Severe Alzheimer's Disease Research Articles

Analytical and Clinical Assessment of Plasma Phospho-Tau Isoforms in Alzheimer’s Disease (AD) (S15.006)

<h3>Objective:</h3> Evaluate the analytical and clinical performance of four p-Tau assays using plasma from AD subjects and healthy controls, and determine correlative and discriminatory relationships for each assay and clinical diagnosis group. <h3>Background:</h3> Highly phosphorylated Tau protein is a major component of neurofibrillary tangles, a primary AD neuropathological cortical marker. Recently, sensitive immunoassays capable of measuring p-Tau isoforms p-Tau217 and p-Tau181 in blood have been developed, with promising diagnostic potential for AD. <h3>Design/Methods:</h3> AD plasma (n=64) and healthy control plasma (n=25) were analyzed with Simoa p-Tau217 developed by Alzpath, p-Tau181V2 and p-Tau181V2.1 (Quanterix) immunoassays using the HD-X analyzer, and the Lumipulse p-Tau181 (Fujirebio) immunoassay using the G1200 system. Plasma p-Tau levels were evaluated within AD sample groups consisting of mild (n=16, MMSE &gt;23–30), moderate (n=20, MMSE=16–22) and severe (n=28, MMSE&lt;16) cognitive impairment, and healthy controls (n=25). <h3>Results:</h3> P-tau levels were detectable by the four assays in &gt;95% of all samples. Analysis by the three p-Tau181 and one p-Tau217 assays revealed significant increases in median p-Tau levels in the combined AD group (2.5–4.4-fold; p&lt;0.0001, n = 64), relative to controls (n=25), and group discrimination (ROC-AUC=0.92). Significant median p-Tau elevations of 2.8–8.5 fold were observed in the moderate and severe dementia groups (p &lt;0.0001) and 1.3–1.8 fold in the mild dementia group (p=0.0001–0.003), although distributions overlapped. Moderate or severe dementia group discrimination from controls was more pronounced (AUC&gt;0.95) compared to mild dementia (AUC=0.75–0.84). Moderate to strong correlations between the p-Tau levels measured by the four assays were observed (Pearson r = 0.7–0.9). <h3>Conclusions:</h3> All p-Tau measurements were significantly elevated in the plasma of mild, moderate, and severe AD groups. All four p-Tau assays demonstrated robust analytical performance, and clinically differentiated AD plasma from healthy control plasma (p&lt;0.0001). Plasma p-Tau181 and p-Tau217 biomarkers provide a practical diagnostic opportunity to identify AD patients. <b>Disclosure:</b> Dr. Chenna has received personal compensation for serving as an employee of LabCorp. Dr. Jeromin has received personal compensation for serving as an employee of AlzPath, Inc. Dr. Jeromin has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Quanterx. Mr. Yee has received personal compensation for serving as an employee of Monogram Biosciences/LabCorp. Mr. Yee has stock in LabCorp. Youssouf Badal has nothing to disclose. Mrs. Mendes has nothing to disclose. Dr. Petropoulos has received personal compensation for serving as an employee of Monogram Biosciences-Labcorp. Dr. Petropoulos has received stock or an ownership interest from Laboratory Corporation of America Holdings. Dr. Petropoulos has received intellectual property interests from a discovery or technology relating to health care. Dr. Winslow has received personal compensation for serving as an employee of Monogram Biosciences/Labcorp. Dr. Winslow has received intellectual property interests from a discovery or technology relating to health care.

Spatial characterization of tangle-bearing neurons and ghost tangles in the human inferior temporal gyrus with three-dimensional imaging.

Studies of post-mortem human tissue provide insight into pathological processes, but are inherently limited by practical considerations that limit the scale at which tissue can be examined, and the obvious issue that the tissue reflects only one time point in a continuous disease process. We approached this problem by adapting new tissue clearance techniques to an entire cortical area of human brain, which allows surveillance of hundreds of thousands of neurons throughout the depth of the entire cortical thickness. This approach allows detection of 'rare' events that may be difficult to detect in standard 5 micrometre-thick paraffin sections. For example, it is well established that neurofibrillary tangles begin within a neuron, and ultimately, in at least some instances, persist in the brain even after the neuron has died. These are referred to as 'ghost tangles', a term that appropriately implies their 'difficult to see' ephemeral qualities. We set out to find ghost tangles as one example of the power of the tissue clearance/image analysis techniques to detect rare events, and to learn what happens at the end-point of a tangle's life history. We were able to identify 8103 tau tangles, 132 465 neurons and 299 640 nuclei in tissue samples from three subjects with severe Alzheimer's disease (Braak V-VI) and 4 tau tangles, 200 447 neurons and 462 715 nuclei in tissue samples from three subjects with no significant tau pathology (Braak 0-I). Among these data, we located 57 ghost tangles, which makes them only 0.7% of the total tau tangles observed. We found that ghost tangles are more likely to be found in cortical layers 3 and 5 (49/57), with a select few scattered across other layers 1, 2, 4 and 6. This ability to find rare events, such as ghost tangles, in large enough quantities to statistically test their distribution exemplifies how tissue clearing can be used as a powerful tool for studying selective vulnerability or resilience to pathology across brain regions.

