Tailoring near-infrared amyloid-ß probes with high-affinity and low background based on CN and amphipathic regulatory strategies and in vivo imaging of AD mice.

Amyloid-ß (Aß) species (Aß fibrils and Aß plaques), as one of the typical pathological markers of Alzheimer's disease (AD), plays a crucial role in AD diagnosis. Currently, some near-infrared I (NIR I) Aß probes have been reported in AD diagnosis. However, they still face challenges such as strong background interference and the lack of effective probe design. In this study, we propose molecular design strategy that incorporates CN group and amphiphilic modulation to synthesize a series of amphiphilic NIR I Aß probes, surpassing the commercial probe ThT and ThS. Theoretical calculations indicate that these probes exhibit stronger interaction with amino acid residues in the cavities of Aß. Notably, the probes containing CN group display the ability of binding two distinct sites of Aß, which dramatically enhanced the affinity to Aß species. Furthermore, these probes exhibit minimal fluorescence in aqueous solution and offer ultra-high signal-to-noise ratio (SNR) for in vitro labeling, even in wash-free samples. Finally, the optimal probe DM-V2CN-PYC3 was utilized for in vivo imaging of AD mice, demonstrating its rapid penetration through the blood-brain barrier and labelling to Aß species. Moreover, it enabled long-term monitoring for a duration of 120 min. These results highlight the enhanced affinity and superior performance of the designed NIR I Aß probe for AD diagnosis. The molecular design strategy of CN and amphiphilic modulation presents a promising avenue for the development Aß probes with low background in vivo/in vitro imaging for Aß species.

Novel insights into famotidine as a GSK-3ß inhibitor: An explorative study in aluminium chloride-induced Alzheimer's disease rat model.

Alzheimer's disease (AD), a chronic neurodegenerative disease, presents a substantial global health challenge. This study explored the potential therapeutic role of famotidine, a histamine (H2) receptor antagonist, as a glycogen synthase kinase-3ß (GSK-3ß) inhibitor in the context of AD induced by aluminium chloride (AlCl3) in a rat model. The intricate relationship between GSK-3ß dysregulation and AD pathogenesis, particularly in amyloid-ß (Aß) production, formed the basis for investigating famotidine's efficacy. Molecular modelling revealed famotidine's efficient binding to GSK-3ß, suggesting inhibitory potential. In behavioural assessments, famotidine-treated groups exhibited dose-dependent improvements in Morris Water Maze, Novel Object Recognition, and Y-Maze tests, comparable to the standard Rivastigmine tartrate group. Biochemical analyses showed that famotidine inhibits acetylcholinesterase, decreases lipid peroxidation, increases antioxidant activity, and mitigates oxidative stress. Moreover, famotidine significantly lowered the levels of GSK-3ß, IL-6, and Aß(1-42). The neuroprotective effects of famotidine were further supported by histopathological analysis. This comprehensive investigation underscores famotidine's potential as a GSK-3ß inhibitor, providing insights into its therapeutic impact on AD induced by AlCl3. The study offers a promising avenue for repurposing famotidine due to its established safety profile and widespread availability, highlighting its potential in addressing the formidable challenge of AD.

Alzheimer's Disease May Benefit from Olive Oil Polyphenols: A Systematic Review on Preclinical Evidence Supporting the Effect of Oleocanthal on Amyloid-ß Load.

BACKGROUND: Mediterranean diet may enhance cognitive function and delay the progression of Alzheimer's disease (AD). We conducted a systematic review to investigate the effect of oleocanthal (OC) from extra-virgin olive oil (EVOO) on amyloid-ß (Aß) burden in preclinical models of AD, considering the anti-inflammatory and neuroprotective effects of EVOO biophenols, which are key components of the Mediterranean dietary model. METHODS: The literature was searched through six electronic databases until February 2023. Screening of 52 retrieved articles for inclusion criteria resulted in 7 preclinical reports evaluating the effect of an OC-supplemented diet on AD trajectories by means of Aß load or clearance in affected models. Reports were appraised for risk of bias using the SYRCLE's RoB tool. A protocol was registered on PROSPERO. RESULTS: Case control prevailed over the case-crossover design, and the geographical distribution was uniformly American. The study population mostly included 5xFAD, otherwise TgSwDI or wild-type C57BL/6 mouse models. We found a role of OC in reducing Aß load in the hippocampal parenchyma and microvessels compared with controls. An increased cerebral clearance of Aß through the bloodbrain barrier and a substantial improvement in metabolic and behavioral parameters were also reported in preclinical models under an OC-enriched diet. The risk of bias was shown to be moderate overall. CONCLUSION: Preclinical data are promising about the effects of OC from the Mediterranean diet's EVOO in relieving the burden of Aß in AD; however, further evidence is needed to corroborate the efficacy of this biophenol and strengthen the speculated causal pathway.

