Markers Of Alzheimer's Disease Research Articles

Independent effects of amyloid and vascular markers on long-term functional outcomes: An 8-year longitudinal study of subcortical vascular cognitive impairment.

Subcortical vascular cognitive impairment (SVCI) is characterized by the presence of cerebral small vessel disease (CSVD) markers. Some SVCI patients also show Alzheimer's disease and cerebral amyloid angiopathy markers. However, the effects of these imaging markers on long-term clinical outcomes have not yet been established. The present study, therefore, aimed to determine how these imaging markers influence functional disability and/or mortality. We recruited 194 participants with SVCI from the memory clinic and followed them up. All participants underwent brain magnetic resonance imaging at baseline, and 177 (91.2%) participants underwent beta-amyloid (Aβ) positron emission tomography. We examined the occurrence of ischemic or hemorrhagic strokes. We also evaluated functional disability and mortality using the modified Rankin scale. To determine the effects of imaging markers on functional disability or mortality, we used Fine and Gray competing regression or Cox regression analysis. During a 8.6-year follow-up period, 46 of 194 patients (23.7%) experienced a stroke, 110 patients (56.7%) developed functional disabilities and 75 (38.6%) died. Aβ positivity (subdistribution hazard ratio [SHR]=2.73), greater white matter hyperintensity (WMH) volume (SHR=3.11) and ≥3microbleeds (SHR=2.29) at baseline were independent predictors of functional disability regardless of the occurrence of stroke. Greater WMH volume (hazard ratio =2.07) was an independent predictor of mortality. Our findings suggest that diverse imaging markers may predict long-term functional disability and mortality in patients with SVCI, which in turn may provide clinicians with a more insightful understanding of the long-term outcomes of SVCI.

Radiogenomics of Alzheimer's disease: exploring gene related metabolic imaging markers.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and considerably determined by genetic factors. Fluorodeoxyglucose positron emission tomography (FDG-PET) can reflect the functional state of glucose metabolism in the brain, and radiomic features of FDG-PET were considered as important imaging markers in AD. However, radiomic features are not highly interpretable, especially lack of explanation of underlying biological and molecular mechanisms. Therefore, this study used radiogenomics analysis to explore prognostic metabolic imaging markers by associating radiomics features and genetic data. In the study, we used the FDG-PET images and genotype data of 389 subjects (Cohort B) enrolled in the ADNI, including 109 AD, 134 healthy controls (HCs), 72 MCI non-converters (MCI-nc) and 74 MCI converters (MCI-c). Firstly, we performed a Genome-wide association study (GWAS) on the genotype data of 998 subjects (Cohort A), including 632 AD and 366 HCs after quality control (QC) steps to identify susceptibility loci as the gene features. Secondly, radiomics features were extracted from the preprocessed PET images. Thirdly, two-sample t-test, rank sum test and F-score were regarded as the feature selection step to select effective radiomic features. Fourthly, a support vector machine (SVM) was used to test the ability of the radiomic features to classify HCs, MCI and AD patients. Finally, we performed the Spearman correlation analysis on the genetic data and radiomic features. As a result, we identified rs429358 and rs2075650 as genome-wide significant signals. The radiomic approach achieved good classification abilities. Two prognostic FDG-PET radiomic features in the amygdala were proven to be correlated with the genetic data.

Superparamagnetic iron oxide loaded chitosan coated bilosomes for magnetic nose to brain targeting of resveratrol