Mechanism and efficacy of drugs for Alzheimer's disease

Alzheimer's disease (AD) has become into a global concern to public health. Since it was first discovered in 1901, people have studied it for more than one hundred years, and many hypotheses have been proposed. However, its pathogenesis has not been completely revealed. In addition, the treatment and diagnosis of AD is a challenge worldwide, especially in low-income countries. Fortunately, however, some classical hypotheses have their validity, such as cholinergic injury hypothesis, Aβ cascade hypothesis and abnormal modification hypothesis of tau protein. And the drugs developed on the basis of these classical hypotheses have finally been proved to have therapeutic effects on Alzheimer's disease through continuous experiments by researchers. Among them, Aricept is a drug used in mild AD treating, which acts as cholinesterase inhibitor, while N-methyl-D-aspartic acid (NMDA) receptor antagonist Namenda is used to treat moderate or severe AD. This review reviews the background of Alzheimer's disease and its two available treatment medicines, called Aricept and Namenda, including drug mechanism, efficacy, safety and their pharmacokinetics.

Long-term radiofrequency electromagnetic fields exposure attenuates cognitive dysfunction in 5×FAD mice by regulating microglial function.

We have previously found that long-term effects of exposure to radiofrequency electromagnetic fields in 5×FAD mice with severe late-stage Alzheimer's disease reduced both amyloid-β deposition and glial activation, including microglia. To examine whether this therapeutic effect is due to the regulation of activated microglia, we analyzed microglial gene expression profiles and the existence of microglia in the brain in this study. 5×FAD mice at the age of 1.5 months were assigned to sham- and radiofrequency electromagnetic fields-exposed groups and then animals were exposed to 1950 MHz radiofrequency electromagnetic fields at a specific absorption rate of 5 W/kg for 2 hours/day and 5 days/week for 6 months. We conducted behavioral tests including the object recognition and Y-maze tests and molecular and histopathological analysis of amyloid precursor protein/amyloid-beta metabolism in brain tissue. We confirmed that radiofrequency electromagnetic field exposure for 6 months ameliorated cognitive impairment and amyloid-β deposition. The expression levels of Iba1 (pan-microglial marker) and colony-stimulating factor 1 receptor (CSF1R; regulates microglial proliferation) in the hippocampus in 5×FAD mice treated with radiofrequency electromagnetic fields were significantly reduced compared with those of the sham-exposed group. Subsequently, we analyzed the expression levels of genes related to microgliosis and microglial function in the radiofrequency electromagnetic fields-exposed group compared to those of a CSF1R inhibitor (PLX3397)-treated group. Both radiofrequency electromagnetic fields and PLX3397 suppressed the levels of genes related to microgliosis (Csf1r, CD68, and Ccl6) and pro-inflammatory cytokine interleukin-1β. Notably, the expression levels of genes related to microglial function, including Trem2, Fcgr1a, Ctss, and Spi1, were decreased after long-term radiofrequency electromagnetic field exposure, which was also observed in response to microglial suppression by PLX3397. These results showed that radiofrequency electromagnetic fields ameliorated amyloid-β pathology and cognitive impairment by suppressing amyloid-β deposition-induced microgliosis and their key regulator, CSF1R.

Assessing What Matters to People Affected by Alzheimer's Disease: A Quantitative Analysis.

In this phase of the ongoing What Matters Most study series, designed to evaluate concepts that are meaningful to people affected by Alzheimer's disease (AD), we quantified the importance of symptoms, impacts, and outcomes of AD to people at risk for or with AD and care partners of people with AD. We administered a web-based survey to individuals at risk for or with AD (Group 1: unimpaired cognition with evidence of AD pathology; Group 2: AD risk factors and subjective cognitive complaints/mild cognitive impairment; Group 3: mild AD) and to care partners of individuals with moderate AD (Group 4) or severe AD (Group 5). Respondents rated the importance of 42 symptoms, impacts, and outcomes on a scale ranging from 1 ("not at all important") to 5 ("extremely important"). Among the 274 respondents (70.4% female; 63.1% white), over half of patient respondents rated all 42 items as "very important" or "extremely important," while care partners rated fewer items as "very important" or "extremely important." Among the three patient groups, the minimum (maximum) mean importance rating for any item was 3.4 (4.6), indicating that all items were at least moderately to very important. Among care partners of people with moderate or severe AD, the minimum (maximum) mean importance rating was 2.1 (4.4), indicating that most items were rated as at least moderately important. Overall, taking medications correctly, not feeling down or depressed, and staying safe had the highest importance ratings among both patients and care partners, regardless of AD phase. Concepts of importance to individuals affected by AD go beyond the common understanding of "cognition" or "function" alone, reflecting a desire to maintain independence, overall physical and mental health, emotional well-being, and safety. Preservation of these attributes may be key to understanding whether interventions deliver clinically meaningful outcomes.