Cytotoxic Effect of Amyloid-ß1-42 Oligomers on Endoplasmic Reticulum and Golgi Apparatus Arrangement in SH-SY5Y Neuroblastoma Cells.

Amyloid-ß oligomers are a cytotoxic structure that is key for the establishment of the beginning stages of Alzheimer's disease (AD). These structures promote subcellular alterations that cause synaptic dysfunction, loss of cell communication, and even cell death, generating cognitive deficits. The aim of this study was to investigate the cytotoxic effects of amyloid-ß1-42 oligomers (AßOs) on the membranous organelles involved in protein processing: the endoplasmic reticulum (ER) and Golgi apparatus (GA). The results obtained with 10 µM AßOs in SH-SY5Y neuroblastoma cells showed that oligomeric structures are more toxic than monomers because they cause cell viability to decrease as exposure time increases. Survivor cells were analyzed to further understand the toxic effects of AßOs on intracellular organelles. Survivor cells showed morphological alterations associated with abnormal cytoskeleton modification 72-96 h after exposure to AßOs. Moreover, the ER and GA presented rearrangement throughout the cytoplasmic space, which could be attributed to a lack of constitutive protein processing or to previous abnormal cytoskeleton modification. Interestingly, the disorganization of both ER and GA organelles exposed to AßOs is likely an early pathological alteration that could be related to aberrant protein processing and accumulation in AD.

Heterotopic Ossification of the Elbow in a Patient With Cerebral Amyloid Angiopathy Following Intraparenchymal Hemorrhage: A Case Report.

Heterotopic ossification (HO) is a rare complication that may be initially discovered in the acute inpatient rehabilitation setting, caused by the abnormal formation of bone tissue in non-skeletal areas of the body. It may be caused by trauma or a neurological injury. When treating a patient with a history of neurological disease complicated by an acute event, treatment should be tailored to suit the patient's needs and to avoid further harm. This case explores the complexity of HO in a patient diagnosed with cerebral amyloid angiopathy following an intraparenchymal hemorrhage (IPH) and highlights the option of management with radiation therapy when non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated, not only to treat but also to prevent the progression of HO in this patient.

Non-Alzheimer's amnestic mild cognitive impairment with medial temporal hypometabolism.

INTRODUCTION: The increasing use of Alzheimer's disease (AD) biomarkers has led to the recognition of a subgroup of non-AD amnestic mild cognitive impairment (aMCI) patients who have medial temporal hypometabolism on fluorodeoxyglucose-positron emission tomography (FDG-PET). METHODS: In this academic memory-clinic-based consecutive series, 16 non-AD aMCI patients and 28 AD controls matched for sex, age, and baseline Mini-Mental State Examination (MMSE) were followed for a median duration of 4.5 years. Our primary outcome was the MMSE decline rate over the subsequent years. We also determined the final diagnosis over time. RESULTS: FDG-PET showed more pronounced medial temporal hypometabolism in non-AD cases and more inferior parietal lobule hypometabolism in AD controls. MMSE decline was slower in non-AD (ß = -0.51) than in AD (ß = -2.00) patients. Five non-AD cases developed frontotemporal dementia years after symptom onset, and one developed dementia with Lewy bodies. DISCUSSION: Non-AD aMCI patients with medial temporal hypometabolism show slower cognitive decline. Highlights: Non-AD aMCI with medial temporal hypometabolism shows slower cognitive decline than AD.FDG-PET revealed distinct metabolic patterns between non-AD aMCI and AD patients.Approximately one-third of non-AD aMCI cases developed frontotemporal dementia.Comprehensive diagnostic biomarkers are crucial for non-AD aMCI characterization.

Diagnostic Value of the Voltage-to-Mass Ratio in Biopsy-Proven Cardiac Amyloidosis.

