Early Alzheimer's Disease Research Articles

Novel Pathogenic Mechanism of Late-onset Alzheimer's Disease by Deficiency of NMDA Receptor Subunit GluN3A

Late-onset Alzheimer’s disease (AD) and related dementia (ADRD) are serious neurodegenerative disorders among aging populations. The progress of AD/ADRD cultivates over years to decades in humans and several months in animal models. Ca<sup>2+</sup> homeostasis is a core function of neurons where the N-methyl-D-aspartate (NMDA) receptor plays a major role in excitatory neuronal activities. The Ca<sup>2+</sup> hypothesis of AD proposes that even slight but sustained Ca<sup>2+</sup> dyshomeostasis in the brain is a critical pathophysiology or pathogenesis of AD. However, instigating factors like the trigger and time/duration of the Ca<sup>2+</sup> dysregulation in AD progression have been largely obscure, while β-amyloid (Aβ) peptides are often indicated as the trigger. Hyperactivities of excitatory neurons and NMDARs have been implicated in AD as a main mediating mechanism caused by AD pathologies such as Aβ deposition. NMDAR overactivation is restrained by the unique regulatory GluN3 subunits (GluN3A and GluN3B; previously known as NR3A and NR3B). Expression of GluN3A in the receptor complex reduces NMDAR currents and Ca<sup>2+</sup> influx, while deletion of GluN3A causes larger NMDA currents and elevated intracellular Ca<sup>2+</sup>. Significant GluN3A levels are detected in both rodent and human adult/aging brains. We hypothesized that the “gatekeeper” role of GluN3A is constantly required for Ca<sup>2+</sup> homeostasis and normal aging; its deficiency can lead to slowly evolved “degenerative excitotoxicity”. Our in vitro, ex vivo, and in vivo studies using GluN3A knockout (KO) mice of young and older ages revealed neuronal hyperactivity, moderate but sustained elevation of cytosolic Ca<sup>2+</sup>, chronic inflammation, neuronal loss/apoptosis, synaptic impairments and progressive cognitive deficits. The AD hallmarks of Aβ and tau pathology were identified after, but not before, cognition decline. In the “gain of function” experiment, expression of GluN3A in the GluN3A KO brain prevented AD progression. Specific regional knockdown of GluN3A in the cortex and hippocampus of wild-type mice at the adult age (3 months old) resulted in similar AD/ADRD phenotypic alterations in the following 3-6 months. The NMDAR antagonist memantine (MEM) is approved by FDA as a symptomatic treatment for moderate-severe AD patients. According to the chronic neurohyperactivity in AD progression and the modified Ca<sup>2+</sup> hypothesis that Ca<sup>2+</sup> dysregulation is an early and “life-long” pathogenesis, the maintenance of NMDAR normal activity by MEM or other safe NMDAR antagonists could be a disease-modifying early treatment in preclinical/prodromal stages. This prediction is endorsed by clinical trials using MEM and other NMDAR antagonists in mild cognitive impairment (MCI) and early AD patients, showing beneficial effects of maintaining cognitive functions. Consistently, we showed that, in GluN3A KO mice and 5xFAD mice, early and chronic MEM treatment (started at 3-month of age and lasted for 3-6 months) prevented or attenuated AD phenotypes. Meanwhile, the chronic MEM therapy in mice showed preconditioning effect of neuroprotection against ischemic stroke that strikes over 50% AD patients. Large clinical trials of long-term and more systematic examinations on AD/ADRD progression and the comorbidity of stroke are warranted for this innovative therapy. Our results support the modification of Ca<sup>2+</sup> hypothesis of AD with the novel amyloid-independent mechanism. Specifically, the deficiency of GluN3A alone causes lifelong Ca<sup>2+</sup>-related progression of AD pathophysiology and amyloid pathology. The long-term GluN3A modulation of NMDARs signifies new therapeutic targets and possible preventive interventions for late-onset AD/ ADRD.

