Presymptomatic Alzheimer's Disease Research Articles

A Strategy for Allowing Earlier Diagnosis and Rigorous Evaluation of BACE1 Inhibitors in Preclinical Alzheimer's Disease.

Given continued failure of BACE1 inhibitor programs at symptomatic and prodromal stages of Alzheimer's disease (AD), clinical trials need to target the earlier preclinical stage. However, trial design is complex in this population with negative diagnosis of classical hippocampal amnesia on standard memory tests. Besides recent advances in brain imaging, electroencephalogram, and fluid-based biomarkers, new cognitive markers should be established for earlier diagnosis that can optimize recruitment to BACE1 inhibitor trials in presymptomatic AD. Notably, accelerated long-term forgetting (ALF) is emerging as a sensitive cognitive measure that can discriminate between asymptomatic individuals with high risks for developing AD and healthy controls. ALF is a form of declarative memory impairment characterized by increased forgetting rates over longer delays (days to months) despite normal storage within the standard delays of testing (20-60 min). Therefore, ALF may represent a harbinger of preclinical dementia and the impairment of systems memory consolidation, during which memory traces temporarily stored in the hippocampus become gradually integrated into cortical networks. This review provides an overview of the utility of ALF in a rational design of next-generation BACE1 inhibitor trials in preclinical AD. I explore potential mechanisms underlying ALF and relevant early-stage biomarkers useful for BACE1 inhibitor evaluation, including synaptic protein alterations, astrocytic dysregulation and neuron hyperactivity in the hippocampal-cortical network. Furthermore, given the physiological role of the isoform BACE2 as an AD-suppressor gene, I also discuss the possible association between the poor selectivity of BACE1 inhibitors and their side effects (e.g., cognitive worsening) in prior clinical trials.

A Novel Peptide Driving Neurodegeneration Appears Exclusively Linked to the α7 Nicotinic Acetylcholine Receptor.

T14, a 14mer peptide, is significantly increased in the pre-symptomatic Alzheimer's disease brain, and growing evidence implies its pivotal role in neurodegeneration. Here, we explore the subsequent intracellular events following binding of T14 to its target α7 nicotinic acetylcholine receptor (nAChR). Specifically, we test how various experimental manipulations of PC12 cells impact T14-induced functional outcomes. Three preparations were compared: (i) undifferentiated vs. NGF-differentiated cells; (ii) cells transfected with an overexpression of the target α7 nAChR vs. wild type cells; (iii) cells transfected with a mutant α7 nAChR containing a mutation in the G protein-binding cluster, vs. cells transfected with an overexpression of the target α7 nAChR, in three functional assays - calcium influx, cell viability, and acetylcholinesterase release. NGF-differentiated PC12 cells were less sensitive than undifferentiated cells to the concentration-dependent T14 treatment, in all the functional assays performed. The overexpression of α7 nAChR in PC12 cells promoted enhanced calcium influx when compared with the wild type PC12 cells. The α7345-348A mutation effectively abolished the T14-triggered responses across all the readouts observed. The close relationship between T14 and the α7 nAChR was further evidenced in the more physiological preparation of ex vivo rat brain, where T30 increased α7 nAChR mRNA, and finally in human brain post-mortem, where levels of T14 and α7 nAChR exhibited a strong correlation, reflecting the progression of neurodegeneration. Taken together these data would make it hard to account for T14 binding to any other receptor, and thus interception at this binding site would make a very attractive and remarkably specific therapeutic strategy.

BDNF Val66Met moderates episodic memory decline and tau biomarker increases in early sporadic Alzheimer's disease.

Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been shown to moderate rates of cognitive decline in preclinical sporadic Alzheimer's disease (AD; i.e., Aβ + older adults), and pre-symptomatic autosomal dominant Alzheimer's disease (ADAD). In ADAD, Met66 was also associated with greater increases in CSF levels of total-tau (t-tau) and phosphorylated tau (p-tau181). This study sought to determine the extent to which BDNF Val66Met is associated with changes in episodic memory and CSF t-tau and p-tau181 in Aβ + older adults in early-stage sporadic AD. Aβ + Met66 carriers (n = 94) and Val66 homozygotes (n = 192) enrolled in the Alzheimer's Disease Neuroimaging Initiative who did not meet criteria for AD dementia, and with at least one follow-up neuropsychological and CSF assessment, were included. A series of linear mixed models were conducted to investigate changes in each outcome over an average of 2.8years, covarying for CSF Aβ42, APOE ε4 status, sex, age, baseline diagnosis, and years of education. Aβ + Met66 carriers demonstrated significantly faster memory decline (d = 0.33) and significantly greater increases in CSF t-tau (d = 0.30) and p-tau181 (d = 0.29) compared to Val66 homozygotes, despite showing equivalent changes in CSF Aβ42. These findings suggest that reduced neurotrophic support, which is associated with Met66 carriage, may increase vulnerability to Aβ-related tau hyperphosphorylation, neuronal dysfunction, and cognitive decline even prior to the emergence of dementia. Additionally, these findings highlight the need for neuropsychological and clinicopathological models of AD to account for neurotrophic factors and the genes which moderate their expression.