OBJECTIVES: The calculation of left ventricular mass varies in different studies, and reference values of the voltage-to-mass ratio for diagnosing cardiac amyloidosis (CA) are lacking. This study aimed to determine the value of the voltage-to-mass ratio in diagnosing CA and provide an optimal cut-off value for different calculation methods. METHODS: We reviewed the electrocardiograms and echocardiograms of 213 consecutive biopsy-proven CA patients, 236 hypertrophic cardiomyopathy (HCM) patients, 100 hypertensive heart disease patients, and 181 healthy controls. Left ventricular mass was calculated using linear and cross-sectional area (CSA) methods. The voltage-to-mass ratios were compared between the CA group and other groups. The voltage-to-mass ratio obtained was used to build multivariate logistic regression models that predicted the log odds of developing CA. RESULTS: The CA group had a significantly lower voltage-to-mass ratio than the HCM, hypertensive heart disease, and healthy control groups. The voltage-to-mass ratio was an independent factor significantly associated with the CA diagnosis after adjusting for baseline characteristics. Linear and CSA methods yielded areas under the ROC curve of 0.86 and 0.90, respectively. Using the CSA method, the optimal cut-off was 16.42 mV/mm2/m2, with 89.0% sensitivity and 80.8% specificity. CONCLUSION: The voltage-to-mass ratio could differentiate patients with CA, HCM, and hypertensive heart disease from healthy controls, potentially providing an accurate and non-invasive alternative to current expensive and invasive diagnostic techniques.

Intracranial Drain-Related Intracerebral Hemorrhage in Two Sporadic Cerebral Amyloid Angiopathy Patients.

 Alzheimer's disease and cerebral amyloid angiopathy (CAA) are often associated. Amyloid accumulation within leptomeningeal and small/median-sized cerebral blood vessels in CAA results in vessel fragility, leading to spontaneous leptomeningeal bleeding, lobar intracerebral hemorrhage (ICH) and cerebral microbleeds. CAA is also associated with non-traumatic subdural hematoma. The role of CAA-related vessel fragility in hemorrhagic complications after trauma, brain surgery, and intracranial drain insertion in CAA is unknown. We present two sporadic CAA patients with intracranial drain-related ICH, probably due to different underlying mechanisms, related to indirect and direct CAA-associated vessel fragility.

Cognitive Function After Stopping Folic Acid and DHA Intervention: An Extended Follow-Up Results from the Randomized, Double Blind, Placebo-Controlled Trial in Older Adults with Mild Cognitive Impairment.

Background: Our previously randomized controlled trial (RCT) showed daily oral folic acid (FA), docosahexaenoic acid (DHA) and their combined treatment for 6 months could significantly improve cognitive function in mild cognitive impairment (MCI) individuals. Objective: This study aimed to evaluate whether this benefit seen in the treatment group would sustain after stopping intervention when patients returned to a real-world. Methods: RCT (ChiCTR-IOR-16008351) was conducted in Tianjin, China. 160 MCI elders aged ≥60 years were randomly divided into four groups: FA + DHA, FA, DHA, and control. 138 MCI elders who completed the 6-month interventional trial underwent another 6-month follow-up without receiving nutritional therapy. Cognitive performance was measured at 6 and 12 months. Blood amyloid-ß peptide (Aß) and homocysteine (Hcy) related biomarkers were measured at baseline and 6 months. Results: In comparison to the end of nutritional therapy, all intervention groups had considerably lower full-scale IQ, arithmetic, and image completion scores during the follow-up period, while the combined intervention and DHA groups had significantly lower picture arrangement scores. Furthermore, after 6-month treatment with FA and FA + DHA, plasma Aß40, Aß42, and Hcy levels were significantly decreased. However, these biomarker levels at the start of follow-up were positively correlated with the degree of cognitive function change during follow-up period. Conclusions: FA and DHA supplementation enhance cognitive performance in MCI elderly following a six-month intervention by reducing Hcy or Aß levels. However, their effects on improving cognitive decline are likely to diminish when the intervention is discontinued.

An Atypical Case of Creutzfeldt-Jakob Syndrome Presenting with Cacosmia and Amyloid Positivity.