Human-derived air–liquid interface cultures decipher Alzheimer’s disease–SARS-CoV-2 crosstalk in the olfactory mucosa

BackgroundThe neurological effects of the coronavirus disease of 2019 (COVID-19) raise concerns about potential long-term consequences, such as an increased risk of Alzheimer's disease (AD). Neuroinflammation and other AD-associated pathologies are also suggested to increase the risk of serious SARS-CoV-2 infection. Anosmia is a common neurological symptom reported in COVID-19 and in early AD. The olfactory mucosa (OM) is important for the perception of smell and a proposed site of viral entry to the brain. However, little is known about SARS-CoV-2 infection at the OM of individuals with AD.MethodsTo address this gap, we established a 3D in vitro model of the OM from primary cells derived from cognitively healthy and AD individuals. We cultured the cells at the air–liquid interface (ALI) to study SARS-CoV-2 infection under controlled experimental conditions. Primary OM cells in ALI expressed angiotensin-converting enzyme 2 (ACE-2), neuropilin-1 (NRP-1), and several other known SARS-CoV-2 receptor and were highly vulnerable to infection. Infection was determined by secreted viral RNA content and confirmed with SARS-CoV-2 nucleocapsid protein (NP) in the infected cells by immunocytochemistry. Differential responses of healthy and AD individuals-derived OM cells to SARS-CoV-2 were determined by RNA sequencing.ResultsResults indicate that cells derived from cognitively healthy donors and individuals with AD do not differ in susceptibility to infection with the wild-type SARS-CoV-2 virus. However, transcriptomic signatures in cells from individuals with AD are highly distinct. Specifically, the cells from AD patients that were infected with the virus showed increased levels of oxidative stress, desensitized inflammation and immune responses, and alterations to genes associated with olfaction. These results imply that individuals with AD may be at a greater risk of experiencing severe outcomes from the infection, potentially driven by pre-existing neuroinflammation.ConclusionsThe study sheds light on the interplay between AD pathology and SARS-CoV-2 infection. Altered transcriptomic signatures in AD cells may contribute to unique symptoms and a more severe disease course, with a notable involvement of neuroinflammation. Furthermore, the research emphasizes the need for targeted interventions to enhance outcomes for AD patients with viral infection. The study is crucial to better comprehend the relationship between AD, COVID-19, and anosmia. It highlights the importance of ongoing research to develop more effective treatments for those at high risk of severe SARS-CoV-2 infection.Graphical

Lecanemab: A Humanized Monoclonal Antibody for the Treatment of Early Alzheimer Disease.

To review current pharmacology, pharmacokinetics/pharmacodynamics, safety, and efficacy of lecanemab in patients with Alzheimer disease. A literature search of PubMed (April 1, 2016-November 15, 2023) and ClinicalTrials.gov search were conducted using the following search terms: lecanemab and BAN2401. Additional articles were identified by hand from references. We included English-language clinical trials, randomized controlled trials, reviews, and systematic reviews evaluating lecanemab pharmacology, efficacy, or safety in humans for the management of Alzheimer disease. In the Clarity AD phase III trial, lecanemab led to a decrease in brain amyloid levels and showed moderate improvement in clinical measures of cognition and function. At 18 months, lecanemab 10 mg/kg biweekly exhibited a lower least squares mean change from baseline (1.21) compared to placebo (1.66) of Clinical Dementia Rating-Sum of Boxes score, signifying a significant difference of -0.45 (95% CI, -0.67 to -0.23; P < 0.001). In a subset of 698 participants, lecanemab reduced brain amyloid burden by -59.1 Centiloids (95% CI, -62.6 to -55.6). Lecanemab demonstrated favorable differences in Alzheimer Disease Assessment Scale-cognitive subscale 14, Alzheimer Disease Composite Score, and Alzheimer Disease Cooperative Study-Mild Cognitive Impairment-Activities of Daily Living scores. Adverse events included infusion-related reactions (26.4%) and amyloid-related imaging abnormalities (12.6%). Lecanemab reduces cognitive decline but raises concerns about intravenous administration, cost, and magnetic resonance imaging needs. Ongoing trials exploring subcutaneous dosing and positron emission tomography scans may offer solutions. Lecanemab is a humanized monoclonal antibody that is selective for soluble amyloid-beta (Aβ) aggregates. Lecanemab has exhibited a decrease in brain Aβ plaques and moderately less decline on clinical measures of cognitive function.