Validation study of the Persian version of behavioral pathology in Alzheimer’s Disease Rating scale (BEHAVE-AD) and the empirical BHAVE-AD (E-BEHAVE-AD)

Introduction Behavioral and psychological symptoms of dementia (BPSD) are observed in more than 90% of patients with Alzheimer’s disease (AD). BPSDs are remediable if detected early and managed appropriately. Behavioral Pathology in Alzheimer’s disease Rating Scale (BEHAVE-AD) and Empirical BEHAVE-AD (E-BEHAVE-AD) were designed to identify BPSD. The aim of this study is to validate and prepare BEHAVE-AD and E-BEHAVE-AD in Persian language for clinical and research applications. Method 120 patients were selected through a combination of intentional and convenience sampling. All participants should fulfill the NINCDS-ADRDA Work Group criteria for a clinical diagnosis of Alzheimer’s disease. Functional Assessment Staging Tool (FAST) was used to determine the rate of AD progression. All patients were evaluated using the BEHAVE-AD and E-BEHAVE-AD questionnaires, as well as the Persian version of the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Mini-Mental State Examination (MMSE). The Content Validity Index (CVI) is determined based on the compatibility of the Persian and the original version of the two scales according to the opinion of expert panels. Correlation of MMSE with BEHAVE-AD and E-BEHAVE-AD as well as the BPSD pattern on AD progression continuum by FAST were considered as indices of construct validity. Concurrent validity was estimated by correlating NPI-Q scores with BEHAVE-AD and E-BEHAVE-AD scores. For both scales, interrater reliability was extracted as a reliability index. Results Pearson correlation coefficients for the BEHAVE-AD scale were as follows: with NPI-Q (r = 0.77, p-value <0.01), with MMSE (r = −0.34, p-value <0.01), indicating concurrent and construct validity, respectively. The result for E-BEHAVE-AD was as follows: with NPI-Q-total (r = 0.59, p-value <0.01), and with MMSE (r = 0.31, p-value <0. 01). BEHAVE-AD and E-BEHAVE-AD scores increased in parallel with AD severity according to FAST, but not on the most severe AD stage. The area under the curve was estimated to be 0.84 (p-value <0.001) for BEHAVE-AD and 0.78 (p-value <0.001) for E-BEHAVE-AD. Correlation between BEHAVE-AD and E-BEHAVE-AD scores ranged from 0.45 to 0.63. The inter-rater reliability index ranged from 0.88 to 0.99 for BEHAVE-AD and from 0.74 to 0.95 for E-BEHAVE-AD. Conclusions The Persian version of BEHAVE-AD and E-BEHAVE-AD is valid and reliable for the assessment of BPSD in patients with AD.

Assessing awareness in severe Alzheimer's disease.

There is an urgent need to understand the nature of awareness in people with severe Alzheimer's disease (AD) to ensure effective person-centered care. Objective biomarkers of awareness validated in other clinical groups (e.g., anesthesia, minimally conscious states) offer an opportunity to investigate awareness in people with severe AD. In this article we demonstrate the feasibility of using Transcranial magnetic stimulation (TMS) combined with EEG, event related potentials (ERPs) and fMRI to assess awareness in severe AD. TMS-EEG was performed in six healthy older controls and three people with severe AD. The perturbational complexity index (PCIST) was calculated as a measure of capacity for conscious awareness. People with severe AD demonstrated a PCIST around or below the threshold for consciousness, suggesting reduced capacity for consciousness. ERPs were recorded during a visual perception paradigm. In response to viewing faces, two patients with severe AD provisionally demonstrated similar visual awareness negativity to healthy controls. Using a validated fMRI movie-viewing task, independent component analysis in two healthy controls and one patient with severe AD revealed activation in auditory, visual and fronto-parietal networks. Activation patterns in fronto-parietal networks did not significantly correlate between the patient and controls, suggesting potential differences in conscious awareness and engagement with the movie. Although methodological issues remain, these results demonstrate the feasibility of using objective measures of awareness in severe AD. We raise a number of challenges and research questions that should be addressed using these biomarkers of awareness in future studies to improve understanding and care for people with severe AD.

