Multiomics Blood-Based Biomarkers Predict Alzheimer’s Predementia with High Specificity in a Multicentric Cohort Study

High Activities of BACE1 in Brains with Mild Cognitive Impairment

BackgroundUnderstanding the relationship among changes in Clinical Dementia Rating (CDR), patient outcomes, and probability of progression is crucial for evaluating the long-term benefits of disease-modifying treatments. We examined associations among changes in Alzheimer’s disease (AD) stages and outcomes that are important to patients and their care partners including activities of daily living (ADLs), geriatric depression, neuropsychiatric features, cognitive impairment, and the probabilities of being transitioned to a long-term care facility (i.e., institutionalization). We also estimated the total time spent at each stage and annual transition probabilities in AD.MethodsThe study included participants with unimpaired cognition, mild cognitive impairment (MCI) due to AD, and mild, moderate, and severe AD dementia in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) database. The associations among change in AD stages and change in relevant outcomes were estimated using linear mixed models with random intercepts. The probability of transitioning to long-term care facilities was modeled using generalized estimating equations. The total length of time spent at AD stages and annual transition probabilities were estimated with multistate Markov models.ResultsThe estimated average time spent in each stage was 3.2 years in MCI due to AD and 2.2, 2.0, and 2.8 years for mild, moderate, and severe AD dementia, respectively. The annual probabilities of progressing from MCI to mild, moderate, and severe AD dementia were 20, 4, and 0.7%, respectively. The incremental change to the next stage of participants with unimpaired cognition, MCI, and mild, moderate, and severe AD dementia (to death) was 3.2, 20, 26.6, 31, and 25.3%, respectively. Changes in ADLs, neuropsychiatric features, and cognitive measures were greatest among participants who transitioned from MCI and mild AD dementia to more advanced stages. Participants with MCI and mild and moderate AD dementia had increasing odds of being transitioned to long-term care facilities over time during the follow-up period.ConclusionsThe findings demonstrated that participants with early stages AD (MCI or mild dementia) were associated with the largest changes in clinical scale scores. Early detection, diagnosis, and intervention by disease-modifying therapies are required for delaying AD progression. Additionally, estimates of transition probabilities can inform future studies and health economic modeling.

The hippocampus is one of the earliest brain regions affected in Alzheimer's disease (AD) and tests of hippocampal function have the potential to detect AD in its earliest stages. Given that the hippocampus is critically involved in allocentric spatial memory, this study applied a short test of spatial memory, the 4 Mountains Test (4MT), to determine whether test performance can differentiate mild cognitive impairment (MCI) patients with and without CSF biomarker evidence of underlying AD and whether the test can distinguish patients with MCI and mild AD dementia when applied in different cultural settings. Healthy controls (HC), patients with MCI, and mild AD dementia were recruited from study sites in UK and Italy. Study numbers were: HC (UK 20, Italy 10), MCI (UK 21, Italy 14), and AD (UK 11, Italy 9). Nineteen UK MCI patients were grouped into CSF biomarker-positive (MCI+, n = 10) and biomarker-negative (MCI-, n = 9) subgroups. Behavioral data were correlated with hippocampal volume and cortical thickness of the precuneus and posterior cingulate gyrus. Spatial memory was impaired in both UK and Italy MCI and AD patients. Test performance additionally differentiated between MCI+ and MCI- subgroups (P = 0.001). A 4MT score of ≤8/15 was associated with 100% sensitivity and 90% specificity for detection of early AD (MCI+ and mild AD dementia) in the UK population, and with 100% sensitivity and 50% specificity for detection of MCI and AD in the Italy sample. 4MT performance correlated with hippocampal volume in the UK population and cortical thickness of the precuneus in both study populations. In conclusion, performance on a hippocampus-sensitive test of spatial memory differentiates MCI due to AD with high diagnostic sensitivity and specificity. The observation that similar diagnostic sensitivity was obtained in two separate study populations, allied to the scalability and usability of the test in community memory clinics, supports future application of the 4MT in the diagnosis of pre-dementia due to AD.