The objective of this study was to improve effectiveness of resveratrol (RES) through brain targeting by the intranasal olfactory mucosa for the treatment Alzheimer’s disease (AD). To attain this, chitosan coated bilosomes (non ionic surfactant vesicles stabilized by bile salts, loaded with RES and superparamagnetic iron oxide nanoparticles (SPIONs) were prepared and incorporated into sodium alginate/PVP wafers. In vitro characterization of bilosomes including colloidal characteristics, entrapment efficiency and in vitro release was carried out. Hydration capacity, porosity percentage, morphology and in vitro release for selected wafer formulation were also investigated. Particle size of selected bilosomes, CS coated bilosome and SPION bilosomes was 208, 238 and 243 nm, respectively and they provided sustained RES release for 24 h. Both formulations were loaded in wafers and intra-nasally administered in mice with lipopolysaccharide induced AD model. Neurobehavioral tests, AD markers analysis, RT-PCR, western blotting and histopathological evaluation of the dissected brains were carried out. Results revealed the superiority of SPION bilosomes over conventional bilosomes and RES suspension in improving cognitive and memory functions, reduction of pro-inflammatory markers levels and down regulation of expression of NF-κB and P38. This may be attributed to enhanced RES therapeutic effects upon nanoencapsulation, loading into wafers, nasal administration and enhanced targeting the application of an external magnetic field.

A Review of Brain-Targeted Nonviral Gene-Based Therapies for the Treatment of Alzheimer's Disease.

Diseases of the central nervous system (CNS) are difficult to treat owing to the complexity of the brain and the presence of a natural blood-brain-barrier (BBB). Alzheimer's disease (AD) is one of the major progressive and currently incurable neurodegenerative disorders of the CNS, which accounts for 60-80% of cases of dementia. The pathophysiology of AD involves the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. Additionally, synaptic loss and imbalance of neuronal signaling molecules are characterized as important markers of AD. Existing treatments of AD help in the management of its symptoms and aim toward the maintenance of cognitive functions, behavior, and attenuation of gradual memory loss. Over the past decade, nonviral gene therapy has attracted increasing interest due to its various advantages over its viral counterparts. Moreover, advancements in nonviral gene technology have led to their increasing contributions in clinical trials. However, brain-targeted nonviral gene delivery vectors come across various extracellular and intracellular barriers, limiting their ability to transfer the therapeutic gene into the target cells. Chief barriers to nonviral gene therapy have been discussed briefly in this review. We have also highlighted the rapid advancement of several nonviral gene therapies for AD, which are broadly categorized into physical and chemical methods. These methods aim to modulate Aβ, beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), apolipoprotein E, or neurotrophic factors' expression in the CNS. Overall, this review discusses challenges and recent advancements of nonviral gene therapy for AD.

Corpus Callosum Atrophy in Detection of Mild and Moderate Alzheimer's Disease Using Brain Magnetic Resonance Image Processing and Machine Learning Techniques.

Background:The total number of people with dementia is projected to reach 82 million in 2030 and 152 in 2050. Early and accurate identification of the underlying causes of dementia, such as Alzheimer’s disease (AD) is of utmost importance. A large body of research has shown that imaging techniques are most promising technologies to improve subclinical and early diagnosis of dementia. Morphological changes, especially atrophy in various structures like cingulate gyri, caudate nucleus, hippocampus, frontotemporal lobe, etc., have been established as markers for AD. Being the largest white matter structure with a high demand of blood supply from several main arterial systems, anatomical alterations of the corpus callosum (CC) may serve as potential indication neurodegenerative disease.Objective:To detect mild and moderate AD using brain magnetic resonance image (MRI) processing and machine learning techniques.Methods:We have performed automatic detection and segmentation of the CC and calculated its morphological features to feed into a multivariate pattern analysis using support vector machine (SVM) learning techniques.Results:Our results using large patients’ cohort show CC atrophy-based features are capable of distinguishing healthy and mild/moderate AD patients. Our classifiers obtain more than 90%sensitivity and specificity in differentiating demented patients from healthy cohorts and importantly, achieved more than 90%sensitivity and > 80%specificity in detecting mild AD patients.Conclusion:Results from this analysis are encouraging and advocate development of an image analysis software package to detect dementia from brain MRI using morphological alterations of the CC.