Predicting clinical progression trajectories of early Alzheimer's disease patients.

Models for forecasting individual clinical progression trajectories in early Alzheimer's disease (AD) are needed for optimizing clinical studies and patient monitoring. Prediction models were constructed using a clinical trial training cohort (TC; n=934) via a gradient boosting algorithm and then evaluated in two validation cohorts (VC 1, n=235; VC 2, n=421). Model inputs included baseline clinical features (cognitive function assessments, APOE ε4 status, and demographics) and brain magnetic resonance imaging (MRI) measures. The model using clinical features achieved R2 of 0.21 and 0.31 for predicting 2-year cognitive decline in VC 1 and VC 2, respectively. Adding MRI features improved the R2 to 0.29 in VC 1, which employed the same preprocessing pipeline as the TC. Utilizing these model-based predictions for clinical trial enrichment reduced the required sample size by 20% to 49%. Our validated prediction models enable baseline prediction of clinical progression trajectories in early AD, benefiting clinical trial enrichment and various applications.

Cortical microstructural associations with CSF amyloid and pTau

Diffusion MRI (dMRI) can be used to probe microstructural properties of brain tissue and holds great promise as a means to non-invasively map Alzheimer’s disease (AD) pathology. Few studies have evaluated multi-shell dMRI models such as neurite orientation dispersion and density imaging (NODDI) and mean apparent propagator (MAP)-MRI in cortical gray matter where many of the earliest histopathological changes occur in AD. Here, we investigated the relationship between CSF pTau181 and Aβ1–42 burden and regional cortical NODDI and MAP-MRI indices in 46 cognitively unimpaired individuals, 18 with mild cognitive impairment, and two with dementia (mean age: 71.8 ± 6.2 years) from the Alzheimer’s Disease Neuroimaging Initiative. We compared findings to more conventional cortical thickness measures. Lower CSF Aβ1–42 and higher pTau181 were associated with cortical dMRI measures reflecting less hindered or restricted diffusion and greater diffusivity. Cortical dMRI measures, but not cortical thickness measures, were more widely associated with Aβ1–42 than pTau181 and better distinguished Aβ+ from Aβ- participants than pTau+ from pTau- participants. dMRI associations mediated the relationship between CSF markers and delayed logical memory performance, commonly impaired in early AD. dMRI metrics sensitive to early AD pathogenesis and microstructural damage may be better measures of subtle neurodegeneration in comparison to standard cortical thickness and help to elucidate mechanisms underlying cognitive decline.

Atrophy of hippocampal subfields relates to memory decline during the pathological progression of Alzheimer's disease.

It has been well documented that atrophy of hippocampus and hippocampal subfields is closely linked to cognitive decline in normal aging and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, evidence is still sparce regarding the atrophy of hippocampus and hippocampal subfields in normal aging adults who later developed MCI or AD. To examine whether atrophy of hippocampus and hippocampal subfields has occurred in normal aging before a diagnosis of MCI or AD. We analyzed structural magnetic resonance imaging (MRI) data of cognitively normal (CN, n = 144), MCI (n = 90), and AD (n = 145) participants obtained from the Alzheimer's Disease Neuroimaging Initiative. The CN participants were categorized into early dementia converters (CN-C) and non-converters (CN-NC) based on their scores of clinical dementia rating after an average of 36.2 months (range: 6-105 months). We extracted the whole hippocampus and hippocampal subfields for each participant using FreeSurfer, and analyzed the differences in volumes of hippocampus and hippocampal subfields between groups. We then examined the associations between volume of hippocampal subfields and delayed recall scores in each group separately. Hippocampus and most of the hippocampal subfields demonstrated significant atrophy during the progression of AD. The CN-C and CN-NC groups differed in the left hippocampus-amygdala transition area (HATA). Furthermore, the volume of presubiculum was significantly correlated with delayed recall scores in the CN-NC and AD groups, but not in the CN-C and MCI groups. Hippocampal subfield atrophy (i.e., left HATA) had occurred in cognitively normal elderly individuals before clinical symptoms were recognized. Significant associations of presubiculum with delayed recall scores in the CN-NC and AD groups highlight the essential role of the hippocampal subfields in both early dementia detection and AD progression.