Evaluating the treatment outcomes of repetitive transcranial magnetic stimulation in patients with moderate-to-severe Alzheimer's disease.

The repetitive transcranial magnetic stimulation (rTMS) shows great potential in the treatment of Alzheimer's disease (AD). However, its treatment efficacy for AD patients in moderate to severe stage is relatively evaluated. Here, we proposed a randomized, sham-controlled, clinical trial of rTMS among 35 moderate-to-severe AD patients. A high frequency (10 Hz) stimulation of the left dorsal lateral prefrontal cortex (DLPFC), 60-session long treatment lasting for 3 months procedure was adopted in the trial. Each participant completed a battery of neuropsychological tests at baseline and post-treatment for evaluation of the rTMS therapeutic effect. Twelve of them completed baseline resting-state functional magnetic resonance imaging (fMRI) for exploration of the underlying neural contribution to individual difference in treatment outcomes. The result showed that the rTMS treatment significantly improved cognitive performance on the severe impairment battery (SIB), reduced psychiatric symptoms on the neuropsychiatric inventory (NPI), and improved the clinician's global impression of change (CIBIC-Plus). Furthermore, the result preliminarily proposed resting-state multivariate functional connectivity in the (para) hippocampal region as well as two clusters in the frontal and occipital cortices as a pre-treatment neuroimaging marker for predicting individual differences in treatment outcomes. The finding could brought some enlightenment and reference for the rTMS treatment of moderate and severe AD patients.

Alpha Rhythm Wavelength of Electroencephalography Signals as a Diagnostic Biomarker for Alzheimer's Disease.

To explore changes in the alpha rhythm wavelength of background electroencephalography in Alzheimer's disease patients with different degrees of dementia in a resting state; examine their correlation with the degree of cognitive impairment; determine whether the alpha rhythm wavelength can distinguish mild Alzheimer's disease patients, moderately severe Alzheimer's disease patients, and healthy controls at the individual level; and identify a cut-off value to differentiate Alzheimer's disease patients from healthy controls. Quantitative electroencephalography signals of 42 patients with mild Alzheimer's disease, 42 patients with moderately severe Alzheimer's disease, and 40 healthy controls during rest state with eyes closed were analyzed using wavelet transform. Electroencephalography signals were decomposed into different scales, and their segments were superimposed according to the same length (wavelength and amplitude) and phase alignment. Phase averaging was performed to obtain average phase waveforms of the desired scales of each lead. The alpha-band wavelengths corresponding to the ninth scale of the background rhythm of different leads were compared between groups. The average wavelength of the alpha rhythm phase of the whole-brain electroencephalography signals in Alzheimer's disease patients was prolonged and positively correlated with the severity of cognitive dysfunction (P < 0.01). The ninth-scale phase average wavelength of each lead had high diagnostic efficacy for Alzheimer's disease, and the diagnostic efficacy of lead P3 (area under the receiver operating characteristic curve = 0.873) was the highest. The average wavelength of the electroencephalography alpha rhythm phase may be used as a quantitative feature for the diagnosis of Alzheimer's disease, and the slowing of the alpha rhythm may be an important neuro-electrophysiological index for disease evaluation.

Cerebrovascular Changes and Cerebral Atrophy in the Development of Dementia during Alzheimer's Disease

Background: Alzheimer's disease (AD) is the world's number one cerebral neurodegenerative disease. Up to 80% of all dementia cases are due to this disease. AD occurs not only because of impaired metabolism of amyloid beta (Aβ) and tau protein in cerebral tissue, but also in connection with specific disorders of cerebral blood supply, manifested in dyscirculatory angiopathy of Alzheimer's type (DAAT). Aims: The present research focuses on the clinical discovery of the sequence of development of dyscirculatory angiopathy of Alzheimer's type, cerebral atrophy, and dementia in patients with AD and their immediate family members. Methods: 99 patients were selected for the research, of whom: Test Group 1 93 (93.94%) suffered from various stages of AD and severity of dementia (age 34-79 (mean age 67): 32 (34.40%) men, 61 (65.59%) women). Test Group 2 6 (6.06%) children aged 8-12 with a high probability of inheriting AD. Each of them had a parent diagnosed with AD with mild dementia (TDR-1), and a grandparent diagnosed with AD with moderate (TDR-2) or severe dementia (TDR-3). Each child complained of fatigue, memory loss, difficulty in remembering, difficulty in concentrating, and frequent headaches. Results: Test Group 1. According to the severity of dementia and atrophic changes in the temporal lobes, the patients were subdivided: preclinical stage TDR-0 - 10 (10.75%) people, mild stage AD TDR-1 - 26 (27.96%) people, moderately severe stage AD TDR-2-40 (43.01%) people, severe AD TDR-3 - 17 (18.28%) people. We identified dyscirculatory angiopathy of Alzheimer's type in all patients, regardless of their AD stage. Test Group 2. There were no signs of dementia of cognitive disorders in any case. Initial involutive cerebral changes were detected in all 6 (100%) patients. Phenomena similar to DAAT were detected in all 6 (100%) patients. Conclusion: Cerebrovascular changes manifested by dyscirculatory angiopathy of Alzheimer's type, regardless of the stage of the disease, are observed in all patients with AD, as well as in all their young offspring. These changes affect amyloid beta metabolism in the brain and contribute to its deposition and accumulation in cerebral tissue, which leads to neurodegeneration and AD development. The data obtained indicate that dyscirculatory angiopathy of Alzheimer's type is primary and, moreover, possibly congenital in AD development.

