AD Patient Research Articles

Blockade of brain alkaline phosphatase efficiently reduces amyloid-β plaque burden and associated cognitive impairment

BackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative disease. Three new drugs for AD based on monoclonal antibodies against the amyloid-β peptide (Aβ) have recently been approved because they favor the reduction of the burden of senile plaque in the AD patient’s brain. Nonetheless, both drugs have very limited applicability and benefits and show several side effects. These limitations invite us to find alternative strategies for treating patients with AD. Here, we explored whether tissue-nonspecific alkaline phosphatase (TNAP), an ectoenzyme upregulated in the brain of AD patients and whose inhibition has beneficial effects on tau-induced pathology, is also efficient in reducing senile plaque burden.MethodsTo evaluate whether TNAP may reduce cerebral senile plaque loading and Aβ-related toxicity, we use both pharmacological and genetic approaches. We analyze postmortem samples from human AD patients, APP/PS1 mice (a mouse model that mimics amyloid pathology observed in AD patients) treated or not with TNAP inhibitors, and the newly generated transgenic mouse line, TNAP-deficient APP/PS1 mice.ResultsFor the first time, we describe that genetic or pharmacological blockade of TNAP effectively reduces senile plaque burden by promoting its clearance, which leads to amelioration of cognitive impairment caused by Aβ-induced toxicity. These beneficial effects of TNAP inhibition occur concomitantly with higher microglial recruitment toward the senile plaque and increased microglial phagocytic capacity of Aβ by a mechanism involving metalloprotease-depending osteopontin processing. In addition, we also found that TNAP blockade favors LRP1-mediated transport of Aβ through the BBB.ConclusionsHere, we have shown that TNAP inhibition effectively reduces brain senile plaque burden and associated behavioral defects. Furthermore, given that we had previously reported that TNAP blockade also ameliorates Tau-induced neurotoxicity and increases lifespan of P301S tauopathy mouse model, we can state that TNAP blockade may be a novel and efficient therapy for treating patients with AD.

Targeting S. aureus Extracellular Vesicles: A New Putative Strategy to Counteract Their Pathogenic Potential.

Long-term inflammatory skin disease atopic dermatitis is characterized by dry skin, itching, and eczematous lesions. During inflammation skin barrier protein impairment promotes S. aureus colonisation in the inflamed skin, worsening AD patient's clinical condition. Proteomic analysis revealed the presence of several immune evasion proteins and virulence factors in S. aureus extracellular vesicles (EVs), suggesting a possible role for these proteins in the pathophysiology of atopic dermatitis. The objective of this study is to assess the efficacy of a wall fragment obtained from a patented strain of C. acnes DSM28251 (c40) and its combination with a mucopolysaccharide carrier (HAc40) in counteract the pathogenic potential of EVs produced by S. aureus ATCC 14458. Results obtained from in vitro studies on HaCaT keratinocyte cells showed that HAc40 and c40 treatment significantly altered the size and pathogenicity of S. aureus EVs. Specifically, EVs grew larger, potentially reducing their ability to interact with the target cells and decreasing cytotoxicity. Additionally, the overexpression of the tight junctions mRNA zona occludens 1 (ZO1) and claudin 1 (CLDN1) following EVs exposure was decreased by HAc40 and c40 treatment, indicating a protective effect on the epidermal barrier's function. These findings demonstrate how Hac40 and c40 may mitigate the harmful effects of S. aureus EVs. Further investigation is needed to elucidate the exact mechanisms underlying this interaction and explore the potential clinical utility of c40 and its mucopolysaccharide carrier conjugate HAc40 in managing atopic dermatitis.

Secure IoT Assistant-Based System For Alzheimer’s Disease

Alzheimer's disease is a neurological condition that gradually impairs a person's capacity for thought and memory. Gradually, it gets worse until it becomes a major hindrance to the way the person with the illness lives and functions in the world. The purpose of this research is to create a prototype for mild to moderate AD that provides safe information transmission and support services, allowing a family member to investigate it and safeguard the AD patient. The wearable prototype can distinguish between family and non-family members in recognized images and give a vocal communication with the individual's name. Additionally, the prototype makes it possible to track the AD person's location. The prototype makes their daily lives easier. Thus far, the prototype follows the individual with AD around and notifies caregivers of their whereabouts so that, if the patient leaves the house, they can securely return them home. Additionally, by detecting dampness, this prototype informs the patient's caregiver of their excrement. So, the prototype will help the patient in their daily life very efficiently.