Association between chronic periodontitis and the risk of Alzheimer\u2019s disease: combination of text mining and GEO dataset

BackgroundAlthough chronic periodontitis has previously been reported to be linked with Alzheimer's disease (AD), the pathogenesis between the two is unclear. The purpose of this study is to analyze and screen the relevant and promising molecular markers between chronic periodontitis and Alzheimer's disease (AD).MethodsIn this paper, we analyzed three AD expression datasets and extracted differentially expressed genes (DEGs), then intersected them with chronic periodontitis genes obtained from text mining, and finally obtained integrated DEGs. We followed that by enriching the matching the matching cell signal cascade through DAVID analysis. Moreover, the MCODE of Cytoscape software was employed to uncover the protein–protein interaction (PPI) network and the matching hub gene. Finally, we verified our data using a different independent AD cohort.ResultsThe chronic periodontitis gene set acquired from text abstracting was intersected with the previously obtained three AD groups, and 12 common genes were obtained. Functional enrichment assessment uncovered 12 cross-genes, which were mainly linked to cell morphogenesis involved in neuron differentiation, leading edge membrane, and receptor ligand activity. After PPI network creation, the ten hub genes linked to AD were retrieved, consisting of SPP1, THY1, CD44, ITGB1, HSPB3, CREB1, SST, UCHL1, CCL5 and BMP7. Finally, the function terms in the new independent dataset were used to verify the previous dataset, and we found 22 GO terms and one pathway, "ECM-receptor interaction pathways", in the overlapping functional terms.ConclusionsThe establishment of the above-mentioned candidate key genes, as well as the enriched signaling cascades, provides promising molecular markers for chronic periodontitis-related AD, which may help the diagnosis and treatment of AD patients in the future.

Retinal Amyloid Imaging for Screening Alzheimer's Disease.

Cost-effective and noninvasive methods for in vivo imaging of amyloid deposition are needed to screen Alzheimer's disease (AD). Although retinal amyloid is a possible diagnostic marker of AD, there are very few studies on in vivo retinal amyloid imaging. To examine the usefulness of in vivo imaging of retinal amyloid in AD patients. To examine amyloid deposition, 30 Japanese subjects (10 normal control (NC), 7 with mild cognitive impairment (MCI), and 13 with AD) underwent a complete ophthalmic examination, including fundus imaging by scanning laser ophthalmoscopy before and after oral curcumin intake. Retinal amyloid deposition was greater in AD than in NC subjects (*p < 0.05) while MCI showed a slight but insignificant increase of retinal amyloid deposition relative to NC subjects. Retinal amyloid deposition was correlated with whole gray matter atrophy (r = 0.51, *p < 0.05) but not with the cognitive score of the Mini-Mental State Examination, nor with medial temporal lobe atrophy. The present noninvasive in vivo detection of retinal amyloid deposition is useful for screening AD patients.

Current Alzheimer disease research highlights: evidence for novel risk factors.

Alzheimer disease (AD) is the most common type of dementia characterized by the progressive cognitive and social decline. Clinical drug targets have heavily focused on the amyloid hypothesis, with amyloid beta (Aβ), and tau proteins as key pathophysiologic markers of AD. However, no effective treatment has been developed so far, which prompts researchers to focus on other aspects of AD beyond Aβ, and tau proteins. Additionally, there is a mounting epidemiologic evidence that various environmental factors influence the development of dementia and that dementia etiology is likely heterogenous. In the past decades, new risk factors or potential etiologies have been widely studied. Here, we review several novel epidemiologic and clinical research developments that focus on sleep, hypoxia, diet, gut microbiota, and hearing impairment and their links to AD published in recent years. At the frontiers of AD research, these findings and updates could be worthy of further attention.

Biological Significance of the Protein Changes Occurring in the Cerebrospinal Fluid of Alzheimer's Disease Patients: Getting Clues from Proteomic Studies.

The fact that cerebrospinal fluid (CSF) deeply irrigates the brain together with the relative simplicity of sample extraction from patients make this biological fluid the best target for biomarker discovery in neurodegenerative diseases. During the last decade, biomarker discovery has been especially fruitful for the identification new proteins that appear in the CSF of Alzheimer’s disease (AD) patients together with amyloid-β (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau). Thus, several proteins have been already stablished as important biomarkers, due to an increase (i.e., CHI3L1) or a decrease (i.e., VGF) in AD patients’ CSF. Notwithstanding this, only a deep analysis of a database generated with all the changes observed in CSF across multiple proteomic studies, and especially those using state-of-the-art methodologies, may expose those components or metabolic pathways disrupted at different levels in AD. Deep comparative analysis of all the up- and down-regulated proteins across these studies revealed that 66% of the most consistent protein changes in CSF correspond to intracellular proteins. Interestingly, processes such as those associated to glucose metabolism or RXR signaling appeared inversely represented in CSF from AD patients in a significant manner. Herein, we discuss whether certain cellular processes constitute accurate indicators of AD progression by examining CSF. Furthermore, we uncover new CSF AD markers, such as ITAM, PTPRZ or CXL16, identified by this study.