Cognitive resilience and severe Alzheimer's disease neuropathology.

Cognitive resilience in Alzheimer's disease (AD) can be defined as retention of high cognition despite presence of considerable cerebral AD lesions. We sought to identify factors associated with this phenomenon. Data were obtained from National Alzheimer's Coordinating Centre (NACC) dataset. Subjects with severe AD neuropathology, based on National Institute on Aging-Reagan (NIA-Reagan) criteria, no other primary neuropathology, and a≤2-year interval between last follow-up and death were included. Mini-mental status examination score≥24 was used as a proxy for normal cognition. In total, 654 cases were included; 59 (9%) were cognitively resilient. Multivariable logistic regression model showed that resilient participants were more educated, had a lower body mass index (BMI), were more likely to be lifetime/recent smoker or use an anticoagulant/antiplatelet agent, compared with cognitively impaired subjects. In addition to expected protective factors such as higher education and lower BMI, our results showed that smoking (especially recent smoking) and anticoagulant/antiplatelet consumption are associated with resilience to clinical cognitive expression of severe AD pathology. Pharmacological approaches using this information might be explored for clinical AD amelioration.

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

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

Systemic Inflammation Causes Microglial Dysfunction With a Vascular AD phenotype

BackgroundStudies in rodents and humans have indicated that inflammation outside CNS (systemic inflammation) affects brain homeostasis contributing to neurodevelopmental disorders. Itis becoming increasingly evident that such early insults may also belinked to neurodegenerative diseases like late-onset Alzheimer's disease (AD). Importantly, lifestyle and stress, such as viral or bacterial infection causing chronic inflammation, may contribute to neurodegenerative dementia. Systemic inflammatory response triggers a cascade of neuroinflammatory responses, altering brain transcriptome, cell death characteristic of AD, and vascular dementia. Our study aimed to assess the temporal evolution of the pathological impact of systemic inflammation evoked by prenatal and early postnatal peripheral exposure of viral mimetic Polyinosinic:polycytidylic acid (PolyI:C) and compare the hippocampal transcriptomic changes with the profiles of human post-mortem AD and vascular dementia brain specimens. MethodsWe have engineered the PolyI:C sterile infection model in wildtype C57BL6 mice to achieve chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months, and 16 months), taking the hippocampus as a reference brain region, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD, and Controls (CTL), in parallel to Vascular dementia (VaD) patients’ specimens. ResultsWe found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological shifts progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression throughout aging, with a peak in differential expression at 9 months. We show that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD and VaD shows the reproducibility of some gene targets in vascular dementia specimens as compared to AD ones. ConclusionsThe PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation causes progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling, and the loss of neuronal functionality seen to some extent in human AD and Vascular dementia suggesting early immune insults could be crucial in neurodegenerative diseases.

Boosting of tau protein aggregation by CD40 and CD48 gene expression in Alzheimer's disease.

Neurodegenerative diseases result from the interplay of abnormal gene expression and various pathological factors. Therefore, a disease-specific integrative genetic approach is required to understand the complexities and causes of target diseases. Recent studies have identified the correlation between genes encoding several transmembrane proteins, such as the cluster of differentiation (CD) and Alzheimer's disease (AD) pathogenesis. In this study, CD48 and CD40 gene expression in AD, a neurodegenerative disease, was analyzed to infer this link. Total RNA sequencing was performed using an Alzheimer's disease mouse model brain and blood, and gene expression was determined using a genome-wide association study (GWAS). We observed a marked elevation of CD48 and CD40 genes in Alzheimer's disease. Indeed, the upregulation of both CD48 and CD40 genes was significantly increased in the severe Alzheimer's disease group. With the elevation of CD48 and CD40 genes in Alzheimer's disease, associations of protein levels were also markedly increased in tissues. In addition, overexpression of CD48 and CD40 genes triggered tau aggregation, and co-expression of these genes accelerated aggregation. The nuclear factor kappa B (NF-ĸB) signaling pathway was enriched by CD48 and CD40 gene expression: it was also associated with tau pathology. Our data suggested that the CD48 and CD40 genes are novel AD-related genes, and this approach may be useful as a diagnostic or therapeutic target for the disease.