Thy1-ApoE4/C/EBPβ double transgenic mice act as a sporadic model with Alzheimer’s disease

Early onset familial Alzheimer’s disease (FAD) with APP, PS1/2 (presenilins) mutation accounts for only a small portion of AD cases, and most are late-onset sporadic. However, majority of AD mouse models are developed to mimic the genetic cause of human AD by overexpressing mutated forms of human APP, PS1/2, and/or Tau protein, though there is no Tau mutation in AD, and no single mouse model recapitulates all aspects of AD pathology. Here, we report Thy1-ApoE4/C/EBPβ double transgenic mouse model that demonstrates key AD pathologies in an age-dependent manner in absence of any human APP or PS1/2 mutation. Using the clinical diagnosis criteria, we show that this mouse model exhibits tempo-spatial features in AD patient brains, including progressive cognitive decline associated with brain atrophy, which is accompanied with extensive neuronal degeneration. Remarkably, the mice display gradual Aβ aggregation and neurofibrillary tangles formation in the brain validated by Aβ PET and Tau PET. Moreover, the mice reveal widespread neuroinflammation as shown in AD brains. Hence, Thy1-ApoE4/C/EBPβ mouse model acts as a sporadic AD mouse model, reconstituting the major AD pathologies.

Early Results of a Pilot Program Providing Virtual Support to Family Caregivers of People with Alzheimer’s Disease to Reduce Their Stress and the Risk of Complications for Their Loved Ones

AbstractBackgroundThe Florida Department of Elder Affairs and Navigating Aging Needs, LLC (NAN) have formed a public‐private partnership providing virtual support to family caregivers of people with Alzheimer’s disease living at home. The program targets patients with high‐level daily care needs and with increased risk for future decline and need for costly Medicaid‐supported care.ObjectivesTo reduce stress for family caregivers and reduce risk of complications for their loved ones with Alzheimer’s disease.MethodsFamily caregivers who qualify for state assistance were offered a 12‐month support program. Support included regular meetings (Zoom or phone) with a personal licensed social worker. The initial assessment included 80 questions on the AD patient’s medical, emotional, social, and legal/financial well‐being and the validated battery of 12 questions comprising the Zarit Burden Scale. Following the assessment, the social worker provided the family caregiver with a personal plan that identified areas of risk that “need attention” or “may need attention,” along with resources to address identified needs. For the following three months, the social worker met with the family caregiver regularly to help resolve areas identified as high risk and discuss other relevant issues as they arose. After three months of guidance and support, the social worker conducted a re‐assessment with the family caregiver.ResultsData are available for the first hundred family caregivers participating in the pilot for three months. Initial results demonstrate a positive impact on AD patients’ medical, emotional, legal/financial outcomes including hospitalizations, falls, depression, anxiety, advanced directives, and financial planning. Early results also show reduced Zarit Burden Scale scores for family caregivers.ConclusionProviding virtual support to family caregivers of people with Alzheimer’s disease shows early signs of reducing the caregivers’ stress and the risk of complications for their loved ones. The Florida Department of Elder Affairs and NAN continue to evaluate the program’s impact on family caregivers, people with AD, and the cost of supporting this complex population.

Investigating the Role of APOE Genotype in Human Microglia

AbstractBackgroundAlthough the pivotal role of apolipoprotein E () in AD has been recognized for three decades, its function in different brain cells is far from understood. Knockout studies of the APOE gene may shed light of the function of ApoE. The aim of the present study was to unravel its function in induced pluripotent stem cell (iPSC) derived microglia.MethodWe studied two human iPSC‐derived microglia cell cultures, one derived from a healthy control (Bioni010‐C – endogenous genotype apolipoprotein E34 (APOE34)) and one from an AD patient (UKBi011‐A – endogenous genotype APOE44) and their edited isogenic cell‐lines (for UKBi011‐A, APOE22 and APOE33 and for Bioni010‐C, hemizygous due to gene editing, APOE2‐ and APOE3‐ (32971461, 29753274)). Additionally, APOE KO lines were generated from both backgrounds. We performed whole genome transcriptomic (IlluminaTruSequencing) and proteomic (TMT‐labelled Nano‐LC peptidomic MS) analysis (n = six per genotype). For transcriptomic data, log2‐normalized intensities were analysed with (in R); there were 13115 unique transcripts. For proteomics analysis, after global normalization, the data were locally normalized (by protein), the limma package was used to calculate FDR‐corrected p‐values (1% cut off); there were 3975 (Bioni010 samples) and 4349 (UKBi011 samples) proteins. In the quality control analysis for the proteomics, we excluded one outlier of the six per line based on principle component/Euclidean distance analysis. We extracted pairwise comparisons to APOE KO in transcriptomic (|logFC|>0.5, FDR <0.05) and proteomic (|logFC|>0 and FDR <0.05) data.ResultTwenty transcripts (including APOE) were concordantly differentially expressed across all comparisons between APOE‐expressing and KO. These are broadly involved in processes related to mitochondrial function/organization, apoptosis, transcriptional regulation, immune functions, extracellular matrix, and energy metabolism among others. Seven proteins were concordantly differentially expressed across all pairwise comparisons with APOE KO, involved in extracellular matrix, immune signalling, energy metabolism, and cytoskeletal structure.ConclusionOur study finds APOE knockout leads to a number of changes related to immune, mitochondrial, and extracellular matrix genes, suggesting that APOE in human iPSC‐derived microglia cells influences immune and mitochondrial functions.