Objective:The present study aimed to compare the social function between mild cognitive impairment (MCI), mild Alzheimer’s disease (AD) dementia, and mild dementia with Lewy bodies (DLB) using the Japanese version of Social Functioning in Dementia scale (SF-DEM-J).Methods:We interviewed 103 patients and family caregivers from June 2020 to March 2021: 54 patients with MCI, 34 with mild AD dementia, and 15 with mild DLB. We compared the caregiver-rated SF-DEM-J, Clinical Dementia Rating (CDR), MMSE, age, length of education, Geriatric Depression Scale (GDS), the University of California, Los Angeles Loneliness Scale (UCLA-LS), Neuropsychiatric Inventory (NPI), and informant version of the Apathy Evaluation Scale (AES) between MCI, mild AD dementia, and mild DLB groups using Kruskal-Wallis test with Dunn-Bonferroni correction for post-hoc analyses. We compared sex, living situation, and caregiver demographics between three groups using chi-square test. We performed correlation analysis between the score of each psychological test and the scores of SF-DEM-J within group using Spearman’s rank correlation coefficient.Results:For SF-DEM-J, the score of section 2 (communicating with others) was significantly worse in mild AD dementia than in mild DLB. The scores of section 1 (spending with others) and section 3 (sensitivity to others) and the total score did not significantly differ between three groups. The score of section 1 was significantly associated with MMSE in MCI, with anxiety and disinhibition of NPI, and AES in mild AD dementia, and with GDS in mild DLB. The score of section 2 was significantly associated with AES in MCI and mild AD dementia, with UCLA-LS in MCI, and with the length of education in mild DLB. The score of section 3 was significantly associated with agitation and irritability of NPI in MCI and mild AD dementia. The total score was associated with UCLA-LS and AES in MCI, and with AES in mild AD dementia.Conclusion:Factors affecting social functioning differed between MCI, mild AD dementia, and mild DLB. Apathy, agitation and irritability affected social functioning in MCI and mild AD dementia while depressive mood affected social functioning in mild DLB.

To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a work group sponsored by the National Institute on Aging and the Alzheimer's Association, on the diagnosis of very mild and mild Alzheimer disease (AD)dementia. Retrospective review of ratings of functional impairment across diagnostic categories. Alzheimer's Disease Centers and the National Alzheimer's Coordinating Center. Individuals (N=17 535) with normal cognition,MCI, or AD dementia. The functional ratings of individuals with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer's Disease Centers and submitted to the National Alzheimer's Coordinating Center were assessed in accordance with the definition of "functional independence" allowed by the revised criteria. Pairwise demographic differences between the 3 diagnostic groups were tested using t tests for continuous variables and 2 for categorical variables. Almost all (99.8%) individuals currently diagnosed with very mild AD dementia and the large majority(92.7%) of those diagnosed with mild AD dementia could be reclassified as having MCI with the revised criteria,based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home.Large percentages of these individuals with AD dementia also meet the revised "functional independence" criterion for MCI as measured by the Functional Assessment Questionnaire. The categorical distinction between MCI and milder stages of AD dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that "MCI due to AD" represents the earliest symptomatic stage of AD.