This report presents a challenging case of Creutzfeldt-Jakob Disease (CJD), a rare and rapidly progressing neurological disorder. The patient exhibited diverse and progressive neuro-psychiatric symptoms, including memory impairment, behavioral changes, and hallucinations associated with cacosmia. The diagnosis of CJD is complicated due to its variable clinical presentation, limited awareness, and the need for tissue pathology confirmation. Diagnostic tests, particularly brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis, played crucial roles in the evaluation. The MRI revealed characteristic cortical ribboning patterns. CSF analysis initially suggested Alzheimer's disease pathology continuum. Repeated Real-time-quaking-induced assay testing (RT-QuIC) confirmed the diagnosis despite an initial negative result. This case underscores the significance of contemplating CJD in individuals exhibiting rapidly progressive dementia, even in the presence of atypical clinical features. Furthermore, it emphasizes the importance of recognizing that an initial negative result from the RT-QuIC test should not preclude consideration of CJD, particularly when characteristic MRI findings are present.

Novel techniques for early diagnosis and monitoring of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is the most common neurodegenerative disorder, which is characterized by a progressive loss of cognitive functions. The high prevalence, chronicity, and multimorbidity are very common in AD, which significantly impair the quality of life and functioning of patients. Early detection and accurate diagnosis of Alzheimer's disease (AD) can stop the illness from progressing thereby postponing its symptoms. Therefore, for the early diagnosis and monitoring of AD, more sensitive, noninvasive, straightforward, and affordable screening tools are needed. AREAS COVERED: This review summarizes the importance of early detection methods and novel techniques for Alzheimer's disease diagnosis that can be used by healthcare professionals. EXPERT OPINION: Early diagnosis assists the patient and caregivers to understand the problem establishing reasonable goals and making future plans together. Early diagnosis techniques not only help in monitoring disease progression but also provide crucial information for the development of novel therapeutic targets. Researchers can plan to potentially alleviate symptoms or slow down the progression of Alzheimer's disease by identifying early molecular changes and targeting altered pathways.

Licochalcone A Ameliorates Cognitive Dysfunction in an Alzheimer's Disease Model by Inhibiting Endoplasmic Reticulum Stress-Mediated Apoptosis.

BACKGROUND: Endoplasmic reticulum (ER) stress-induced neurodegeneration has been considered an underlying cause of Alzheimer disease (AD). Here, we investigated the beneficial effects of licochalcone A (Lico A), a valuable flavonoid of the root of the Glycyrrhiza species, against cognitive impairment in AD by regulating ER stress. METHODS: The triple transgenic mouse AD models were used and were administrated 5 or 15 mg/kg Lico A. Cognitive deficits, Aß deposition, ER stress, and neuronal apoptosis were determined using Morris Water Maze test, probe trial, immunofluorescence staining, western blotting, and TUNEL staining. To investigate the mechanisms of how Lico A exerts anti-AD effects, primary hippocampal neurons were isolated from the AD model mice and treated with Lico A, salubrinal, an eIF2α phosphatase inhibitor, ML385, a Nrf2 inhibitor, or LY294002, an inhibitor of PI3K. Pharmacokinetics and toxicity of Lico A (15 mg/kg) in AD mice were evaluated. RESULTS: We found that Lico A improved cognitive impairment, decreased Aß plaques, inhibited ER stress, and reduced neuronal apoptosis in the hippocampus and cortex of AD mice. Treatment with Lico A in primary hippocampal neurons exerted the same effects as it did in vivo. Additionally, cotreatment with ML385 or LY294002 significantly impeded the effects of Lico A against ER stress. Moreover, 15 mg/kg Lico A had a good bioavailability and low toxicity in AD mice. CONCLUSION: Our results demonstrated that Lico A ameliorates ER stress-induced neuronal apoptosis by inhibiting PERK/eIF2α/ATF4/CHOP signaling, suggesting the therapeutic potential of Lico A in AD treatment.

Connexin43 Contributes to Alzheimer's Disease by Promoting the Mitochondria-Associated Membrane-Related Autophagy Inhibition.

The perturbed structure and function of mitochondria-associated membranes (MAM), instead of the amyloid cascade, have been gradually proposed to play a basic role in the pathogenesis of Alzheimer's disease (AD). Notably, autophagy inhibition is one of the main mechanisms of MAM dysfunction and plays an important role in neuronal injury. However, the upstream molecular mechanism underlying the MAM dysfunctions remains elusive. Here, we defined an unexpected and critical role of connexin43 (Cx43) in regulating the MAM structure. The expression levels of Cx43 and mitofusin-2 (MFN2, the MAM biomarker) increase significantly in 9-month-old APPswe/PS1dE9 double-transgenic AD model mice, and there is an obvious colocalization relationship. Moreover, both AD mice and cells lacking Cx43 exhibit an evident reduction in the MAM contact sites, which subsequently promotes the conversion from microtubule-associated protein 1 light-chain 3B I (LC3B-I) to LC3B-II via inhibition mTOR-dependent pathway and then initiates the generation of autophagosomes. Autophagosome formation ultimately promotes ß-amyloid (Aß) clearance and attenuates Aß-associated pathological changes in AD, mainly including astrogliosis and neuronal apoptosis. Our findings not only reveal a previously unrecognized effect of Cx43 on MAM upregulation but also highlight the major player of MAM-induced autophagy inhibition in Cx43-facilitated AD pathogenesis, providing a novel insight into the alternative therapeutic strategies for the early treatment of AD.