Uncovering new tau aggregation and spreading mechanism through AD tau‐seed interactome analysis

AbstractBackgroundPathological tau aggregates are key features of Alzheimer’s disease and other tauopathies. The current research aims to understand how tau aggregates spread in AD patient brains, but the mechanisms remain unclear. Our recent‐published study found that the protein Bassoon plays a key role in tau spreading and pathology in a mouse model for tauopathy using mass spectrometry to identify proteins interacting with tau seeds. Considering our finding enhancing the relevance of tau‐seed interactor on disease pathology, we aim to characterize the interactome of the tau‐seed isolated from AD brains using a similar approach.MethodIn this study, we used Size Exclusion Chromatography (SEC) to separate TBS‐soluble AD and healthy brain extracts into fractions and measured tau seeding activity using a flow cytometry‐based biosensor cell line (n = 3). Then, the fractions with higher seeding activity were subjected to immunoprecipitation to isolate the tau seed and performed a TMT‐tags‐based unbiased quantitative mass spectrometry to uncover the specific tau species involved in tau propagation and identify new tau‐seed interactors.ResultThe strongest seeding activity in AD brains was found in fraction 9, which contains high molecular weight (HMW) proteins (>2,000 kDa), including only 5% of total tau, as assayed by ELISA for tau. Levels of tau were similar in fraction 9 in age‐matched controls but lacked seeding activity. Our bioinformatic analysis revealed that a total of 504 proteins interact with HWM tau without seeding activity isolated from controls and 1192 proteins interact with HWM tau‐seed isolated from AD cases. In addition, a total of 385 interacting proteins were found in both HWM tau from control and tau‐seed from AD cases. Interestingly, DAVID analysis as well as networks and interactions analysis (STRING analysis), revealed enrichment in proteins related to both synaptic and mitochondrial pathways.ConclusionOur findings significantly contribute to our understanding of the mechanisms involved in tau propagation and offer new insights into the potential for targeting tau‐seed interactions as a therapeutic strategy for tauopathies. Previously, we have identified BSN as a key interactor of tau seeds, and our data suggest that inhibiting these interactions could represent a promising new approach to treating these debilitating conditions.

Advanced Alzheimer's Disease Patients Show Safe, Significant, and Persistent Benefit in 6-Month Bryostatin Trial.

In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies. To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing. In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms. With no safety events noted by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p = 0.409, NS), treatment versus placebo p < 0.007. The Moderate Cohort patients showed no significant benefit. The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients' decline of -12.8 SIB points.

Trametinib activates endogenous neurogenesis and recovers neuropathology in a model of Alzheimer's disease.

Enhancing adult neurogenesis in the brain has been suggested as a potential therapeutic strategy for AD. We developed a screening platform, ATRIVIEW®, for molecules that activate neuronal differentiation of adult mouse NSCs. The most potent hit from an FDA-approved drug library was SNR1611 (trametinib), a selective MEK1/2 inhibitor. We found that trametinib increases the levels of P15INK4b and Neurog2, suggesting a mechanism by which MEK1/2 inhibition induces neuronal differentiation. Oral administration of trametinib increased adult neurogenesis in the dentate gyrus and subventricular zone of the 5XFAD AD mouse model. Surprisingly, we also found that trametinib enhanced adult neurogenesis in the cortex. Consequently, trametinib rescued AD pathologies such as neuronal loss and cognitive impairment in 5XFAD mice. Finally, trametinib induced neurogenic differentiation of NSCs derived from AD patient iPSCs, which suggests its potential therapeutic application. Altogether, we suggest that restoration of endogenous adult neurogenesis by trametinib may be a promising therapeutic approach to AD.