Choriocapillaris and Retinal Vascular Alterations in Presymptomatic Alzheimer's Disease.

To compare optical coherence tomography angiography (OCTA) retina metrics between cognitively healthy subjects with pathological versus normal cerebrospinal fluid (CSF) Aβ42/tau ratios. Swept-source OCTA scans were collected using the Zeiss PLEX Elite 9000 and analyzed on 23 cognitively healthy (CH) subjects who had previously undergone CSF analysis. Thirteen subjects had a pathological Aβ42/tau (PAT) ratio of <2.7132, indicative of presymptomatic Alzheimer's disease (AD), and 10 had a normal Aβ42/tau (NAT) ratio of ≥2.7132. OCTA en face images of the superficial vascular complex (SVC) and deep vascular complex were binarized and skeletonized to quantify the perfusion density (PD), vessel length density (VLD), and fractal dimension (FrD). The foveal avascular zone (FAZ) area was calculated using the SVC slab. Choriocapillaris flow deficits (CCFDs) were computed from the en face OCTA slab of the CC. The above parameters were compared between CH-PATs and CH-NATs. Compared to CH-NATs, CH-PATs showed significantly decreased PD, VLD, and FrD in the SVC, with a significantly increased FAZ area and CCFDs. Swept-source OCTA analysis of the SVC and CC suggests a significant vascular loss at the CH stage of pre-AD that might be an indicator of a neurodegenerative process initiated by the impaired clearance of Aβ42 in the blood vessel wall and by phosphorylated tau accumulation in the perivascular spaces, a process that most likely mirrors that in the brain. If confirmed in larger longitudinal studies, OCTA retinal and inner choroidal metrics may be important biomarkers for assessing presymptomatic AD.

Validation of the "Perceptions Regarding pRE-Symptomatic Alzheimer's Disease Screening" (PRE-ADS) Questionnaire in the German Population: Attitudes, Motivations, and Barriers to Pre-Symptomatic Dementia Screening.

Attitudes, motivations, and barriers to pre-symptomatic screening for Alzheimer's disease (AD) in the general population are unclear, and validated measurement tools are lacking. Translation and validation of the German version of the "Perceptions regarding pRE-symptomatic Alzheimer's Disease Screening" (PRE-ADS) questionnaire. A convenience sample (N = 256) was recruited via an online platform. Validation of the PRE-ADS-D consisted of assessments of reliability, structural validity using Principal Component Analysis (PCA) and Exploratory Factor Analysis (EFA) and construct validity using known-group tests. A subscale "Acceptability of Screening", with 5 PRE-ADS-D items, was extracted to measure acceptance of screening in clinical practice. The STROBE checklist was used for reporting. EFA revealed a three-factor model for the PRE-ADS-D. Acceptable to good internal consistency was found for the 25-item scale (α= 0.78), as well as for the three factors "Concerns about Screening" (α= 0.85), "Intention to be Screened" (α= 0.87), and "Preventive Health Behaviors" (α= 0.81). Construct validity was confirmed for both the 25-item PRE-ADS-D and the "Acceptability of Screening" scale (α= 0.91). Overall, 51.2% of the participants showed a preference for screening. Non-parametric tests were conducted to further explore group differences of the sample. The PRE-ADS-D is a reliable and valid tool to measure attitudes, motives, and barriers regarding pre-symptomatic dementia screening in the German-speaking general population. Additionally, the subscale "Acceptability of Screening" demonstrated good construct validity and reliability, suggesting its promising potential as a practical tool in clinical practice.

Attitudes of Family Members and Caregivers Regarding Alzheimer's Disease Pre-Symptomatic Screening.