Background Souvenaid is a dietary supplement with a patented composition (Fortasyn Connect™)which is intended to be used by people with Alzheimer's disease (AD). It has been designed to support the formation and function of synapses in the brain, which are thought to be strongly correlated with cognitive function. If effective, it might improve symptoms of Alzheimer's disease and also prevent the progression from prodromal Alzheimer's disease to dementia. We sought in this review to examine the evidence for this proposition. Objectives To assess the effects of Souvenaid on incidence of dementia, cognition, functional performance, and safety in people with Alzheimer's disease. Search methods We searched ALOIS, i.e. the specialised register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), Web of Science (ISI Web of Science), Cinahl (EBSCOhost), Lilacs (BIREME), and clinical trials registries up to 24 June 2020. We also reviewed citations of reference lists of landmark papers, reviews, and included studies for additional studies and assessed their suitability for inclusion in the review. Selection criteria We included randomised, placebo-controlled trials which evaluated Souvenaid in people diagnosed with mild cognitive impairment (MCI) due to AD (also termed prodromal AD) or with dementia due to AD, and with a treatment duration of at least 16 weeks. Data collection and analysis Our primary outcome measures were incidence of dementia, global and specific cognitive function, functional performance, combined cognitive-functional outcomes and adverse events. We selected studies, extracted data, assessed the quality of trials and intended to conduct meta-analyses according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of the evidence using the GRADE approach. We present all outcomes grouped by stage of AD. Main results We included three randomised, placebo-controlled trials investigating Souvenaid in 1097 community-dwelling participants with Alzheimer's disease. One study each included participants with prodromal AD, mild AD dementia and mild-to-moderate AD dementia. We rated the risks of bias of all trials as low. One study (in prodromal AD) was funded by European grants. The other two studies were funded by the manufacturer of Souvenaid. One trial investigated the incidence of dementia in people with prodromal AD at baseline, and found little to no difference between the Souvenaid group and the placebo group after 24 months (RR 1.09, 95% CI 0.82 to 1.43; 1 trial, 311 participants; moderate quality of evidence). In prodromal AD, and in mild and mild-to-moderate Alzheimer's disease dementia, Souvenaid probably results in little or no difference in global or specific cognitive functions (moderate quality of evidence). Everyday function, or the ability to perform activities of daily living, were measured in mild and mild-to-moderate AD dementia. Neither study found evidence of a difference between the groups after 24 weeks of treatment (moderate quality of evidence). Two studies investigated combined cognitive-functional outcomes with the Clinical Dementia Rating Sum of Boxes and observed conflicting results. Souvenaid probably results in slight improvement, which is below estimates of meaningful change, in participants with prodromal Alzheimer's disease after 24 months (moderate quality of evidence), but probably has little to no effect in mild-to-moderate Alzheimer's disease dementia after 24 weeks (moderate quality of evidence). Adverse effects observed were low in all trials, and the available data were insufficient to determine any connection with Souvenaid. Authors' conclusions Two years of treatment with Souvenaid probably does not reduce the risk of progression to dementia in people with prodromal AD. There is no convincing evidence that Souvenaid affects other outcomes important to people with AD in the prodromal stage or mild-to-moderate stages of dementia. Conflicting evidence on combined cognitive-functional outcomes in prodromal AD and mild AD dementia warrants further investigation. Adverse effects of Souvenaid seem to be uncommon, but the evidence synthesised in this review does not permit us to make a definitive statement on the long-term tolerability of Souvenaid. The effects of Souvenaid in more severe AD dementia or in people with AD at risk of nutritional deficiencies remain unclear.

Souvenaid is a dietary supplement with a patented composition (Fortasyn Connect™)which is intended to be used by people with Alzheimer's disease (AD). It has been designed to support the formation and function of synapses in the brain, which are thought to be strongly correlated with cognitive function. If effective, it might improve symptoms of Alzheimer's disease and also prevent the progression from prodromal Alzheimer's disease to dementia. We sought in this review to examine the evidence for this proposition. To assess the effects of Souvenaid on incidence of dementia, cognition, functional performance, and safety in people with Alzheimer's disease. We searched ALOIS, i.e. the specialised register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), Web of Science (ISI Web of Science), Cinahl (EBSCOhost), Lilacs (BIREME), and clinical trials registries up to 24 June 2020. We also reviewed citations of reference lists of landmark papers, reviews, and included studies for additional studies and assessed their suitability for inclusion in the review. We included randomised, placebo-controlled trials which evaluated Souvenaid in people diagnosed with mild cognitive impairment (MCI) due to AD (also termed prodromal AD) or with dementia due to AD, and with a treatment duration of at least 16 weeks. Our primary outcome measures were incidence of dementia, global and specific cognitive function, functional performance, combined cognitive-functional outcomes and adverse events. We selected studies, extracted data, assessed the quality of trials and intended to conduct meta-analyses according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of the evidence using the GRADE approach. We present all outcomes grouped by stage of AD. We included three randomised, placebo-controlled trials investigating Souvenaid in 1097 community-dwelling participants with Alzheimer's disease. One study each included participants with prodromal AD, mild AD dementia and mild-to-moderate AD dementia. We rated the risks of bias of all trials as low. One study (in prodromal AD) was funded by European grants. The other two studies were funded by the manufacturer of Souvenaid. One trial investigated the incidence of dementia in people with prodromal AD at baseline, and found little to no difference between the Souvenaid group and the placebo group after 24 months (RR 1.09, 95% CI 0.82 to 1.43; 1 trial, 311 participants; moderate quality of evidence). In prodromal AD, and in mildand mild-to-moderate Alzheimer's disease dementia, Souvenaid probably results in little or no difference in global or specific cognitive functions (moderate quality of evidence). Everyday function, or the ability to perform activities of daily living, were measured in mild and mild-to-moderate AD dementia. Neither study found evidence of a difference between the groups after 24 weeks of treatment (moderate quality of evidence). Two studies investigated combined cognitive-functional outcomes with the Clinical Dementia Rating Sum of Boxes and observed conflicting results. Souvenaid probably results in slight improvement, which is below estimates of meaningful change, in participants with prodromal Alzheimer's disease after 24 months (moderate quality of evidence), but probably has little to no effect in mild-to-moderate Alzheimer's disease dementia after 24 weeks (moderate quality of evidence). Adverse effects observed were low in all trials, and the available data were insufficient to determine any connection with Souvenaid. Two years of treatment with Souvenaid probably does not reduce the risk of progression to dementia in people with prodromal AD. There is no convincing evidence that Souvenaid affects other outcomes important to people with AD in the prodromal stage or mild-to-moderate stages of dementia. Conflicting evidence on combined cognitive-functional outcomes in prodromal AD and mild AD dementia warrants further investigation. Adverse effects of Souvenaid seem to be uncommon, but the evidence synthesised in this review does not permit us to make a definitive statement on the long-term tolerability of Souvenaid. The effects of Souvenaid in more severe AD dementia or in people with AD at risk of nutritional deficiencies remain unclear.