A proteomics analysis of 5xFAD mouse brain regions reveals the lysosome-associated protein Arl8b as a candidate biomarker for Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is characterized by the intra- and extracellular accumulation of amyloid-β (Aβ) peptides. How Aβ aggregates perturb the proteome in brains of patients and AD transgenic mouse models, remains largely unclear. State-of-the-art mass spectrometry (MS) methods can comprehensively detect proteomic alterations, providing relevant insights unobtainable with transcriptomics investigations. Analyses of the relationship between progressive Aβ aggregation and protein abundance changes in brains of 5xFAD transgenic mice have not been reported previously.MethodsWe quantified progressive Aβ aggregation in hippocampus and cortex of 5xFAD mice and controls with immunohistochemistry and membrane filter assays. Protein changes in different mouse tissues were analyzed by MS-based proteomics using label-free quantification; resulting MS data were processed using an established pipeline. Results were contrasted with existing proteomic data sets from postmortem AD patient brains. Finally, abundance changes in the candidate marker Arl8b were validated in cerebrospinal fluid (CSF) from AD patients and controls using ELISAs.ResultsExperiments revealed faster accumulation of Aβ42 peptides in hippocampus than in cortex of 5xFAD mice, with more protein abundance changes in hippocampus, indicating that Aβ42 aggregate deposition is associated with brain region-specific proteome perturbations. Generating time-resolved data sets, we defined Aβ aggregate-correlated and anticorrelated proteome changes, a fraction of which was conserved in postmortem AD patient brain tissue, suggesting that proteome changes in 5xFAD mice mimic disease-relevant changes in human AD. We detected a positive correlation between Aβ42 aggregate deposition in the hippocampus of 5xFAD mice and the abundance of the lysosome-associated small GTPase Arl8b, which accumulated together with axonal lysosomal membranes in close proximity of extracellular Aβ plaques in 5xFAD brains. Abnormal aggregation of Arl8b was observed in human AD brain tissue. Arl8b protein levels were significantly increased in CSF of AD patients.ConclusionsWe report a comprehensive biochemical and proteomic investigation of hippocampal and cortical brain tissue derived from 5xFAD transgenic mice, providing a valuable resource to the neuroscientific community. We identified Arl8b, with significant abundance changes in 5xFAD and AD patient brains. Arl8b might enable the measurement of progressive lysosome accumulation in AD patients and have clinical utility as a candidate biomarker.

Levels of blood memory CD8 T cells that induce AD‐like pathology in mice correlate with decreased Aβ42 and increased total Tau in CSF of AD patients

AbstractBackgroundWe previously engineered mice to accumulate elevated levels of age‐related, antigen‐specific memory CD8 T cells as in humans. These mice spontaneously develop all major hallmarks of AD with aging. Analogous T cells reactive to an epitope on Amyloid Precursor Protein (APP) were found in aging humans, accumulated in AD brain, and decreased in AD blood. Here, we examine whether their levels are associated with established AD biomarkers in CSF.MethodAntigen‐specific CD8 T cells in blood were quantified by flow cytometric analysis after staining with anti‐CD8, anti‐KLRG1 and APP peptide‐HLA‐A2 multimers in normal aging, MCI with or without AD biomarkers, and confirmed late‐onset AD patient cohorts (n = 50). Aβ1‐42, total Tau, and pTau181 were quantified in CSF, and cognitive performance assessed by MMSE.ResultPercentage of APP‐specific memory CD8 T cells was significantly decreased with dementia (0.68 + 0.29% for MMSE &lt;25; 1.63 + 0.32% for MMSE &gt;24), reaching minimal levels in AD blood, which precluded meaningful correlations in AD patients. Nevertheless, increasing levels of APP‐specific memory CD8 T cells in blood from all subjects combined corresponded with increased CSF Aβ1‐42 (r = 0.373, P &lt; 0.0004) and decreased total Tau but not pTau181 or MMSE (r = ‐0.234, P &lt; 0.0292; r = ‐0.208, P &lt; 0.0531; and r = ‐0.009, P &lt; 0.9410, respectively). Decreases in the larger parental (KLRG1+) memory CD8 T cell population also correlated with decreased CSF Aβ1‐42 in AD patients alone (r = 0.511, P = 0.003 for % KLRG1+ of CD8 T cells; r = 0.682, P &lt; 0.00009 for % KLRG1+CD8+ cells; n = 31).ConclusionOur results reveal that age‐related memory CD8 T cells in blood decrease with dementia, and in proportion to decreased CSF Aβ1‐42 and total Tau in all patients, while their parental KLRG1+ population is directly proportional to Aβ1‐42 in AD patients only. This validates our previous findings that loss of APP‐specific memory CD8 T cells from blood accurately tracks the AD continuum, and support the notion that antigen‐specific memory CD8 T cells are associated with the earliest detectable pathologic changes in AD.