Interplay between microglia and environmental risk factors in Alzheimer's disease.

Alzheimer's disease, among the most common neurodegenerative disorders, is characterized by progressive cognitive impairment. At present, the Alzheimer's disease main risk remains genetic risks, but major environmental factors are increasingly shown to impact Alzheimer's disease development and progression. Microglia, the most important brain immune cells, play a central role in Alzheimer's disease pathogenesis and are considered environmental and lifestyle "sensors." Factors like environmental pollution and modern lifestyles (e.g., chronic stress, poor dietary habits, sleep, and circadian rhythm disorders) can cause neuroinflammatory responses that lead to cognitive impairment via microglial functioning and phenotypic regulation. However, the specific mechanisms underlying interactions among these factors and microglia in Alzheimer's disease are unclear. Herein, we: discuss the biological effects of air pollution, chronic stress, gut microbiota, sleep patterns, physical exercise, cigarette smoking, and caffeine consumption on microglia; consider how unhealthy lifestyle factors influence individual susceptibility to Alzheimer's disease; and present the neuroprotective effects of a healthy lifestyle. Toward intervening and controlling these environmental risk factors at an early Alzheimer's disease stage, understanding the role of microglia in Alzheimer's disease development, and targeting strategies to target microglia, could be essential to future Alzheimer's disease treatments.

Gene therapy: an alternative to treat Alzheimer's disease.

Alzheimer's disease (AD), a neuro-degenerative disease that primarily affects the elderly, is a worldwide phenomenon. Loss of memory, cognitive decline, behavioural changes, and many other signs are used to classify it. Various hypotheses that may contribute to Alzheimer's disease have been found during decades of survey, including tau theory, the amyloid theory, the cholinergic hypothesis, and the oxidative stress hypothesis. According to some theories, the two leading causes of AD are the accumulation of amyloid beta plaque and development of NFTs in the brain. The hippocampus and cerebral cortex are the primary sites where amyloid beta plaques gather in the body. NFT formation in the brain impairs the brain's neurons' potential of signalling. According to the age at which it manifests in a person, there are two subtypes of AD: 'LOAD (Late Onset Alzheimer's Disease)' and 'EOAD (Early Onset Alzheimer's Disease)'. Long-term research into AD treatment has resulted in the introduction of some medications that provided symptomatic relief to patients but did not alter the disease's pathophysiology, like cholinesterase inhibitors, inhibitors of tau aggregation, and monoclonal antibodies to Aβ aggregation. Even though the medications did not halt the progression of AD, researchers did not discontinue their work, which lead to the introduction of gene therapy - a recently created cutting-edge method of delivering genes to target sites where they can express the intended functionalities. Viral or non-viral vectors could be used to deliver the gene, each with advantages and limitations of their own. Gene therapy is proven to be a potential disease-modifying treatment for AD. This article discusses about gene therapy, its merits and demerits and the various ways of gene delivery. Additionally, it focuses on AD as the target for treatment through gene therapy, the pathophysiology of AD, and the multiple targets for gene therapy in the treatment of AD.

Evidences and therapeutic advantages of donanemab in the treatment of early Alzheimer's disease.