In recent years, studies have examined the acceptability and attitudes that influence the intention to early screen for Alzheimer's disease (AD) in the general population, older people, carers, and asymptomatic individuals who report a family history of AD. However, it remains unclear what specific factors promote or reduce the acceptability of pre-symptomatic screening. The aim of this study is to explore the attitudes of family and non-family members as well as caregivers and non-caregivers toward the pre-symptomatic screening of AD. A total of 213 participants completed the Perceptions regarding pRE-symptomatic Alzheimer's Disease Screening (PRE-ADS) Questionnaire. Group comparisons using t-test and one-way ANOVA were used to examine differences in attitudes toward pre-symptomatic screening regarding age, family history, knowing someone with AD, influence of depression, and feelings of anxiety. The subscale "Acceptability of Screening" was developed to investigate the willingness to undergo pre-symptomatic screening. Participants with a family history showed greater acceptance of pre-symptomatic screening while both caregivers and non-caregivers had similar attitudes. People with a family history as well as those with personal connections to dementia indicate a greater need for knowledge. The findings suggest that younger adults appear to perceive less harm from testing, whereas those who experience higher levels of anxiety and depression seem to perceive more testing harms. Comparing the attitudes of people with and without a family history as well as caregivers and non-caregivers toward pre-symptomatic screening of AD is critical to understand the differences between these groups and develop comprehensive screening programs.

Front Cover Image

ON THE FRONT COVER: Localization of tau phosphorylated at S217 (a biomarker for early, presymptomatic Alzheimer's disease), MAP2 (neuronal soma and dendrite marker) and PSD95 (dendritic spine marker), in green, red and purple respectively.Credit: Binita Rajbanshi (UCSF; formerly University of Virginia) and George Bloom (University of Virginia).image

Alzheimer's disease biomarker utilization at first referral enhances differential diagnostic precision with simultaneous exclusion of Creutzfeldt-Jakob disease.

Most suspected Creutzfeldt-Jakob disease (CJD) cases are eventually diagnosed with other disorders. We assessed the utility of investigating Alzheimer's disease (AD) biomarkers and neurofilament light (NfL) in patients when CJD is suspected. The study cohort consisted of cerebrospinal fluid (CSF) samples referred for CJD biomarker screening wherein amyloid beta 1-42 (Aβ1-42), phosphorylated tau 181 (p-tau181), and total tau (t-tau) could be assessed via Elecsys immunoassays (n=419) and NfL via enzyme-linked immunosorbent assay (ELISA; n=161). In the non-CJD sub cohort (n=371), 59% (219/371) had A+T- (abnormal Aβ1-42 only) and 21% (79/371) returned A+T+ (abnormal Aβ1-42 and p-tau181). In the 48 CJD subjects, a similar AD biomarker profile distribution was observed. To partially address the prevalence of likely pre-symptomatic AD, NfL was utilized to assess for neuronal damage. NfL was abnormal in 76% (25/33) of A+T- subjects 40 to 69 years of age, 80% (20/25) of whom had normal t-tau. This study reinforces AD as an important differential diagnosis of suspected CJD, highlighting that incorporating AD biomarkers and NfL at initial testing is worthwhile.

Attitudes toward pre-symptomatic screening for Alzheimer's dementia in five European countries: a comparison of family members of people with Alzheimer's dementia versus non-family members.

Introduction: Pre-symptomatic screening is getting more attention in healthcare as it detects the risk for developing neurodegenerative diseases like Alzheimer's disease (AD), which is very useful for treatment or prevention. AD screening could play an important role in individuals with at least one affected first-degree relative, but also without family history. As the demand for screening is rising worldwide, it is important to consider possible cross-cultural differences in attitudes toward pre-symptomatic screening in order to tailor healthcare services to the needs of each country. Objective: This study aims to investigate the attitudes of family members and non-family members of people with dementia toward pre-symptomatic screening and explore possible differences in attitudes across five European countries (Belgium, Germany, Greece, Spain, Turkey) using translated versions of the "Perceptions regarding pRE-symptomatic Alzheimer's Disease Screening" questionnaire (PRE-ADS). Methods: The multicultural sample (N = 650) was recruited from samples that were previously used in validation studies of the translated PRE-ADS versions. The subscale "Acceptability of Screening", consisting of five PRE-ADS items to specifically explore willingness to undergo screening, was created. Ιnternal consistency was measured, and structural validity was determined using Confirmatory Factor Analysis (CFA). Group comparisons were performed to investigate differences in attitudes toward pre-symptomatic AD screening regarding family history and country of origin using the PRE-ADS and the "Acceptability of Screening" mean scores. Results: Construct validity was acceptable for the PRE-ADS. Both the PRE-ADS (α = 0.76) and its subscale "Acceptability of Screening" (α = 0.90) had good internal consistency. Overall, 56.9% of the total sample expressed a positive intention toward pre-symptomatic AD screening. T-tests showed significantly higher mean scores of participants with an affected family member. An international comparison revealed differences in the "Acceptability of Screening" mean score across the five European countries. No cross-cultural differences were found for the PRE-ADS mean score after adjusting for confounding variables. Conclusion: The PRE-ADS and its subscale are reliable tools for assessing pre-symptomatic AD screening attitudes. Variations in the acceptability of screening seem to be linked to family history and cultural influences. Further research with larger samples is needed to explore underlying relationships.