Concordance of Intrinsic Brain Connectivity Measures Is Disrupted in Alzheimer's Disease.

Background: Recently, a new resting-state functional magnetic resonance imaging (rs-fMRI) measure to evaluate the concordance between different rs-fMRI metrics has been proposed and has not been investigated in Alzheimer's disease (AD). Methods: 3T rs-fMRI data were obtained from healthy young controls (YC, n = 26), healthy senior controls (SC, n = 29), and AD patients (n = 35). The fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were analyzed, followed by the calculation of their concordance using Kendall's W for each brain voxel across time. Group differences in the concordance were compared globally, within seven intrinsic brain networks, and on a voxel-by-voxel basis with covariates of age, sex, head motion, and gray matter volume. Results: The global concordance was lowest in AD among the three groups, with similar differences for the single metrics. When comparing AD to SC, reductions of concordance were detected in each of the investigated networks apart from the limbic network. For SC in comparison to YC, lower global concordance without any network-level difference was observed. Voxel-wise analyses revealed lower concordance in the right middle temporal gyrus in AD compared to SC and lower concordance in the left middle frontal gyrus in SC compared to YC. Lower fALFF were observed in the right angular gyrus in AD in comparison to SC, but ReHo and DC showed no group differences. Conclusions: The concordance of resting-state measures differentiates AD from healthy aging and may represent a novel imaging marker in AD.

Connected Speech Characteristics of Bengali Speakers With Alzheimer's Disease: Evidence for Language-Specific Diagnostic Markers.

Background and aim: Speech and language characteristics of connected speech provide a valuable tool for identifying, diagnosing and monitoring progression in Alzheimer's Disease (AD). Our knowledge of linguistic features of connected speech in AD is primarily derived from English speakers; very little is known regarding patterns of linguistic deficits in speakers of other languages, such as Bengali. Bengali is a highly inflected pro-drop language from the Indo-Aryan language family. It is the seventh most spoken language in the world, yet to date, no studies have investigated the profile of linguistic impairments in Bengali speakers with AD. The aim of this study was to characterize connected speech production and identify the linguistic features affected in Bengali speakers with AD.Methods: Participants were six Bengali speaking AD patients and eight matched controls from the urban metropolis, Kolkata, India. Narrative samples were elicited in Bengali using the Frog Story. Samples were analyzed using the Quantitative Production Analysis and the Correct Information Unit analyses to quantify six different aspects of speech production: speech rate, structural and syntactic measures, lexical measures, morphological and inflectional measures, semantic measures and measure of spontaneity and fluency disruptions.Results and conclusions: In line with the extant literature from English speakers, the Bengali AD participants demonstrated decreased speech rate, simplicity of sentence forms and structures, and reduced semantic content. Critically, differences with English speakers' literature emerged in the domains of Bengali specific linguistic features, such as the pro-drop nature of Bengali and its inflectional properties of nominal and verbal systems. Bengali AD participants produced fewer pronouns, which is in direct contrast with the overuse of pronouns by English AD participants. No obvious difficulty in producing nominal and verbal inflections was evident. However, differences in the type of noun inflections were evident; these were characterized by simpler inflectional features used by AD speakers. This study represents the first of its kind to characterize connected speech production in Bengali AD participants and is a significant step forward toward the development of language-specific clinical markers in AD. It also provides a framework for cross-linguistic comparisons across structurally distinct and under-explored languages.

Unbalanced Regulation of α7 nAChRs by Ly6h and NACHO Contributes to Neurotoxicity in Alzheimer's Disease.

