INTRODUCTION: Standardized cognitive assessment would enhance diagnostic reliability across memory clinics. An expert consensus adapted the Uniform Dataset (UDS)-3 for European centers, the clinician's UDS (cUDS). This study assessed its implementation acceptability and feasibility. METHODS: We developed a survey investigating barriers, facilitators, and willingness to implement the cUDS. With a mixed-methods design, we analyzed data from academic memory clinics. RESULTS: Seventy-eight percent of responding clinicians were experienced neuropsychologists/psychologists and 22% were medical specialists coming from 18 European countries. Sixty-five percent clinicians were willing to implement cUDS. General barriers related to implementation (43%) and clinical-methodological domains (21%). Favorable clinicians reported finances (15%) and digitalization (9%) as facilitating, but unavailability of local norms (23%) as hindering. Unfavorable clinicians reported logistical (23%) and time issues (18%). DISCUSSION: Despite challenges, data showed moderate clinicians' acceptability and requirements to improve feasibility. Nonetheless, these results come from academic clinicians. The next steps will require feasibility evaluation in non-academic contexts.

Disentangling the relationship of subjective cognitive decline and depressive symptoms in the development of cognitive decline and dementia.

INTRODUCTION: Subjective cognitive decline (SCD) and depressive symptoms (DS) frequently co-occur prior to dementia. However, the temporal sequence of their emergence and their combined prognostic value for cognitive decline and dementia is unclear. METHODS: Temporal relationships of SCD, DS and memory decline were examined by latent difference score modeling in a high-aged, population-based cohort (N = 3217) and validated using Cox-regression of dementia-conversion. In 334 cognitively unimpaired SCD-patients from memory-clinics, we examined the association of DS with cognitive decline and with cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. RESULTS: In the population-based cohort, SCD preceded DS. High DS were associated with increased risk of dementia conversion in individuals with SCD. In SCD-patients from memory-clinics, high DS were associated with greater cognitive decline. CSF Aß42 predicted increasing DS. DISCUSSION: SCD typically precedes DS in the evolution to dementia. SCD-patients from memory-clinics with DS may constitute a high-risk group for cognitive decline. HIGHLIGHTS: Subjective cognitive decline (SCD) precedes depressive symptoms (DS) as memory declines. Emerging or persistent DS after SCD reports predict dementia. In SCD patients, more amyloid pathology relates to increasing DS. SCD patients with DS are at high risk for symptomatic progression.

Apathy in patients with Alzheimer's disease is a cost-driving factor.

BACKGROUND: Apathy is the most frequent neuropsychiatric symptom in patients with dementia of the Alzheimer's type (DAT). We analyzed the influence of apathy on the resource use of DAT patients and their caregivers. METHODS: Included were baseline data of 107 DAT patients from a randomized clinical trial on apathy treatment. The Resource Utilization in Dementia (RUD) instrument assessed costs over a 1-month period prior to baseline. Cost predictors were determined via a least absolute shrinkage and selection operator (LASSO). RESULTS: On average, total monthly costs were €3070, of which €2711 accounted for caregivers' and €359 for patients' costs. An increase of one point in the Apathy Evaluation Scale resulted in a 4.1% increase in total costs. DISCUSSION: Apathy is a significant cost driving factor for total costs in mild to moderate DAT. Effective treatment of apathy might be associated with reduced overall costs in DAT.

Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits.

INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.

[Mild cognitive impairment in geriatric practice: patient orientation, diagnostics, treatment and ethics]. / Leichte kognitive Beeinträchtigung (MCI) in der altersmedizinischen Praxis: Patientenorientierung, Diagnostik, Behandlung und Ethik.

Mild cognitive impairment (MCI) is a common problem in old people, which can be distressing for patients and their families. The main feature of MCI is a decrease in cognitive performance with activities of daily living still unimpaired. The identification of treatable risk factors, recognition of early cognitive changes and a timely differential diagnosis, comprehensive information and counselling are important tasks in geriatric medicine. The aim of this article is to present practical recommendations to support physicians working with geriatric patients in recognizing cognitive deficits at an early stage, provide high-quality care focusing on counselling, treatment, and comorbidity management and to maximize the potential of the available treatment options.

Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.

Amyloid-beta 42 (Aß42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aß42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aß42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

Don't forget about tau: the effects of ApoE4 genotype on Alzheimer's disease cerebrospinal fluid biomarkers in subjects with mild cognitive impairment-data from the Dementia Competence Network.