Attitudes, Motivations, and Barriers to Pre-Symptomatic Alzheimer's Disease Screening: Development and Validation of the 'Perceptions regarding pRE-symptomatic Alzheimer's Disease Screening' (PRE-ADS) Questionnaire.

Pre-symptomatic screening methods for detecting a higher risk of Alzheimer's disease (AD) are gaining popularity; thus, more people are seeking these tests. However, to date, not much is known about the attitudes toward pre-symptomatic AD screening. The goal of this study is to examine the psychometric properties of a tool for assessing the attitudes, barriers, and motivations to pre-symptomatic AD screening. This is a cross-sectional study performed on 208 Greek participants (189 students and 19 caregivers) provided with an online questionnaire. Psychometric properties were assessed through the examination of its construct validity (principal component analysis) and internal consistency. Exploratory factor analysis revealed the presence of four factors. The first factor is labeled as "Perceived harms of testing" (10 items), the second "Acceptance of testing" (5 items), the third "Perceived benefits of testing" (6 items), and the fourth factor "Need for knowledge" (4 items). The reliability (internal consistency) of each factor separately was acceptable to good (0.70-0.87) while the internal consistency of the overall questionnaire (25 items) was good (Cronbach's α=0.82). PRE-ADS is a valid questionnaire that might help in the research of peoples' attitudes related to the pros and cons of pre-symptomatic screening for AD, and the development of effective counseling programs and prevention strategies. However, future research is required in the target population.

Anesthesia-induced hippocampal-cortical hyperactivity and tau hyperphosphorylation impair remote memory retrieval in Alzheimer's disease.

Anesthesia often exacerbates memory recall difficulties in individuals with Alzheimer's disease (AD), but the underlying mechanisms remain unclear. We used in vivo Ca2+ imaging, viral-based circuit tracing, and chemogenetic approaches to investigate anesthesia-induced remote memory impairment in mouse models of presymptomatic AD. Our study identified pyramidal neuron hyperactivity in the anterior cingulate cortex (ACC) as a significant contributor to anesthesia-induced remote memory impairment. This ACC hyperactivation arises from the disinhibition of local inhibitory circuits and increased excitatory inputs from the hippocampal CA1 region. Inhibiting hyperactivity in the CA1-ACC circuit improved memory recall after anesthesia. Moreover, anesthesia led to increased tau phosphorylation in the hippocampus, and inhibiting this hyperphosphorylation prevented ACC hyperactivity and subsequent memory impairment. Hippocampal-cortical hyperactivity plays a role in anesthesia-induced remote memory impairment. Targeting tau hyperphosphorylation shows promise as a therapeutic strategy to mitigate anesthesia-induced neural network dysfunction and retrograde amnesia in AD.

Cerebellar EEG source localization reveals age-related compensatory activity moderated by genetic risk for Alzheimer's disease.