α7 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the brain where they promote fast cholinergic synaptic transmission and serve important neuromodulatory functions. However, their high permeability to Ca2+ also predisposes them to contribute to disease states. Here, using transfected HEK-tsa cells and primary cultured hippocampal neurons from male and female rats, we demonstrate that two proteins called Ly6h and NACHO compete for access to α7 subunits, operating together but in opposition to maintain α7 assembly and activity within a narrow range that is optimal for neuronal function and viability. Using mixed gender human temporal cortex and cultured hippocampal neurons from rats we further show that this balance is perturbed during Alzheimer's disease (AD) because of amyloid β (Aβ)-driven reduction in Ly6h, with severe reduction leading to increased phosphorylated tau and α7-mediated neurotoxicity. Ly6h release into human CSF is also correlated with AD severity. Thus, Ly6h links cholinergic signaling, Aβ and phosphorylated tau and may serve as a novel marker for AD progression.SIGNIFICANCE STATEMENT One of the earliest and most persistent hypotheses regarding Alzheimer's disease (AD) attributes cognitive impairment to loss of cholinergic signaling. More recently, interest has focused on crucial roles for amyloid β (Aβ) and phosphorylated tau in Alzheimer's pathogenesis. Here, we demonstrate that these elements are linked by Ly6h and its counterpart, NACHO, functioning in opposition to maintain assembly of nicotinic acetylcholine receptors (nAChRs) within the physiological range. Our data suggests that Aβ shifts the balance away from Ly6h and toward NACHO, resulting in increased assembly of Ca2+-permeable nAChRs and thus a conversion of basal cholinergic to neurotoxic signaling.

Semi-automated assessment of the principal diffusion direction in the corpus callosum: differentiation of idiopathic normal pressure hydrocephalus from neurodegenerative diseases.

Idiopathic normal pressure hydrocephalus (iNPH) shares clinical and radiological features with progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). Corpus callosum (CC) involvement in these disorders is well established on structural MRI and diffusion tensor imaging (DTI), but alterations overlap and lack specificity to underlying tissue changes. We propose a semi-automated approach to assess CC integrity in iNPH based on the spatial distribution of DTI-derived principal diffusion direction orientation (V1). We processed DTI data from 121 subjects (Site1: iNPH = 23, PSP = 27, controls = 14; ADNI: AD = 35, controls = 22) to obtain V1, fractional anisotropy (FA) and mean diffusivity (MD) maps. To increase the estimation accuracy of DTI metrics, analyses were restricted to the midsagittal CC portion (± 6 slices from midsagittal plane). Group-wise comparison of normalized altered voxel count in midsagittal CC was performed using Kruskal-Wallis tests, followed by post hoc comparisons (Bonferroni-corrected p < 0.05). ROC analysis was used to evaluate the diagnostic power of DTI alterations compared to callosal volume. We found specific changes of V1 distribution in CC splenium of iNPH compared to AD and PSP, while MD and FA showed patterns of alterations common to all disorders. ROC curves showed that, compared to splenial volume, V1 represented the most accurate marker of iNPH diagnosis versus AD and PSP. Our results provide evidence that V1 is a powerful biomarker for distinguishing patients with iNPH from patients with AD or PSP. Indeed, our findings also provide more specific insight into the pathophysiological mechanisms that underlie tissue damage across iNPH and its mimics.

The diagnosis of amnestic mild cognitive impairment by combining the characteristics of brain functional network and support vector machine classifier