ApoE4, the strongest genetic risk factor for Alzheimer's disease (AD), has been shown to be associated with both beta-amyloid (Aß) and tau pathology, with the strongest evidence for effects on Aß, while the association between ApoE4 and tau pathology remains inconsistent. This study aimed to investigate the associations between ApoE4 with CSF Aß42, total tau (t-tau), phospho-tau181 (p-tau), and with the progression of decline in a large cohort of MCI subjects, both progressors to AD and other dementias, as well as non-progressors. We analyzed associations of CSF Aß42, p-tau and t-tau with ApoE4 allele frequency cross-sectionally and longitudinally over 3 years of follow-up in 195 individuals with a diagnosis of MCI-stable, MCI-AD converters and MCI progressing to other dementias from the German Dementia Competence Network. In the total sample, ApoE4 carriers had lower concentrations of CSF Aß42, and increased concentrations of t-tau and p-tau compared to non-carriers in a gene dose-dependent manner. Comparisons of these associations stratified by MCI-progression groups showed a significant influence of ApoE4 carriership and diagnostic group on all CSF biomarker levels. The effect of ApoE4 was present in MCI-stable individuals but not in the other groups, with ApoE4 + carriers having decreased CSF Aß 42 levels, and increased concentration of t-tau and p-tau. Longitudinally, individuals with abnormal t-tau and Aß42 had a more rapid progression of cognitive and clinical decline, independently of ApoE4 genotype. Overall, our results contribute to an emerging framework in which ApoE4 involves mechanisms associated with both CSF amyloid-ß burden and tau aggregation at specific time points in AD pathogenesis.

Sensory and motor correlates of frailty: dissociation between frailty phenotype and frailty index.

BACKGROUND: Frailty has been associated with a decline in sensory and motor function. However, given that different frailty measures were shown to overlap but also differ in their diagnostic properties, sensory and motor correlates of frailty might be different depending on the operationalization of frailty. Our objective was to identify sensory and motor determinants of frailty and compare the results between frailty phenotype (FP) and frailty index (FI). METHODS: Data from 44 pre-frail and frail subjects aged 65 and above were used. Frailty was measured using the FP and the FI. Sensory function in the visual, auditory, and tactile domain was assessed using visual acuity, absolute hearing threshold and mechanical detection threshold. Upper extremity motor performance was evaluated by the Purdue Pegboard Test and the Short Physical Performance Battery was used to assess lower extremity motor function. Multiple logistic regression models were employed to determine associations of sensory and motor function with frailty vs. pre-frailty for both frailty measures. RESULTS: The frailty measures were moderately correlated (0.497, p ≤ 0.01) and had a Kappa agreement of 0.467 (p = 0.002). Using the FP, frailty was significantly associated with reduced upper extremity motor function only (OR = 0.50, 95% CI 0.29-0.87, p = 0.014). Frailty as assessed by the FI was significantly related to higher hearing thresholds (OR = 1.21, 95% CI 1.02-1.43, p = 0.027) and reduced lower extremity performance (OR = 0.32, 95% CI 0.13-0.77, p = 0.012). CONCLUSION: Frailty is related to reduced performance in measures of sensory and motor function. However, traditional measures of frailty might be differentially sensitive to capture sensory and motor decline, possibly contributing to the much-observed discordance between the diagnostic instruments. This should be taken into account by researchers and clinicians when planning and evaluating therapeutic interventions for frailty. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666039 . Registered 11 September 2018 - Retrospectively registered.

[The Cost of Early Diagnosis of Cognitive Decline in German Memory Clinics]. / Kosten der Diagnostik kognitiver Störungen in deutschen Gedächtnisambulanzen.

Dementias are expensive diseases: the net annual cost in European healthcare is about € 28.000 per case with a strong stage dependency, of which medical care accounts for about 19%. Diagnostic costs, on the other hand, account for only a small proportion of the total costs. With changes in the guidelines, biomarker tests are becoming increasingly important. At present, the concrete economic impact of biomarker-based diagnosis is largely unknown. To determine the actual costs of diagnostic procedures based on guidelines, we conducted a survey among the members of the German Memory Clinic Network (DNG). From 15 expert centres, the staff engagement time for all procedures was collected. Based on the individual engagement times of the different professions, the total of personnel costs for diagnostics was calculated using current gross personnel costs. The total sum of diagnostic costs (personnel plus procedures) was calculated for three different scenarios e. g. € 633,97 for diagnostics without biomarkers, € 1.214,90 for diagnostics with CSF biomarkers and € 4.740,58 € for diagnostics with FDG- plus Amyloid-PET. In addition, the actual diagnostic costs of the current practice in expert memory clinics were estimated, taking into account personnel costs, costs for the different procedures and the frequency of their use across all patients. This results in total average costs of € 1.394,43 per case as the mean across all centres (personnel costs € 351,72, costs for diagnostic procedures € 1.042,71). The results show that state-of-the-art diagnosis of dementia and pre-dementia states, such as mild cognitive impairment (MCI) requires financial resources, which are currently not fully reimbursed in Germany. The need for a biomarker-based etiological diagnosis of dementia and pre-dementia states will increase, due to availability of disease-modifying treatments. Therefore, the current gap of reimbursement must be filled by new models of compensation.