The apolipoprotein-E (APOE) ε4 allele is the greatest genetic risk factor for late-onset Alzheimer's disease (AD), but alone it is not sufficiently predictive. Because neuropathological changes associated with AD begin decades before cognitive symptoms, neuroimaging of healthy, cognitively intact ε4 carriers (ε4+) may enable early characterization of patterns associated with risk for future decline. Research in the cerebral cortex highlights a period of compensatory recruitment in elders and ε4+, which serves to maintain cognitive functioning. Yet, AD-related changes may occur even earlier in the cerebellum. Advances in electroencephalography (EEG) source localization now allow effective modeling of cerebellar activity. Importantly, healthy aging and AD are associated with declines in both cerebellar functions and executive functioning (EF). However, it is not known whether cerebellar activity can detect pre-symptomatic AD risk. Thus, the current study analyzed cerebellar EEG source localization during an EF-dependent stop-signal task (i.e., inhibitory control) in healthy, intact older adults (Mage = 80 years; 20 ε4+, 25 ε4-). Task performance was comparable between groups. Older age predicted greater activity in left crus II and lobule VIIb during the P300 window (i.e., performance evaluation), consistent with age-related compensation. Age*ε4 moderations specifically showed that compensatory patterns were evident only in ε4-, suggesting that cerebellar compensatory resources may already be depleted in healthy ε4+ elders. Thus, the posterolateral cerebellum is sensitive to AD-related neural deficits in healthy elders. Characterization of these patterns may be essential for the earliest possible detection of AD risk, which would enable critical early intervention prior to symptom onset.

A history of repeated alcohol intoxication promotes cognitive impairment and gene expression signatures of disease progression in the 3xTg mouse model of Alzheimer's disease.

The impact of alcohol abuse on Alzheimer's disease (AD) is poorly understood. Here, we show that the onset of neurocognitive impairment in a mouse model of AD is hastened by repeated alcohol intoxication through exposure to alcohol vapor, and we provide a comprehensive gene expression dataset of the prefrontal cortex by the single-nucleus RNA sequencing of 113,242 cells. We observed a broad dysregulation of gene expression that involves neuronal excitability, neurodegeneration, and inflammation, including interferon genes. Several genes previously associated with AD in humans by genome-wide association studies were differentially regulated in specific neuronal populations. Gene expression patterns of AD mice with a history of alcohol intoxication were more similar to gene expression signatures of older AD mice with more advanced disease and cognitive impairment than those of younger AD mice with prodromic disease, suggesting that alcohol promotes transcriptional changes consistent with AD progression. Our gene expression dataset at the single-cell level provides a unique resource for investigations of the molecular bases of the detrimental role of excessive alcohol intake in AD.Significance statementAlzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Many efforts have been geared toward the identification of environmental and genetic risk factors. However, alcohol has received limited attention as a potential risk factor for AD. We explored effects of the interaction of a history of alcohol intoxication with genetic AD susceptibility on cognitive performance and gene expression at the single-cell level. We found that a history of repeated alcohol intoxication promotes the emergence of spatial learning and memory impairments in pre-symptomatic triple transgenic AD (3xTg-AD) mice. We also show that a history of repeated alcohol intoxication induces prefrontal cortex transcriptional changes associated with AD progression.

Blood biomarkers for Alzheimer's disease in clinical practice and trials.

Blood-based biomarkers hold great promise to revolutionize the diagnostic and prognostic work-up of Alzheimer's disease (AD) in clinical practice. This is very timely, considering the recent development of anti-amyloid-β (Aβ) immunotherapies. Several assays for measuring phosphorylated tau (p-tau) in plasma exhibit high diagnostic accuracy in distinguishing AD from all other neurodegenerative diseases in patients with cognitive impairment. Prognostic models based on plasma p-tau levels can also predict future development of AD dementia in patients with mild cognitive complaints. The use of such high-performing plasma p-tau assays in the clinical practice of specialist memory clinics would reduce the need for more costly investigations involving cerebrospinal fluid samples or positron emission tomography. Indeed, blood-based biomarkers already facilitate identification of individuals with pre-symptomatic AD in the context of clinical trials. Longitudinal measurements of such biomarkers will also improve the detection of relevant disease-modifying effects of new drugs or lifestyle interventions.

Early Detection of Alzheimer's Disease-Related Pathology Using a Multi-Disease Diagnostic Platform Employing Autoantibodies as Blood-Based Biomarkers.

Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer's disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis. To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages. A total of 328 serum samples from multiple cohorts, including ADNI subjects with confirmed pre-symptomatic, prodromal, and mild-moderate AD, were screened using Luminex xMAP® technology to predict the probability of the presence of AD-related pathology. A panel of eight autoantibodies with age as a covariate was evaluated using randomForest and receiver operating characteristic (ROC) curves. Autoantibody biomarkers alone predicted the probability of the presence of AD-related pathology with 81.0% accuracy and an area under the curve (AUC) of 0.84 (95% CI = 0.78-0.91). Inclusion of age as a parameter to the model improved the AUC (0.96; 95% CI = 0.93-0.99) and overall accuracy (93.0%). Blood-based autoantibodies can be used as an accurate, non-invasive, inexpensive, and widely accessible diagnostic screener for detecting AD-related pathology at pre-symptomatic and prodromal AD stages that could aid clinicians in diagnosing AD.