The humanised monoclonal antibody donanemab is being developed to treat early onset Alzheimer's disease (AD). This drug targets N-truncated pyroglutamate amyloid-peptide at position 3 (N3pG), a modified form of deposited amyloid-peptide. The symptoms of Alzheimer's disease include gradual memory loss and other cognitive impairments. This disease is characterized by amyloid plaques, which are formed as a result of an accumulation of amyloid-(A-β) peptides. Despite granting donanemab breakthrough therapy designation in June 2021, the FDA rejected donanemab's accelerated approval application in January 2023, due to inadequate safety data. According to the baseline amyloid level, the time to achieve plaque clearance (amyloid plaque level <24.1 centiloids) varied. Patients with higher baseline levels were more likely to achieve amyloid clearance. The safety of the drug was demonstrated by amyloid-related imaging abnormalities (ARIA), which ranged from 26.1 to 30.5 % in the studies. Clinical trial results have shown that donanemab delays cognitive and functional deterioration in patients with mild to moderate AD. However, it is not yet known whether donenameb offers therapeutic benefits that can change and improve the clinical condition of AD patients. To achieve significant clinical benefits in AD patients with cognitive impairment, further studies may be needed to investigate the interaction between A-β plaque reduction and toxic tau levels.

Discovery of potential scaffolds for glutaminyl cyclase inhibitors: Virtual screening, synthesis, and evaluation

Glutaminyl cyclase (QC) plays a crucial role in the early stages of Alzheimer’s disease (AD), thus inhibition of QC may be a promising strategy for the treatment of early AD. Therefore, QC inhibitors with novel chemical scaffolds may contribute to the development of additional anti-AD agents. We conducted a virtual screening of 3 million compounds from the Chemdiv and Enamine databases, to discover potential scaffolds for QC inhibitors. Three scaffolds, 120974, 147706, and 141449, were selected from this structure-based virtual screening through a combination of pharmacophore modeling, a receptor-ligand pharmacophore model, and the GALAHAD model, and furtherly filtered by chelation with zinc ion and docking properties. Consequently, three compounds, 1, 2, and 3, were designed and synthesized based on these three scaffolds, respectively. The IC50 of compounds 1 and 3 against QC were 14.19 ± 4.21 and 4.34 ± 0.35 μM, respectively. Our results indicate that the new scaffolds selected using a virtual screening process exhibit potential as novel QC inhibitors.

Electroacupuncture promotes neurogenesis in the dentate gyrus and improves pattern separation in an early Alzheimer's disease mouse model

BackgroundImpaired pattern separation occurs in the early stage of Alzheimer’s disease (AD), and hippocampal dentate gyrus (DG) neurogenesis participates in pattern separation. Here, we investigated whether spatial memory discrimination impairment can be improved by promoting the hippocampal DG granule cell neogenesis-mediated pattern separation in the early stage of AD by electroacupuncture (EA).MethodsFive familial AD mutations (5 × FAD) mice received EA treatment at Baihui and Shenting points for 4 weeks. During EA, mice were intraperitoneally injected with BrdU (50 mg/kg) twice a day. rAAV containing Wnt5a shRNA was injected into the bilateral DG region, and the viral efficiency was evaluated by detecting Wnt5a mRNA levels. Cognitive behavior tests were conducted to assess the impact of EA treatment on cognitive function. The hippocampal DG area Aβ deposition level was detected by immunohistochemistry after the intervention; The number of BrdU+/CaR+ cells and the gene expression level of calretinin (CaR) and prospero homeobox 1(Prox1) in the DG area of the hippocampus was detected to assess neurogenesis by immunofluorescence and western blotting after the intervention; The gene expression levels of FZD2, Wnt5a, DVL2, p-DVL2, CaMKII, and p-CaMKII in the Wnt signaling pathway were detected by Western blotting after the intervention.ResultsCognitive behavioral tests showed that 5 × FAD mice had impaired pattern separation (P < 0.001), which could be improved by EA (P < 0.01). Immunofluorescence and Western blot showed that the expression of Wnt5a in the hippocampus was decreased (P < 0.001), and the neurogenesis in the DG was impaired (P < 0.001) in 5 × FAD mice. EA could increase the expression level of Wnt5a (P < 0.05) and promote the neurogenesis of immature granule cells (P < 0.05) and the development of neuronal dendritic spines (P < 0.05). Interference of Wnt5a expression aggravated the damage of neurogenesis (P < 0.05), weakened the memory discrimination ability (P < 0.05), and inhibited the beneficial effect of EA (P < 0.05) in AD mice. The expression level of Wnt pathway related proteins such as FZD2, DVL2, p-DVL2, CAMKII, p-CAMKII increased after EA, but the effect of EA was inhibited after Wnt5a was knocked down. In addition, EA could reduce the deposition of Aβ plaques in the DG without any impact on Wnt5a.ConclusionEA can promote hippocampal DG immature granule cell neogenesis-mediated pattern separation to improve spatial memory discrimination impairment by regulating Wnt5a in 5 × FAD mice.