Concordance and discordance in disease severity classification between clinician judgments and cognitive testing scores for Alzheimer’s disease in the United States Veterans Affairs Healthcare System

AbstractBackgroundThe current standard of practice for assessment of Alzheimer’s disease (AD) severity in the Department of Veterans Affairs (VA) Healthcare System is primarily based on clinical examination and cognitive testing. We aimed to assess the consistency between clinician judgements of AD severity compared with that classified by cognitive test scores in the VA system.MethodWe identified medical notes for patients with mild, moderate, or severe AD from the VA electronic healthcare records (EHR) database between March 2008 and October 2021, using the natural language processing technology. Mini‐Mental Status Exam (MMSE) and Montreal Cognitive Assessment (MoCA) scores from the corresponding medical notes with physician judgments were classified and used for comparisons of severity levels. A binary variable was coded to indicate concordance or discordance for each paired comparison.ResultWe screened clinical notes from 51,809 AD patients and analyzed 8,888 clinical notes that had either an MMSE or MoCA test score from 5,150 AD patients (3.5% female; average age at 78.1±9.4 years). Clinician judgements and test‐score‐based classification of AD severity were concordant in 53.2% of comparisons (weighted Kappa = 0.39, 95% CI:0.38‐0.41, p = 0.009); whereas clinician judgments were less severe in 25.7% and more severe in 21.1% comparisons, relative to the test‐score‐based severity level. Clinician judgments were concordant with 54.1%, 51.8%, and 53.0% cognitive test‐score‐based classifications, of mild, moderate, and severe AD, respectively. Concordance was observed in 55.9% clinician judgments involving internist, 53.0% involving psychiatrist or neurologist, and 51.7% involving psychologist specialties, and in 50.4% involving nurse practitioners. Among discordant severity classifications, clinician judgments tended to be less severe than test scores (Figure).ConclusionExamination of VA EHR reveals that nearly one half of clinician judgments of AD severity are discordant with severity classification based on the MMSE or MoCA test scores. Discordance is more pronounced in the moderate relative to mild and severe AD categories but does not vary substantially over clinicians’ specialty background. Research will aim to find plausible explanations for the variation of concordance vs discordance by further examining the relative contributions of patient, clinician, and system characteristics in the process of AD clinical assessments.

Resilience to Alzheimer’s Disease in a pathologicaly confirmed cohort

AbstractBackgroundWhy some individuals with significant Alzheimer’s disease(AD) lesions in their brain retain their cognitive abilities while others with the same level of pathology manifest symptoms of dementia remains incompletely understood. The term cognitive resilience refers to this phenomenon. With limited success in pharmacological interventions that prevent the onset of AD pathology, more efforts are aiming toward developing strategies to delay the clinical expression of AD; acetylcholinesterase inhibitors serve as an example, and compounds with similar pharmacodynamics such as nicotine may play a similar role. Here we sought to identify demographic, clinical, genetic, and neuropathological features associated with cognitive resilience in participants with severe AD neuropathology.MethodData for this retrospective cohort was collected from the datasets developed by the National Alzheimer’s Coordinating Centre (NACC). Individuals with severe AD pathology and no other primary neuropathology diagnoses who had their last visit within 2 years of their time of death were included. Severe AD pathology definition was based on National Institute on Aging–Reagan (NIA‐Reagan) criteria pathology, i.e., frequent neuritic plaques and Braak &amp; Braak stage V/VI pathology. Cognition was assessed using the Mini‐Mental Status Examination (MMSE) score at their last visit and cases with scores ≥24 were defined as being cognitively intact, and thus resilient. Following bivariate analysis to compare resilient with non‐resilient groups, significantly different variables were adjusted for demographics using logistic regression analysis. Subsequently, statistically significant characteristics were entered in a multivariable model.ResultsWe classified 59(9%) individuals as resilient and 595(91%) as non‐resilient. The binary logistic regression model showed that resilient subjects were older (odds ratio[OR] = 1.03;95% confidence interval[CI] = 1–1.07), had more years of education (OR = 1.16;95%CI = 1.04‐1.29), had lower BMI (OR = 0.91;95%CI = 0.85‐0.99), were more likely to be a smoker (OR = 2.78;95% CI = 1.45‐5.34), and were more likely to use an anticoagulant/antiplatelet at last visit compared with subjects with impaired cognition (OR = 1.87;95%CI = 1.01‐3.48).ConclusionsOur results corroborated previous findings that lower BMI and higher education are associated with AD cognitive resilience, and additionally demonstrated that the level of smoking and usage of anticoagulant/antiplatelet medication have a direct relationship with cognitive resilience to AD severe pathology. Nicotine mimetics could be explored as a potential option for preventing AD clinical expression.