Using the clock drawing test to differentiate impairments in executive functioning between Alzheimer’s Dementia and Parkinson’s disease

AbstractBackgroundPrevious studies suggest the usefulness of CDT in distinguishing between neurodegenerative diseases. The purpose of this study was to examine differences in CDT performance in individuals with AD and PD compared to normal controls.MethodsTotal of 194 participants. Four groups included in analysis: patients that met diagnostic criteria for late MCI/mild AD, moderate AD, PD with no cognitive impairment, and normal controls. All participants completed MMSE and CDT. MMSE score ≤ 23 considered moderate AD, MMSE score &gt;24 considered mixed late MCI/mild AD, all PD patients had MMSE score &gt;24.ResultsAn ANOVA was used to examine group differences in CDT and MMSE scores. There was a significant main effect of group for both CDT and MMSE scores (p &lt; 0.001). Moderate AD group had significantly lower MMSE scores compared to other groups (average MMSE score of 19.4 for moderate AD compared to 26.6 for mild AD, 26.9 for Parkinson’s, and 28.2 for controls). Post‐hoc t‐tests (Bonferroni corrected for multiple comparisons) showed moderate AD group had significantly higher error scores on CDT compared to controls (p&lt;0.001). Moderate AD group also had significantly higher error score compared to both MCI/mild AD and PD patient groups (p&lt;0.001). No statistical significance existed in error scores between MCI/mild AD group compared to controls (p = 0.134) or to Parkinson’s disease (p = 1.000). No statistical significance in CDT error scores between the Parkinson’s group compared to controls (p = 0.904). Findings suggest executive functioning may only begin to significantly decline in advanced stages of AD.ConclusionOur findings suggest that deficits in executive functions measured by CDT is impaired in moderate AD but relatively preserved in MCI/mild AD and PD with no cognitive impairment, which is consistent with previous studies. One limitation of the study is that we did not include a copy trial for the CDT, which may support that our findings are due to executive dysfunction rather than visuospatial deficits. Future directions include increasing sample sizes, including individuals with PD with cognitive impairment, and using novel digital versions of the CDT to different variables of the CDT such as time to start and complete, visuospatial coordination, and graphic size.

Vision transformers for the prediction of mild cognitive impairment to Alzheimer's disease progression using mid-sagittal sMRI.

Alzheimer's disease (AD) is one of the most common causes of neurodegenerative disease affecting over 50 million people worldwide. However, most AD diagnosis occurs in the moderate to late stage, which means that the optimal time for treatment has already passed. Mild cognitive impairment (MCI) is an intermediate state between cognitively normal people and AD patients. Therefore, the accurate prediction in the conversion process of MCI to AD may allow patients to start preventive intervention to slow the progression of the disease. Nowadays, neuroimaging techniques have been developed and are used to determine AD-related structural biomarkers. Deep learning approaches have rapidly become a key methodology applied to these techniques to find biomarkers. In this study, we aimed to investigate an MCI-to-AD prediction method using Vision Transformers (ViT) to structural magnetic resonance images (sMRI). The Alzheimer's Disease Neuroimaging Initiative (ADNI) database containing 598 MCI subjects was used to predict MCI subjects' progression to AD. There are three main objectives in our study: (i) to propose an MRI-based Vision Transformers approach for MCI to AD progression classification, (ii) to evaluate the performance of different ViT architectures to obtain the most advisable one, and (iii) to visualize the brain region mostly affect the prediction of deep learning approach to MCI progression. Our method achieved state-of-the-art classification performance in terms of accuracy (83.27%), specificity (85.07%), and sensitivity (81.48%) compared with a set of conventional methods. Next, we visualized the brain regions that mostly contribute to the prediction of MCI progression for interpretability of the proposed model. The discriminative pathological locations include the thalamus, medial frontal, and occipital-corroborating the reliability of our model. In conclusion, our methods provide an effective and accurate technique for the prediction of MCI conversion to AD. The results obtained in this study outperform previous reports using the ADNI collection, and it suggests that sMRI-based ViT could be efficiently applied with a considerable potential benefit for AD patient management. The brain regions mostly contributing to prediction, in conjunction with the identified anatomical features, will support the building of a robust solution for other neurodegenerative diseases in future.