GRADUATE I AND II: Revisiting the key findings from two Phase III studies evaluating the efficacy and safety of subcutaneous gantenerumab in early Alzheimer’s disease (AD)

AbstractBackgroundGantenerumab is a fully human monoclonal antibody administered subcutaneously. It binds to aggregated forms of amyloid‐beta protein. GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973) were two 27‐month, global, Phase III, randomized, placebo‐controlled trials designed to investigate the efficacy and safety of gantenerumab in participants with early AD (mild cognitive impairment due to AD or mild AD dementia).MethodEligible participants with early AD were randomized 1:1 to receive gantenerumab or placebo. A universal titration scheme was used for all participants receiving gantenerumab, irrespective of APOEε4 genotype, in order to reach target dose of 510 mg every 2 weeks. The primary endpoint was change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes (CDR‐SB). Secondary efficacy endpoints, imaging and fluid biomarkers were also assessed.ResultGRADUATE I and II enrolled 985 and 980 participants, respectively. The studies did not meet their primary endpoints. Change from baseline in CDR‐SB at Week 116 for the gantenerumab and placebo groups respectively was 3.35 and 3.65 in GRADUATE I (difference –0.31; 95% confidence interval [CI] –0.66 to 0.05; p = 0.095; 8% relative reduction [RR]) and 2.82 and 3.01 in GRADUATE II (difference –0.19; 95% CI –0.55 to 0.17; p = 0.2998; 6% RR). Secondary measures including ADAS‐Cog13, ADCS‐ADL, FAQ had non‐significant point estimates in favor of gantenerumab, as did the majority of exploratory measures, including NPI‐Q (Table 1). In the gantenerumab arm, change in amyloid PET from baseline to Week 116 was –57.4 (SE 2.84) centiloids for GRADUATE I and –48.0 (SE 2.85) centiloids for GRADUATE II. ARIA‐E occurred with gantenerumab and were manageable and mostly asymptomatic. Plasma exposure using Q2W dosing was comparable to previous data and similar between the GRADUATE studies (At steady state: mean Cmax and Cmin: GRADUATE I 88.1 µg/mL and 54.1 µg/mL; GRADUATE II 88.5 µg/mL and 56.8 µg/mL).ConclusionThe GRADUATE studies did not meet their primary endpoints, although non‐statistically significant effects favoring gantenerumab were observed across the majority of clinical outcome measures. Clinical benefit may require amyloid plaque removal to a threshold level; however, the parameters remain to be defined.

Circulating cell‐free mitochondrial DNA (ccf‐mtDNA) and memory in mild cognitive impairment (MCI) and Alzheimer’s disease (AD)