Plasma phosphorylated tau 217 in preclinical Alzheimer's disease.

An accurate blood test for Alzheimer's disease that is sensitive to preclinical proteinopathy and cognitive decline has clear implications for early detection and secondary prevention. We assessed the performance of plasma phosphorylated tau 217 ( ) against brain PET markers of amyloid [ -labelled Pittsburgh compound B (PiB)] and tau ( MK-6240) and its utility for predicting longitudinal cognition. Samples were analysed from a subset of participants with up to 8 years follow-up in the Wisconsin Registry for Alzheimer's Prevention (WRAP; 2001-present; plasma 2011-present), a longitudinal cohort study of adults from midlife, enriched for parental history of Alzheimer's disease. Participants were a convenience sample who volunteered for at least one PiB scan, had usable banked plasma and were cognitively unimpaired at first plasma collection. Study personnel who interacted with participants or samples were blind to amyloid status. We used mixed effects models and receiver-operator characteristic curves to assess concordance between plasma and PET biomarkers of Alzheimer's disease and mixed effects models to understand the ability of plasma to predict longitudinal performance on WRAP's preclinical Alzheimer's cognitive composite (PACC-3). The primary analysis included 165 people (108 women; mean age = 62.9 6.06; 160 still enrolled; 2 deceased; 3 discontinued). Plasma was strongly related to PET-based estimates of concurrent brain amyloid ( = 0.83 (0.75, 0.90), P < 0.001). Concordance was high between plasma and both amyloid PET (area under the curve = 0.91, specificity = 0.80, sensitivity = 0.85, positive predictive value = 0.58, negative predictive value = 0.94) and tau PET (area under the curve = 0.95, specificity = 1, sensitivity = 0.85, positive predictive value = 1, negative predictive value = 0.98). Higher baseline levels were associated with worse cognitive trajectories ( = -0.07 (-0.09, -0.06), P < 0.001). In a convenience sample of unimpaired adults, plasma levels correlate well with concurrent brain Alzheimer's disease pathophysiology and with prospective cognitive performance. These data indicate that this marker can detect disease before clinical signs and thus may disambiguate presymptomatic Alzheimer's disease from normal cognitive ageing.

Improving community health-care systems' early detection of cognitive decline and dementia.

Preliminary estimates suggest that current global health-care systems lack the resource capacity to provide persons with dementia timely access to diagnosis, treatment, and care. There is an increasing need to improve timely identification of individuals who will likely progress to Alzheimer's disease (AD) dementia particularly among under-represented, underserved, and vulnerable populations. The rapidly evolving area of bioinformatics of health system data and the emergence of fluid-based biomarkers for pre-symptomatic AD may provide an innovative strategic option for health system planners. A think-tank style meeting entitled "The Campaign to Prevent Alzheimer's Disease Work Group on Community-Based Detection and Assessment of Cognitive Decline" developed recommendations to guide future sustainability activities, public policy campaigns, and implementation pilots. The group identified and explored different pathways of community-based detection using electronic health records, from different international health-care systems, to detect and surveil individuals with early possible cognitive impairment.

Novel Ultrasensitive Detection Technologies for the Identification of Early and Minimally Invasive Alzheimer's Disease Blood Biomarkers.

Single molecule array (SIMOA) and other ultrasensitive detection technologies have allowed the determination of blood-based biomarkers of Alzheimer's disease (AD) for diagnosis and monitoring, thereby opening up a promising field of research. To review the published bibliography on plasma biomarkers in AD using new ultrasensitive techniques. A systematic review of the PubMed database was carried out to identify reports on the use of blood-based ultrasensitive technology to identify biomarkers for AD. Based on this search, 86 works were included and classified according to the biomarker determined. First, plasma amyloid-β showed satisfactory accuracy as an AD biomarker in patients with a high risk of developing dementia. Second, plasma t-Tau displayed good sensitivity in detecting different neurodegenerative diseases. Third, plasma p-Tau was highly specific for AD. Fourth, plasma NfL was highly sensitive for distinguishing between patients with neurodegenerative diseases and healthy controls. In general, the simultaneous determination of several biomarkers facilitated greater accuracy in diagnosing AD (Aβ42/Aβ40, p-Tau181/217). The recent development of ultrasensitive technology allows the determination of blood-based biomarkers with high sensitivity, thus facilitating the early detection of AD through the analysis of easily obtained biological samples. In short, as a result of this knowledge, pre-symptomatic and early AD diagnosis may be possible, and the recruitment process for future clinical trials could be more precise. However, further studies are necessary to standardize levels of blood-based biomarkers in the general population and thus achieve reproducible results among different laboratories.