Live Tracking and Health Monitoring of Alzheimer Patient Using IoT

This Alzheimer's is a long- term disease which degrades the neural capacity. Over time, the illness progressively gets worse. Patients with Alzheimer's are always reliant on other people. Caretakers find it more challenging to manage the patients as the condition worsens. The design and construction process for an electronic gadget used to track Alzheimer's patient care is described in this study. The vitals of a patient will be tracked using the wearable sensors. Several bodily touch sensors gather information. The cloud server receives this data. For this research, we're employing a variety of sensors, including temperature and pulse sensors, to track the patients' health in real time. To identify the patients' major health issues so that effective medical care can be provided. Alzheimer causes patients to lose memory. They occasionally get lost, thus a technology is employed to track them and communicate the information to family members. The Internet of Things (IOT) can play a major part in helping the Alzheimer patient. The smartphone device application will be utilised to guide the Alzheimer patients and aid them in their daily activities. It will also help the doctors, carers, and family members to monitor patients' reports. The purpose of this work is to create a prototype for a system that offers psychological support services and assures secure transmission of data that can be examined by a family member to safeguard the AD patient.

Microtubule associated protein tau p.R406W patient carriers present with a nonconforming clinical phenotype

AbstractBackground MAPT p.R406W is an autosomal dominantly inherited missense mutation associated with FTLD with an amnestic, AD‐like phenotype. Our group first described a carrier pedigree (labeled ADG) in 2003, with 47 relatives.We aim to delineate phenotypic and genetic characteristics of MAPT p.R406W carriers through 19‐year follow‐up, and to provide first data on mutation frequency in FTD and AD.MethodWe extended the ADG pedigree, obtained data over 19 years on symptoms, biomarkers and neuropathology. Furthermore, we screened FTD (n=647) and AD (n=1100) patient cohorts for new carriers.ResultThe ADG family now counts 38 mutation carriers. 7 unrelated carriers were identified in AD and FTD cohorts. Inclusion of additional relatives procured 56 mutation carriers (39 affected).p.R406W mutation frequencies were 0.62% (FTD) and 0.27% (AD). All probands shared genetic kinship, suggesting a common ancestor.Average onset age and disease duration were 60.9 and 12.4 years (ranges 54‐69, 5‐25). Remarkably, two distinct phenotypes (clinical AD(n=10) or bvFTD(n=9)) emerged. bvFTD patients had significantly worse prognosis. Disinhibition/aggression were highly common (100% of bvFTD, 40% of AD patients). CSF amyloid‐β1‐42 was decreased in all 5 patients with CSF data, 2/5 with concomitant tau elevation. Neuropathology was FTLD‐tau, notably showing only 3R‐tau‐isoforms.ConclusionWe are first to report MAPT p.R406W mutation frequencies, unexpectedly high in FTD ànd AD. Contrary to previous reports, we observed a unique phenotypic shift in Belgian p.R406W carriers, with prominent behavioral symptoms, as well as memory decline. Surprisingly, CSF biomarkers showed decreased amyloid‐β1‐42, and neuropathology was FTLD‐tau with isolated 3R‐tau, highly unusual findings for this tauopathy.

Public policy and Alzheimer care in India

AbstractBackgroundIn India we do not have proper data in respect of Alzheimer disease and its impact on the social and demographic set up.MethodSome studies have been conducted in Kerala West Bengal and some parts of North India. The present study is aimed at analyzing the challenges faced by family caregivers and also institutional caregivers. The methods employed cause both quantitative and qualitative. The study was conducted in care centers run by ARDSI (Alzheimer’s Related Disorder Society of India) and family caregivers were interviewed at homes were Alzheimer’s patients are living. A total of197 caregivers and 70 Alzheimer’s patients were selected for the study overs a period of one year from Jan 2021to Jan2012. To analyze the burden level Zarit Burden Interview was adopted.ResultsThe study revealed that caregiving is a complex experience which involves strong inter professional collaboration and proper education among caregivers regarding elimination of social stigma. The results also revealed more than 80% of the caregivers belong to female gender and more than 90% of the Alzheimer’s patients are in the age group of 65 years and above. In Indian conditions institutional caregiving is highly selective and it has been utilized by high income group of families as they have to spend around 25000 per month for keeping the AD patient at care homes.ConclusionThrough the study it has been identified Government support in taking care of Alzheimer’s patients has been extraordinarily effective in the entire Kerala state whereas from available literature, such type of care centers are yet to be established in other states. Regarding family caregivers more awareness programs are needed which will facilitate proper care of Alzheimer’s patients without any social stigma.