AbstractBackgroundCirculating cell‐free mitochondrial DNA (ccf‐mtDNA), a measure of mitochondrial dysfunction, is emerging as a potential biomarker for early Alzheimer’s disease (AD). Decreased levels of cerebrospinal fluid ccf‐mtDNA concentrations have been detected in early AD patients. Few studies have investigated peripheral ccf‐mtDNA in early AD or with cognitive measures, much less evaluating the role of physical activity within the relationships. Considering the hallmark of episodic memory impairment in early AD, we examined the association between serum ccf‐mtDNA and memory, while considering potential contributing factors, physical activity level and age.MethodsParticipants were diagnosed with mild cognitive impairment (MCI) or mild AD using the Diagnostic and Statistical Manual of Mental Disorders criteria for mild or major neurocognitive disorder. Serum ccf‐mtDNA concentration (copies/uL) was measured using quantitative polymerase chain reaction from circulating cell free DNA purified by spin columns with primer for the MT‐ND4 gene. Memory was assessed using the Word Recall Task from the Alzheimer’s Disease Assessment Scale‐Cog (ADAS‐Cog). Physical activity level was assessed by Leisure‐Time Exercise Questionnaire (LTEQ). Linear regression analyses were used to assess the association between ccf‐mtDNA levels and recall memory with a priori covariates, age and LTEQ score. Ccf‐mtDNA levels were log‐transformed prior to analyses due to significant departure from normality in Shapiro‐Wilk tests.ResultsOf 29 participants [17 (59%) male, 21 (72%) MCI], the mean (SD) age was 74.2 (8.7), years of education was 16.2 (2.2), Montreal Cognitive Assessment (MoCA) total score was 22.1 (3.3), LTEQ score was 36.2 (17.4), and ccf‐mtDNA levels were 2545.8 (2223.6) copies/uL. Higher ccf‐mtDNA was associated with worse recall [F(3,25) = 5.21, R2 = .39, p = .006]. Controlling for LTEQ and age, one log ccf‐mtDNA unit was associated with 1.87 (SE = .71) fewer words recalled (p = .01, f2 = .21).ConclusionIn this sample, higher serum ccf‐mtDNA concentrations were associated with worse recall, controlling for age and physical activity level. This relationship supports the potential involvement of mitochondrial dysfunction in cognitive functions and neurodegenerative diseases and suggest the need for further research to explore the role of physical activity and age with mitochondrial dysfunction and memory.

CO166 Efficacy of Lecanemab in Patients With Early Alzheimer Disease: A Systematic Review and Meta-Analysis

CO166 Efficacy of Lecanemab in Patients With Early Alzheimer Disease: A Systematic Review and Meta-Analysis

Memory dysfunction in mild cognitive impairment (MCI) and early Alzheimer disease (AD) dementia is closely associated with synapse loss, and shows significant correlation with pathological tau in synapses and inflammatory glial cell responses in postmortem human brain

AbstractBackgroundSynapse density loss is among the strongest histopathological correlates of dementia in AD. Prodromal stages of AD, comprising amnestic MCI and mild AD dementia, represent the most promising timepoints for interventions aimed at attaining efficacious neurobiological and clinical effects. Yet, the understanding of other contributing neuropathologic changes in these prodromal disease stages and their impact on early cognitive dysfunction remains limited.MethodsWe studied the visual cortex of 28 demented and non‐demented human brains who had died at Braak III‐IV stages of NFT pathology, and who showed a comparable β‐amyloid plaque burden and absence of NFT deposits in the studied brain region, and a group of age‐matched healthy controls. We used immunohistochemical analyses with artificial intelligence quantifications, expansion microscopy, synaptosome extractions, and Western blotting, to assess associations between antemortem MMSE scores and synapse densities, glial cell phenotypes, and pathological tau.ResultsWe found a significant loss of presynapses (Synapsin 1+), excitatory postsynapses (PSD95+), and colocalized synapses (Synapsin1‐PSD95+) in the brains of demented compared to non‐demented and controls. Moreover, we observed an association between excitatory synapse loss and memory dysfunction (MMSE score) as well as rate of disease progression (MMSE loss/time). MMSE scores were further associated with increase in tau oligomers (TOC1+) and phospho‐tau (AT270+) in synaptosomes, but not with 4G8+ β‐amyloid burden. Additionally, disease severity and rate of progression were significantly correlated with inflammatory glial changes.ConclusionsOur data suggest that excitatory synapse loss could serve as an early and robust neuropathologic correlate of disease severity and rate of progression from MCI stages of the disease, and be a closer and better determinant of cognitive decline than β‐amyloid and tau deposits. Moreover, early increases in soluble tau in synapses together with local inflammatory glial cell responses could drive development of incipient changes in memory function and serve as potential early biomarkers. Our results point to the importance of early detection and interventions aimed at synapse preservation from prodromal stages of AD, and suggest soluble tau and inflammatory glial cell changes as key targets in the early AD phases.