BackgroundAmnestic mild cognitive impairment (aMCI) is an essential stage of early detection and potential intervention for Alzheimer’s disease (AD). Patients with aMCI exhibit partially abnormal functional brain connectivity and it is suggested that these features may represent a new diagnostic marker of early AD. New methodIn this paper, we constructed two brain network models, a phase synchronization index (PSI) undirected network and a directed transfer function (DTF) directed network, to evaluate the cognitive function in patients with aMCI. We then built SVM classification models using the network clustering coefficient, global efficiency and average node degree as features to distinguish between aMCI patients and controls. ResultsOur results reveal a classification accuracy and AUC of 66.6 ± 1.7% and 0.7475 and 80.0 ± 2.2% and 0.7825, respectively, for the two network models (PSI and DTF). As the directed network model performed better than the undirected model, we introduced an improved graph theory feature, efficiency density, which resulted in an increased classification accuracy and AUC value 86.6 ± 2.6% and 0.8295, respectively. Comparison with existing methodsThe analysis of network models and the directionality of information flow is suitable for analysis of nonlinear EEG signals for assessment of the functional state of the brain. Compared with traditional network features, our proposed improved features more comprehensively evaluate transmission efficiency and density of the brain. ConclusionIn this study, we demonstrate that an improved efficiency density feature is helpful for enhancing classification the accuracy of aMCI. Moreover, directed brain network models exhibit better classification for aMCI diagnosis than undirected networks.

Convergent and Discriminant Validity of Default Mode Network and Limbic Network Perfusion in Amnestic Mild Cognitive Impairment Patients.

Previous studies reported default mode network (DMN) and limbic network (LIN) brain perfusion deficits in patients with amnestic mild cognitive impairment (aMCI), frequently a prodromal stage of Alzheimer's disease (AD). However, the validity of these measures as AD markers has not yet been tested using MRI arterial spin labeling (ASL). To investigate the convergent and discriminant validity of DMN and LIN perfusion in aMCI. We collected core AD markers (amyloid-β 42 [Aβ42], phosphorylated tau 181 levels in cerebrospinal fluid [CSF]), neurodegenerative (hippocampal volumes and CSF total tau), vascular (white matter hyperintensities), genetic (apolipoprotein E [APOE] status), and cognitive features (memory functioning on Paired Associate Learning test [PAL]) in 14 aMCI patients. Cerebral blood flow (CBF) was extracted from DMN and LIN using ASL and correlated with AD features to assess convergent validity. Discriminant validity was assessed carrying out the same analysis with AD-unrelated features, i.e., somatomotor and visual networks' perfusion, cerebellar volume, and processing speed. Perfusion was reduced in the DMN (F = 5.486, p = 0.039) and LIN (F = 12.678, p = 0.004) in APOE ɛ4 carriers compared to non-carriers. LIN perfusion correlated with CSF Aβ42 levels (r = 0.678, p = 0.022) and memory impairment (PAL, number of errors, r = -0.779, p = 0.002). No significant correlation was detected with tau, neurodegeneration, and vascular features, nor with AD-unrelated features. Our results support the validity of DMN and LIN ASL perfusion as AD markers in aMCI, indicating a significant correlation between CBF and amyloidosis, APOE ɛ4, and memory impairment.

Herpes simplex virus, early neuroimaging markers and incidence of Alzheimer\u2019s disease

While previous studies suggest the implication of herpes simplex virus (HSV) in the onset of Alzheimer’s disease (AD), no study has investigated its association with early neuroimaging markers of AD. In the Three-City and the AMI cohorts, the associations between HSV infection and (i) hippocampal volume (n = 349), (ii) white matter alterations in the parahippocampal cingulum and fornix using diffusion tensor imaging (n = 260), and (iii) incidence of AD (n = 1599) were assessed according to APOE4 status. Regardless of APOE4 status, infected subjects presented (i) significantly more microstructural alterations of the parahippocampal cingulum and fornix, (ii) lower hippocampal volumes only when their anti-HSV IgG level was in the highest tercile—reflecting possibly more frequent reactivations of the virus (p = 0.03 for subjects with a high anti-HSV IgG level while there was no association for all infected subjects, p = 0.19), and (iii) had no increased risk of developing AD. Nevertheless, among APOE4 carriers, infected subjects presented lower hippocampal volumes, although not significant (p = 0.09), and a two or three times higher risk of developing AD (adjusted Hazard ratio (aHR) = 2.72 [1.07–6.91] p = 0.04 for infected subjects and aHR = 3.87 [1.45–10.28] p = 0.007 for infected subjects with an anti-HSV IgG level in the highest tercile) while no association was found among APOE4 noncarriers. Our findings support an association between HSV infection and AD and a potential interaction between HSV status and APOE4. This reinforces the need to further investigate the infectious hypothesis of AD, especially the associated susceptibility factors and the possibility of preventive treatments.