Crop Filling: artefact removal for real‐world clinical neuroimaging data

AbstractBackgroundThe use of standard clinical neuroimaging data for quantitative research is often precluded by imaging artefacts caused by real‐world limitations. For example, partial coverage (cropping) of T1‐weighted MRI scans can occur when a memory clinic prioritises visual ratings on T2‐weighted MRI, and so the T1 scan field‐of‐view is reduced to minimise the overall acquisition time. This study investigated cropping‐induced biases in T1‐MRI volumetric measurements and proposed and validated a solution.MethodThis study involved 1.5T T1‐weighted and T2‐weighted MRI data from 577 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI): 173 cognitively normal (CN); 262 mild cognitive impairment (MCI); 114 probable Alzheimer’s disease dementia (AD). The ADNI data was preprocessed to resemble clinical data seen in the CODEC dataset from the Essex Memory Clinic in the UK. The T1w scans were artificially cropped to a field of view of 120mm laterally. The T2w scans were down‐sampled to have axial slice thickness of 5mm. FreeSurfer’s synthSR tool was used to synthesize a super‐resolved T1wSR from the down‐sampled T2w. The T1wSR image was registered to the cropped T1w using mri_robust_registration, with the data from the T1wSR used to fill the missing voxels in the cropped image. FreeSurfer’s recon‐all tool was used to estimate regional brain volumes in cropped , crop‐filled and original T1w images, with results compared using Bland‐Altman analysis, R2 correlation metric, and T‐test between original and cropped/crop‐filled values.ResultFigure 1 shows an example T1w from ADNI (coronal/axial view, AD patient): original (top); artificially cropped (centre); crop‐filled (bottom). Table 1 shows groupwise demographics of the ADNI participants and overall experimental results. Figure 2‐5 shows Bland‐Altman plots and R2 correlation metric for the volumes of three AD‐relevant brain regions: hippocampus, middle temporal gyrus, and ventricles. Results suggest that the proposed crop‐filling solution works well: low percentage bias (&lt;1% crop‐filled; ∼2% cropped), high correlation (R2∼0.9 crop‐filled; ∼0.85 cropped).ConclusionThe new crop‐filling methodology was effective at removing this specific artefact seen in clinical neuroimaging data. This is an important step towards making real‐world neuroimaging data amenable to quantitative analyses.

Alternative Theory of AD Pathogenesis: Membrane Delimitation of the Histone Acetyltransferase Tip60/Kat5

AbstractBackgroundFor decades, mounting genetic and physiological data have pointed to the APP proteolysis as a seminal event in AD pathogenesis. This data has been viewed as supporting the amyloid hypothesis. However, growing data from multiple disciplines disputes that amyloid is a causal mechanism of neurodegeneration. Evidence suggests that FAD mutations are loss of function, inhibiting normal proteolytic processing of APP. APP extracellular and intracellular domains exhibit a broad array of binding interactions. Tip60 (a histone acetyltransferase, also known as Kat5) is an intracellular binding partner that supports the long‐standing speculation that APP functions as a signaling receptor. Recently, a conditional knockout (cKO) of Tip60 demonstrated neurodegenerative pathology and massive reactive gliosis, supporting a role for Tip60 in neurodegeneration. Reports that Tip60 is restricted from the nucleus in AD patient brains bolsters this idea.MethodTo assess the overlap of the cKO Tip60 model and human AD pathogenesis, we compared the dysregulated gene sets (DEGs) in the cKO Tip60 mouse and late‐onset AD postmortem brains. We break DEGs from mouse and human models into AD “biological domains” (BDs), and perform GSEA of GO enrichment within each BD. We then perform downstream analyses using network reconstruction applications and by examining the enriched BDs with pseudotime measures of disease progression in LOAD patients.ResultWe find significant overlap between DEGs in LOAD patients and the Tip60 cKO in multiple BDs, including, mitochondrial metabolism, immune response, structural stabilization, synaptic function, and endolysosomal trafficking. GSEA of LOAD and cKO Tip60 further implicates similar deficits in both models. The network analysis shows a convergence of gene dysregulation at core nodes, further implicating similar processes of dysregulation may impact particularly significant genes in human and mouse models. The pseudotime analysis shows that this dysfunction is an early signature of AD, suggesting Tip60 dysregulation may trigger early‐stage homeostatic destabilization.ConclusionWe propose that aberrant APP proteolysis traps Tip60 at the membrane, preventing the nuclear localization of Tip60, and altering both positive and negative gene regulation that is necessary for neuronal and glial homeostasis, and hypothesize that this is an explanation for the genetic linkage of APP proteolytic processing and AD.