Examining Automatic Generated Language Features of Chinese Spontaneous Speech for Early Detection of Cognitive Decline

AbstractBackgroundConnected speech is sensitive on detecting cognitive decline in early Alzheimer disease. In this study, we apply artificial intelligence to develop an automatic assessment for analyzing speech data.Method79 samples of picture description speech data were collected. All participants were native Chinese speakers including 31 normal controls (59‐88 yrs) and 49 patients (amnestic mild cognitive impairment and early Alzheimer’s disease) (58‐88 yrs). We extracted 16 linguistic features from the manually transcribed text. These linguistic features were generated by well‐trained linguists or automatically processed by the machine. We also trained decision tree models with those two sets of linguistic features. Seventy percent of the data was used for training and the remainder was used for testing. We also applied a cross‐validation method to avoid overfitting.ResultTotal words, unique words, and content words generated from linguists or machines were highly correlated (about r = 0.99, p &lt; .001). However, the correlations between verb ratio, mean length of sentences, and filler ratio were relatively low (about r = 0.75, p &lt; .001). With manually corrected features, the model could achieve 91.67% accuracy. Among them, the pronoun ratio and MLU (mean length of utterance) appeared to be equally crucial for model prediction. By contrast, with automatically generated features, the model achieved 83.33% accuracy only. MLU and MLS (mean length of sentences) were essential features for prediction.ConclusionAutomatic assessment could also achieve a good accuracy rate compared to humans (83.33% v.s. 91.67%). Some linguistic features such as fillers or sentences were still highly dependent on the expert’s judgment. Interestingly, MLU was critical in the prediction model of automatic or experts.

Lecanemab phase 3 clarity AD trial: ARIA with the use of antiplatelets or anticoagulants in early Alzheimer's disease

Lecanemab phase 3 clarity AD trial: ARIA with the use of antiplatelets or anticoagulants in early Alzheimer's disease

Foresight AD: A multimodal prognostic tool to forecast cognitive and functional decline in early Alzheimer's disease

Foresight AD: A multimodal prognostic tool to forecast cognitive and functional decline in early Alzheimer's disease

Isolated ARIA-H in patients treated with lecanemab in the phase 3 clarity AD study in early Alzheimer's disease

Isolated ARIA-H in patients treated with lecanemab in the phase 3 clarity AD study in early Alzheimer's disease

Impact of Independent Review on Potential MMSE Score Inflation at Screening in AD trials

AbstractBackgroundThe Mini‐Mental State Examination (MMSE) is widely used as a screening tool in Alzheimer’s Disease (AD) clinical trials. Screening score inflation is documented in clinical trials of depression and anxiety. We investigated whether score distributions on several multi‐site multinational AD trials showed truncated scores around MMSE inclusion criteria cut‐off, and whether Independent Review (IRev), where site assessments are reviewed by independent clinicians, is an effective methodology to mitigate inclusion bias.MethodMMSE screening score distributions from several clinical trials of Early Symptomatic and Mild to Moderate AD were examined. To assess the impact of IRev on screening score distribution, we compared two studies with similar inclusion criteria (Early AD, MMSE ≥ 22; CDR GS = 0.5 or 1) one with no IRev and one with IRev via audio recording.ResultMMSE screening frequency distributions showed a statistically significant difference between IRev and No‐IREV groups (p &lt; 0.001). The distributions for the two groups were also compared using several score ranges around the threshold. Significant group differences were observed across the score ranges; 20‐24 (D = 0.099, p = 0.01), 19‐25 (D = 0.094, p = 0.002), and 18‐26 (D = 0.0987, p &lt; 0001), suggesting a smaller inclusion bias around the threshold in the IRev group.ConclusionWe observed that screening score inflation occurs in AD trials and Independent Review may be an effective strategy to reduce the number of subjects inappropriately enrolled in the study. IRev should be applied to assessments that fall around the required scored for study participation.