European Academy of Neurology/European Alzheimer's Disease Consortium position statement on diagnostic disclosure, biomarker counseling, and management of patients with mild cognitive impairment.

BACKGROUND AND PURPOSE: Careful counseling through the diagnostic process and adequate postdiagnostic support in patients with mild cognitive impairment (MCI) is important. Previous studies have indicated heterogeneity in practice and the need for guidance for clinicians. METHODS: A joint European Academy of Neurology/European Alzheimer's Disease Consortium panel of dementia specialists was appointed. Through online meetings and emails, positions were developed regarding disclosing a syndrome diagnosis of MCI, pre- and postbiomarker sampling counseling, and postdiagnostic support. RESULTS: Prior to diagnostic evaluation, motives and wishes of the patient should be sought. Diagnostic disclosure should be carried out by a dementia specialist taking the ethical principles of "the right to know" versus "the wish not to know" into account. Disclosure should be accompanied by written information and a follow-up plan. It should be made clear that MCI is not dementia. Prebiomarker counseling should always be carried out if biomarker sampling is considered and postbiomarker counseling if sampling is carried out. A dementia specialist knowledgeable about biomarkers should inform about pros and cons, including alternatives, to enable an autonomous and informed decision. Postbiomarker counseling will depend in part on the results of biomarkers. Follow-up should be considered for all patients with MCI and include brain-healthy advice and possibly treatment for specific underlying causes. Advice on advance directives may be relevant. CONCLUSIONS: Guidance to clinicians on various aspects of the diagnostic process in patients with MCI is presented here as position statements. Further studies are needed to enable more evidence-based and standardized recommendations in the future.

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

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

Promoting neuroplasticity and neuropsychological functioning in frailty through an app-based sensorimotor training: study protocol for a randomized trial.

BACKGROUND: Frailty is characterized by an age-related decline in multiple physiological systems, leading to a high vulnerability to stressors, adverse health outcomes, and low quality of life. Neuroscientific models of pathological aging emphasize the loss of sensorimotor stimulation and reduced neuromodulatory capacities as core processes in age-related cognitive and bodily decline, which may be associated with maladaptive plastic changes in the brain. We plan to increase sensorimotor stimulation in frail persons through a newly developed app-based training program and link the training trials to biological and psychological correlates of age-associated vulnerability and health indices. METHODS: We will conduct a randomized trial, applying an app-based sensorimotor home training (N = 30) in people suffering from frailty. An app-based relaxation training will serve as an active control condition (N = 30). Both interventions will last for 90 days each. The sensorimotor training includes unimodal and multimodal sensory discrimination tasks in the visual, auditory, and tactile domain, as well as sensorimotor precision tasks. The tasks will be implemented using an adaptive training algorithm and enriched with motivational components embedded in a virtual training environment. We expect a pre-post reduction of frailty status and associated functional decline related to refinement of representational maps within the sensorimotor system and improved sensorimotor function such as extremity function. Secondary analyses will study the influence of BDNF genotype as moderating variable. Additional outcomes will include measures of perceptual and cognitive functioning, quality of life as well as BDNF serum levels. Measurements will take place before training (baseline), after 60 days (assessment 1), and at the end of the training after 90 days (assessment 2). DISCUSSION: In our randomized trial, we aim to characterize a multidimensional concept of frailty and to target maladaptive behaviors and neuroplasticity using an app-based sensorimotor training. This type of intervention might provide further knowledge and new possibilities for preventing decline and preserving function in older adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666039 . Registered 11 September 2018 - Retrospectively registered. Protocol version: Version 4 revised (issue date: 19 May 2021).

Replication study of plasma proteins relating to Alzheimer's pathology.

INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.

[Disease-modifying treatment approaches for Alzheimer's disease]. / Krankheitsmodifizierende Therapieansätze bei Alzheimer-Krankheit.

Alzheimer's disease is one the major common diseases but so far only with symptomatic treatment options. New insights define the disease as a slowly progressive continuum with very long preclinical and early symptomatic phases. Innovative molecular treatment strategies are based on an improved understanding of the molecular neurobiology of the disease, opening up a variety of therapeutic targets. For the first time, an anti-amyloid antibody has been approved in the USA in 2021 as a disease-modifying treatment for Alzheimer's disease, representing a first highly controversial step towards a molecular, cause-oriented treatment. This review presents the most advanced molecular treatment strategies and discusses the implications of the approved antibody treatment for the clinical practice. The special features of this long-term treatment with i.v. infusions in a particularly vulnerable population and a special side effect profile will impose significant challenges for implementation in the practice and will require a high degree of cooperation within the healthcare system. The future of Alzheimer's treatment with a multimodal therapeutic approach with different classes of drugs will probably reinforce these trends.