Investigating a new neocortical mask for Centiloid quantification

AbstractBackgroundThe Centiloid (CL) project was developed to harmonise the quantification of Amyloid PET scans to a unified scale. The neocortical mask used for quantification was obtained using a private dataset of 19 mild AD patient and 25 older controls imaged using 11C‐PiB. The mean difference SUVR images were smoothed, subtracted and thresholded at 1.05 SUVR. While this threshold was chosen to maximise areas of specific Amyloid binding while avoiding areas of non‐specific binding, it was not evaluated in terms of agreement between different tracers or group separation. In this study, we created a new mask using an independent dataset of 11C‐PiB images, and investigated its impact on inter‐tracer agreement, tracer variability and group separation.MethodUsing the AIBL and OASIS databases, 63 mild AD (MMSE=20‐24;CL&gt;20) and 63 Healthy controls (MMSE&gt;=28;CDR=0;CL&lt;20) matched based on age and gender, were selected. Their 11C‐PiB images were spatially normalised using the SPM CL pipeline and transformed into SUVR using the whole cerebellum. A mean AD‐HC difference image was computed and thresholds of [0.6‐1.2] SUVR were explored. The resulting masks were evaluated in the 5 Amyloid tracers using the GAAIN head‐to‐head calibration datasets in terms of inter‐tracer agreement, variance in the young controls (YC) and YC‐AD effect‐size (ES). The recalibrated CL were evaluated on the AIBL dataset with the ES on the HC‐AD and HC‐MCI using baseline and rate of change (CL/yr).ResultUsing a higher threshold resulted in a smaller neocortical mask, better targeting regions of high Amyloid update. In the GAAIN dataset, the smaller masks led to higher R2 for each 11C‐PiB/18F‐Tracer pairs and higher YC‐AD ES. They also led to a lower variance in the YC for all tracers except for Flutemetamol. In AIBL, while it increased the ES at baseline, it decreased in the HC‐MCI when using CL/yr.ConclusionWhile using a smaller neocortical mask improved inter‐tracer agreement and reduced variance in YC, the results in AIBL indicate that it might not be as sensitive to detect early changes as highlighted with poorer HC‐MCI ES.

CT-Detected MTA Score Related to Disability and Behavior in Older People with Cognitive Impairment.

Our study aims to investigate the relationship between medial temporal lobe atrophy (MTA) score, assessed by computed tomography (CT) scans, and functional impairment, cognitive deficit, and psycho-behavioral disorder severity. Overall, 239 (M = 92, F = 147; mean age of 79.3 ± 6.8 years) patients were evaluated with cognitive, neuropsychiatric, affective, and functional assessment scales. MTA was evaluated from 0 (no atrophy) to 4 (severe atrophy). The homocysteine serum was set to two levels: between 0 and 10 µmol/L, and >10 µmol/L. The cholesterol and glycemia blood concentrations were measured. Hypertension and atrial fibrillation presence/absence were collected. A total of 14 patients were MTA 0, 44 patients were MTA 1, 63 patients were MTA 2, 79 patients were MTA 3, and 39 patients were MTA 4. Cognitive (p < 0.0001) and functional (p < 0.0001) parameters decreased according to the MTA severity. According to the diagnosis distribution, AD patient percentages increased by MTA severity (p < 0.0001). In addition, the homocysteine levels increased according to MTA severity (p < 0.0001). Depression (p < 0.0001) and anxiety (p = 0.001) increased according to MTA severity. This study encourages and supports the potential role of MTA score and CT scan in the field of neurodegenerative disorder research and diagnosis.