CD34+ progenitor cells as diagnostic and therapeutic targets in Alzheimer's disease.

To the Editor: Alzheimer disease (AD) is the most common form of dementia, and the central pathogenic event is the abnormal accumulation of amyloid β–protein (Aβ) in extracellular amyloid deposits and cerebral blood vessels.1 AD is a complex and genetically heterogeneous disease. Mild cognitive impairment (MCI), a cognitive disorder in the transition between normal cognition and AD, is a known risk factor for AD, with a conversion rate of ≈10% per year.2 Apolipoprotein E (apoE), a lipid transporter, has been found to be contained in amyloid plaques. The apoE4 isoform or APOE e4 allele is associated with the development of AD1 and an increased risk of MCI.3 Cholesterol has also been identified as a risk factor for AD1,4 and MCI.5 A direct role of cholesterol in the pathogenesis of AD has been suggested by studies in transgenic animal models of AD: cholesterol feeding increases Aβ accumulation and accelerates AD-related pathology,6 whereas cholesterol lowering with statin reduces Aβ pathology.7 Although CAD is a prevalent finding in AD,8 whether or not plasma lipoprotein subfractions are associated with MCI and AD has not yet been investigated. The separation and determination of lipoprotein subfractions are generally labor-intensive and time-consuming. Recently, however, the research group of Schmitz and coworkers developed a new automated technique to separate and quantify lipoprotein subfractions in minutes using capillary isotachophoresis (cITP).9,10 Therefore, in the present study, we investigated the associations among lipoprotein subfractions as determined by cITP, apoE phenotype, MCI, and AD. Twenty-eight patients with MCI, 47 patients with AD, and 26 nondemented control subjects were evaluated at the Neurology Department of Fukuoka …

Medical Journey of Patients with Mild Cognitive Impairment and Mild Alzheimer's Disease Dementia: A Cross-sectional Survey of Patients, Care Partners, and Neurologists.

IntroductionAlzheimer’s disease (AD) is a chronic and progressive neurodegenerative disease that places a substantial burden on patients and caregivers. Aducanumab is the first AD therapy approved by the US Food and Drug Administration to reduce a defining pathophysiological feature of the disease, brain amyloid plaques. In the phase 3 clinical trial EMERGE (NCT02484547), aducanumab reduced clinical decline in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia and confirmed amyloid pathology.MethodsWe used a Markov modeling approach to predict the long-term clinical benefits of aducanumab for patients with early AD based on EMERGE efficacy data. In the model, patients could transition between AD severity levels (MCI due to AD; mild, moderate, and severe AD dementia) and care settings (community vs. institution) or transition to death. The intervention was aducanumab added to standard of care (SOC), and the comparator was SOC alone. Data sources for base-case and scenario analyses included EMERGE, published National Alzheimer’s Coordinating Center analyses, and other published literature.ResultsPer patient over a lifetime horizon, aducanumab treatment corresponded to 0.65 incremental patient quality-adjusted life-years (QALYs) and 0.09 fewer caregiver QALYs lost compared with patients treated with SOC. Aducanumab treatment translated to a lower lifetime probability of transitioning to AD dementia, a lower lifetime probability of transitioning to institutionalization (25.2% vs. 29.4%), delays in the median time to transition to AD dementia (7.50 vs. 4.92 years from MCI to moderate AD dementia or worse), and an incremental median time in the community of 1.32 years compared with SOC.ConclusionThe model predicted long-term benefits of aducanumab treatment in patients with MCI due to AD and mild AD dementia and their caregivers. The predicted outcomes provide a foundation for healthcare decision-makers and policymakers to understand the potential clinical and socioeconomic value of aducanumab.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00273-0.

BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is up‐regulated in activated microglia related neuroinflammation in Alzheimer’s disease (AD). Most magnetic resonance spectroscopy (MRS) studies consistently demonstrated neuroinflammatory changes with elevated glial marker myoinositol (MI) or MI/total creatine (tCr) and lower levels of neuronal marker N‐acetylasparate (NAA) or NAA/tCr in patients with AD. We propose that the higher systemic TREM2 expression measured by TREM2 mRNA expression in peripheral blood might be associated with the neuroinflammatory marker in MRS.MethodWe recruited subjects with mild cognitive impairment (MCI) and dementia due to AD from two teaching hospitals in Taiwan. All of the subjects underwent clinically functional assessments and a neuropsychological test battery. Quantitative estimates of TREM2 mRNA and the soluble form of TREM2 (an alternatively spliced TREM2 transcript (TREM2alt)) mRNA levels were measured. Proton magnetic resonance spectroscopy (MRS) was performed by using a 2 × 2 × 2 cm3 voxel situated in the midsagittal posterior cingulate cortex (PCC)/precuneus region. We analyzed the association between MRS and peripheral TREM2 mRNA expression.ResultIn total, 15 MCI patients and 26 AD patients were recruited. The mean age of MCI and AD patients was 72.1 ± 6.0 and 76.7 ± 7.6 years. The mean MMSE score was 25.8 ± 2.1 in MCI patients and 20.8 ± 3.4 in AD patients. The percentage of apolipoprotein (APOE) ɛ4 carrier status in MCI and AD patients was 21.4% and 38.5%. The correlation analysis showed the TREM2alt mRNA expression level was associated with MI/tCr at PCC in AD (r = ‐0.68, p < 0.001) and MCI (r = ‐0.63, p = 0.013) subjects, but TREM2 mRNA expression was not.ConclusionThe TREM2alt mRNA expression is associated with the MI/tCr at PCC in both AD and MCI patients, which suggested the peripheral soluble TREM2 expression might reflect the central neuroinflammatory changes in AD patients.

Mild cognitive impairment (MCI) is a clinical concept that categorizes subjects who are in an intermediate cognitive state between normal aging and dementia. The aims of this study are to determine the prevalence of significant depressive symptoms in MCI and Alzheimer's disease (AD) patients and to characterize the behavior associated with significant depressive symptoms in MCI and AD patients. A cross-sectional analysis of baseline data from a prospective, longitudinal study on behavioral symptoms of dementia and MCI was performed. The study population consisted of 270 MCI and 402 AD patients. Behavioral assessment was performed by means of Middelheim Frontality Score, Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) and Cohen-Mansfield Agitation Inventory. The presence of significant depressive symptoms was defined as a Cornell Scale for Depression in Dementia total score >7. The prevalence of significant depressive symptoms in AD patients (25%) was higher compared with MCI patients (16%) (p = 0.005). Patients with significant depressive symptoms showed an increased severity of frontal lobe symptoms, behavioral symptoms and agitation (Middelheim Frontality Score, Behave-AD and Cohen-Mansfield Agitation Inventory total scores; p < 0.001). Also, most of the individual frontal lobe and behavioral symptoms were more prevalent and severe, resulting in higher Behave-AD global scores. Mild cognitive impairment patients with depressive symptoms showed more severe behavioral symptoms and more severe verbally agitated behavior than AD patients without depressive symptoms (p < 0.001). Frontal lobe and behavioral symptoms are more prevalent and severe in MCI and AD patients with significant depressive symptoms as compared with patients without depressive symptoms.

Peripheral blood mononuclear cells from mild cognitive impairment patients show deregulation of Bax and Sod1 mRNAs

Aducanumab and the “post-amyloid” era of Alzheimer research?