TMEM176B regulates phagosome maturation of glial cells and its increased activity contributes to the therapy of Alzheimer’s disease

AbstractBackgroundGiven recent interest in using amyloid b (Aβ)‐targeted antibodies as a therapy for patients with Alzheimer’s disease (AD), removal of Aβ by phagocytosis likely protective early in AD. Impaired phagocytic function of glial cells surrounding Aβ plaques during later stages in AD likely contributes to worsened disease outcomes, therefore enhancing phagocytic activity of glial cells could be a potent strategy for AD therapy.MethodChanges in TMEM176B expression according to the progression of AD pathology was assessed by measuring TMEM176B protein in human AD brain lysates and TMEM176B transcripts in Ab‐treated primary rat astrocytes. The roles of TMEM176B in phagosome maturation of glial cells was investigated by measuring Rab5, Rab7, LAMP1, LAMP2, cathepsin D, and LC3B in presence of Aβ. Intracellular pH of glial cells was detected using fluorescent dye‐based pHrodo Red AM intracellular pH indicator (Invitrogen, Carlsbad, CA). In 5xFAD and 3xTg AD mice model, therapeutic effects of AAV‐TMEM176B was examined. AAV (adenovirus‐associated virus)‐TMEM176B (1 – 2×1010 GC) was intracerebroventricularly injected, and Aβ plaque and p‐tau in brains were assessed 3 months later. Behavioral studies such as Y‐maze, Morris water maze, and novel‐object‐recognition were conducted to exam the effect of TMEM176B overexpression in alleviation of cognition decline.ResultIn human AD brains, Tmem176B expression was increased in moderate AD (Braak III‐IV) was decreased in severe AD (Braak V‐VI). TMEM176B was upregulated by acute Aβ treatment in primary rat astrocytes, and was gradually downregulated concomitantly with impairment of Aβ phagocytosis activity by chronic exposure to Aβ. The TMEM176B agonistic compound augmented phagosome maturation and phagosomal acidification, which led to increased Aβ phagocytosis and lysosomal degradation. Studies confirmed that intracerebroventrical administration of AAV carrying TMEM176B in AD mice results in enhanced glial phagocytosis followed by lowered Aβ burden in brain. Moreover, overexpression of TMEM176B by AAV injection significantly improved cognition impairment of AD mice.ConclusionData from these studies suggest that TMEM176B plays a direct and critical role in phagolysosmal function of glial cells and AD pathogenesis and highlight this ion channel as a potential therapeutic target for treating AD.

Age‐at‐Onset and APOE Related Heterogeneity in the Clinical, Plasma Biomarker, and Neuropathologic Presentation of Alzheimer’s Disease (AD)

AbstractBackgroundPatients with sporadic early‐onset AD (EOAD) show less pronounced memory impairment, faster cognitive decline, and greater likelihood of focal cortical syndromes than those with later onset (LOAD), while often lacking the APOE ε4 allele classically associated with younger onset. This heterogeneity could arise from differences in the distribution of AD pathology or presence of concomitant pathologies.MethodWe examined clinical and cognitive heterogeneity in relation to age‐at‐onset, APOE genotype, and concomitant neuropathology (Lewy body, TDP‐43, and vascular) in patients with autopsy‐confirmed severe AD from the National Alzheimer’s Coordinating Center database (N=1750). In patients from the UCSD Alzheimer’s Disease Research Center (N=121) we examined how age‐related heterogeneity relates to differences in distribution of neurofibrillary tangle (NFT) pathology and plasma biomarkers of AD.ResultAge‐at‐onset distribution in APOE ε4‐ patients was bimodal with best separation at age 63. Patients with EOAD (age ≤63) had faster cognitive and functional decline than LOAD regardless of APOE genotype; and were more likely to present with nonmemory cognitive complaints (OR=5.56, 99%CI: 3.32‐9.39), show greater executive dysfunction (β=2.59 SD, 99%CI: 2.10‐3.09), and receive a non‐AD clinical diagnosis (OR=1.54, 99%CI: 1.19‐1.97), particularly for ε4‐ EOAD (p’s&lt;0.01, APOE × age‐at‐onset interactions). Despite this atypicality, groups did not differ in their high rates of AD biomarker positivity, and ε4‐ EOAD patients were most likely to have pure AD without concomitant pathology. TDP‐43 (OR=0.37; 99%CI: 0.18–0.72) and microvascular (OR=0.65; 99%CI: 0.47–0.88) pathology were less common in EOAD, while Lewy pathology was more common in ε4+ (OR=1.48; 99% CI, 1.02–2.17). Midfrontal NFT density was higher in EOAD than LOAD (β= 0.87 SD, 99%CI: 0.44‐1.29). Greater hippocampal NFT density was associated with APOE ε4+ (β=0.49 SD, 99%CI: 0.02‐0.96). Mediation analyses suggest that differences in midfrontal/hippocampal NFT ratio, rather than concomitant neuropathology, mediate the atypical cognitive profiles and decline of EOAD (p&lt;0.01).ConclusionA relatively more neocortical NFT distribution, rather than concomitant non‐AD pathology, accounts for the atypical, non‐memory dominant clinical presentation and rapid progression in EOAD. This suggests that selective cortical vulnerability may explain the earlier‐than‐expected onset and atypical profile in these individuals without the APOE ε4 risk allele.