Exploring the Efficacy of Anti-amyloid-β Therapeutics in Treating Alzheimer Disease

Alzheimer Disease (AD) is the most prevalent cause of dementia, characterized by initial memory impairment and progressive cognitive decline. The exact cause of AD is not yet completely understood. However, the presence of neurotoxic amyloid-beta (Aβ) peptides in the brain is often cited as the main causative agent in AD pathogenesis. In accordance with the amyloid hypothesis, Aβ accumulation initially occurs 15-20 years prior to the development of clinical symptoms. Current therapies focus on the prodromal and preclinical stages of AD due to past treatment failures involving patients with mild to moderate AD. Passive immunization via exogenous monoclonal antibodies (mAbs) administration has emerged as a promising anti-Aβ treatment in AD. This is reinforced by the recent approval of the mAb, aducanumab. mAbs have differential selectivity in their epitopes, each recognising different conformations of Aβ. In this way, various Aβ accumulative species can be targeted. mAbs directed against Aβ oligomers, the most neurotoxic species, are producing encouraging clinical results. Through understanding the process by which mAbs target the amyloid cascade, therapeutics could be developed to clear Aβ, prevent its aggregation, or reduce its production. This review examines the clinical efficacy evidence from previous clinical trials with anti-Aβ therapeutics, in particular, the mAbs. Future therapies are expected to involve a combined-targeted approach to the multiple mechanisms of the amyloid cascade in a particular stage or disease phenotype. Additional studies of presymptomatic AD will likely join ongoing prevention trials, in which mAbs will continue to serve as the focal point.

Multi-omics data integration reveals clinically meaningful molecular profiles of Alzheimer disease.

Alzheimer disease (AD) is a complex polygenic disease in which multiple molecular pathways and biological processes are affected in distinct cell-types of the brain. Increasingly, novel machine learning approaches have been applied in other areas of similarly high complexity (e.g., cancer) to integrate different modalities of "-omics" data and provide novel insights. We sought to apply high-throughput "multi-omics" and machine learning approaches to a large assembly of clinically and neuropathologically well-characterized brain samples to identify genes and biological pathways that may lead to new biomarkers and therapies for AD. We analyzed high-throughput transcriptomics, proteomics, metabolomics and lipidomics profiles of postmortem parietal cortex samples from the Knight ADRC (n=328) and the DIAN (n =21) participants including APP, PSEN1 and PSEN2 autosomal dominant AD mutation carriers (ADAD, n=28), sporadic AD (sAD, n=282), presymptomatic AD (preAD, n=14), and controls with minimal neuropathologic changes (n=25). We applied a Bayesian integrative clustering method (iClusterBayes), designed to identify disease subtypes, to cluster sAD samples on the basis of 2,676 transcripts, 1,067 proteins, 350 metabolites, and 277 lipids. Our analyses identified four different molecular signatures among sAD cases (Figure 1A). Cluster 4 was associated with higher Clinical Dementia Rating (CDR; p=2.2 x10-20) scores and shorter life span (p=5.6 x10-3, HR=1.6; Figure 1B). In particular, alpha-synuclein (SNCA) transcriptomic and proteomic levels were differentially expressed between samples in cluster 4 and others representing sAD, ADAD, preAD, and controls (Figure 1C) suggesting a unique role for SNCA in sAD cases with unfavorable outcomes. The lower levels of soluble SNCA protein in AD samples may be associated with insoluble aggregated SNCA (Lewy bodies) reported in 50-60% of sAD. By applying machine learning approaches to sAD samples with high-throughput multi-omic profiles, we identified novel molecular signatures missed by single layer analyses. These signatures are associated with clinical phenotypes and offer new insights into which molecules may wax or wane as cognition declines. The association of SNCA with poor outcomes suggests that concomitant Lewy bodies may be a negative prognostic factor in sAD. Currently, we are extending these analyses to incorporate replication cohorts and to perform downstream pathway and enrichment analyses.