Cognitive Activity and Onset Age of Incident Alzheimer Disease Dementia.

To test the hypothesis that higher level of cognitive activity predicts older age at dementia onset in Alzheimer disease (AD) dementia. As part of a longitudinal cohort study, 1,903 older persons without dementia at enrollment reported their frequency of participation in cognitively stimulating activities. They had annual clinical evaluations to diagnose dementia and AD, and the deceased underwent neuropathologic examination. In analyses, we assessed the relation of baseline cognitive activity to age at diagnosis of incident AD dementia and to postmortem markers of AD and other dementias. During a mean of 6.8 years of follow-up, 457 individuals were diagnosed with incident AD at a mean age of 88.6 (SD 6.4, range 64.1-106.5) years. In an extended accelerated failure time model, higher level of baseline cognitive activity (mean 3.2, SD 0.7) was associated with older age at AD dementia onset (estimate 0.026; 95% confidence interval 0.013-0.039). Low cognitive activity (score 2.1, 10th percentile) was associated with a mean onset age of 88.6 years compared to a mean onset age of 93.6 years associated with high cognitive activity (score 4.0, 90th percentile). Results were comparable in subsequent analyses that adjusted for potentially confounding factors. In 695 participants who died and underwent a neuropathologic examination, cognitive activity was unrelated to postmortem markers of AD and other dementias. A cognitively active lifestyle in old age may delay the onset of dementia in AD by as much as 5 years.

Tau PET correlates with different Alzheimer’s disease‐related features compared to CSF and plasma p‐tau biomarkers

PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)‐related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER‐2 (n = 400) and ADNI (n = 371). All had tau‐PET ([18F]RO948 in BioFINDER‐2, [18F]flortaucipir in ADNI) and CSF p‐tau181 biomarkers available. Plasma p‐tau181 and plasma/CSF p‐tau217 were available in BioFINDER‐2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66 and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p‐tau181 and p‐tau217 levels were independently of tau PET associated with higher age, and APOEɛ4‐carriership and Aβ‐positivity, while increased tau‐PET signal in the temporal cortex was associated with worse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p‐tau181 and p‐tau217 levels being more tightly linked with early markers of AD (especially Aβ‐pathology), while tau‐PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression.

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

ObjectiveTo assess the role of biomarkers of Alzheimer disease (AD), neurodegeneration, and small vessel disease (SVD) as mediators in the association between diabetes mellitus and cognition.MethodsThe study sample was derived from MEMENTO, a cohort of French adults recruited in memory clinics and screened for either isolated subjective cognitive complaints or mild cognitive impairment. Diabetes was defined based on blood glucose assessment, use of antidiabetic agent, or self-report. We used structural equation modeling to assess whether latent variables of AD pathology (PET mean amyloid uptake, Aβ42/Aβ40 ratio, and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) mediate the association between diabetes and a latent variable of cognition (5 neuropsychological tests), adjusting for potential confounders.ResultsThere were 254 (11.1%) participants with diabetes among 2,288 participants (median age 71.6 years; 61.8% women). The association between diabetes and lower cognition was significantly mediated by higher neurodegeneration (standardized indirect effect: −0.061, 95% confidence interval: −0.089, −0.032), but not mediated by SVD and AD markers. Results were similar when considering latent variables of memory or executive functioning.ConclusionIn a large clinical cohort in the elderly, diabetes is associated with lower cognition through neurodegeneration, independently of SVD and AD biomarkers.

VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome

BackgroundThere is an urgent need for objective markers of Alzheimer’s disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment.MethodsWe quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aβ42:40 ratio, CSF Aβ1-42, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing.ResultsIn adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aβ42:40 (adj.p = .0001), p-tau (adj.p < .0001), and NFL (adj.p < .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p < .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p < .002).ConclusionThese data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.