Dysphagia in Alzheimer's disease

The article highlights the problem of dysphagia, which is often present in patients with Alzheimer's disease (AD), as a rule, at advanced stages of the disease and significantly complicates the management of this group of patients. Issues of age-related physiologic swallowing changes are considered. Mechanisms of dysphagia development in the elderly and in AD patients are discussed. It is noted that in AD areas of the cerebral cortex, involved in the act of normal swallowing are affected. The most dangerous complication of dysphagia is aspiration, which increases the risk of pneumonia and death. It is noted that dysphagia in patients with AD leads to weight loss and increased dependence on nutrition. Weight loss increases the risk of opportunistic infections in patients with AD. In the case of dysphagia symptoms development, pill administration causes great problems. In this scenario, the solution is the use of dispersible or liquid forms of drugs. We describe a clinical case of severe AD in which a dispersible form of memantine, Memoritab, was used. The complications associated with dysphagia in patients with AD highlight the importance of early detection and treatment of this symptom. Understanding the specific pathological processes of the underlying disease that contribute to the development of dysphagia is necessary in order to adapt the treatment of patients in a timely fashion.

Assessing the Cost-effectiveness of a Hypothetical Disease-modifying Therapy With Limited Duration for the Treatment of Early Symptomatic Alzheimer Disease

PurposeClinical trials have produced promising results for disease-modifying therapies (DMTs) for Alzheimer’s disease (AD); however, the evidence on their potential cost-effectiveness is limited. This study assesses the cost-effectiveness of a hypothetical DMT with a limited treatment duration in AD. MethodsWe developed a Markov state–transition model to estimate the cost-effectiveness of a hypothetical DMT plus best supportive care (BSC) versus BSC alone among Americans living with mild cognitive impairment (MCI) due to AD or mild AD. AD states included MCI due to AD, mild AD, moderate AD, severe AD, and death. A hypothetical DMT was assumed to confer a 30% reduction in progression from MCI and mild AD. The base case annual drug acquisition cost was assumed to be $56,000. Other medical and indirect costs were obtained from published literature or list prices. Utilities for patients and caregivers were obtained from the published literature and varied by AD state and care setting (community care or long-term care). We considered 3 DMT treatment strategies: (1) treatment administered until patients reached severe AD (continuous strategy), (2) treatment administered for a maximum duration of 18 months or when patients reached severe AD (fixed-duration strategy), and (3) 40% of patients discontinuing treatment at 6 months because of amyloid plaque clearance and the remaining patients continuing treatment until 18 months or until they reached severe AD (test-and-discontinue strategy). Incremental cost-effectiveness ratios (ICERs) were calculated as the incremental cost per quality-adjusted life-year (QALY) gained. FindingsFrom the health care sector perspective, continuous treatment with a hypothetical DMT versus BSC resulted in an ICER of $612,354 per QALY gained. The ICER decreased to $157,288 per QALY gained in the fixed-duration strategy, driven by large reductions in treatment costs. With 40% of patients discontinuing treatment at 6 months (test-and-discontinue strategy), the ICER was $125,631 per QALY gained. In sensitivity and scenario analyses, the ICER was the most sensitive to changes in treatment efficacy, treatment cost, and the initial population AD state distribution. From the modified societal perspective, ICERs were 6.3%, 20.4%, and 25.1% lower than those from the health care sector perspective for the continuous, fixed-duration, and test-and-discontinue strategies, respectively. ImplicationsUnder a set of assumptions for annual treatment costs and the magnitude and duration of treatment efficacy, DMTs used for a limited duration may deliver value consistent with accepted US cost-effectiveness thresholds.