Mica Lattice Orientation of Epitaxially Grown Amyloid ß25-35 Fibrils.

ß-amyloid (Aß) peptides form self-organizing fibrils in Alzheimer's disease. The biologically active, toxic Aß25-35 fragment of the full-length Aß-peptide forms a stable, oriented filament network on the mica surface with an epitaxial mechanism at the timescale of seconds. While many of the structural and dynamic features of the oriented Aß25-35 fibrils have been investigated before, the ß-strand arrangement of the fibrils and their exact orientation with respect to the mica lattice remained unknown. By using high-resolution atomic force microscopy, here, we show that the Aß25-35 fibrils are oriented along the long diagonal of the oxygen hexagon of mica. To test the structure and stability of the oriented fibrils further, we carried out molecular dynamics simulations on model ß-sheets. The models included the mica surface and a single fibril motif built from ß-strands. We show that a sheet with parallel ß-strands binds to the mica surface with its positively charged groups, but the C-terminals of the strands orient upward. In contrast, the model with antiparallel strands preserves its parallel orientation with the surface in the molecular dynamics simulation, suggesting that this model describes the first ß-sheet layer of the mica-bound Aß25-35 fibrils well. These results pave the way toward nanotechnological construction and applications for the designed amyloid peptides.

CT1812, a Small Molecule Sigma-2 Receptor Antagonist for Alzheimer's Disease Treatment: A Systematic Review of Available Clinical Data.

Background: Alzheimer's disease (AD) is of growing concern worldwide as the demographic changes to a more aged population. Amyloid-ß (Aß deposition is thought to be a key target for treating AD. However, Aß antibodies have had mixed results, and there is concern over their safety. Studies have shown that the sigma-2 receptor (σ-2R)/TMEM97 is a binding site for Aß oligomers. Therefore, targeting the receptor may be beneficial in displacing Aß oligomers from the brain. CT1812 is a σ-2R/TMEM97 antagonist that is effective in preclinical studies of AD and has been entered into clinical trials. Objective: The objective of this study was to systematically review the safety and efficacy of CT1812 for the treatment of AD. Methods: Between June and August 2023, we searched the primary literature (PubMed, Scopus, Google Scholar, etc.) and clinical trials databases (http://www.clinicaltrails.gov). The extracted data is evaluated within this manuscript. Results: CT1812 is relatively safe, with only mild adverse events reported at doses up to 840 mg. CT1812 can displace Aß in the clinical studies, in line with the preclinical data. Studies have investigated brain connectivity and function in response to CT1812. However, the cognitive data is still lacking, with only one study including cognitive data as a secondary outcome. Conclusions: CT1812 safely works to displace Aß however, whether this is enough to prevent/slow the cognitive decline seen in AD remains to be seen. Longer clinical trials are needed to assess the efficacy of CT1812; several trials of this nature are currently ongoing.

BACE Inhibitor Clinical Trials for Alzheimer's Disease.

The amyloid hypothesis posits that the amyloid-ß aggregates in the brain initiate a cascade of events that eventually lead to neuron loss and Alzheimer's disease. Recent clinical trials of passive immunotherapy with anti-amyloid-ß antibodies support this hypothesis, because clearing plaques led to better cognitive outcomes. Orally available small molecule BACE1 inhibitors are another approach to slowing the buildup of plaques and thereby cognitive worsening by preventing the cleavage of amyloid-ß protein precursor (AßPP) into amyloid-ß peptide, the major component of plaques. This approach is particularly attractive because of their ease of use, low cost, and advanced clinical stage. However, although effective in preventing amyloid-ß production in late-stage clinical trials, BACE inhibitors have been associated with early, non-progressive, likely reversible, cognitive decline. The clinical trials tested high levels of BACE inhibition, greater than 50%, whereas genetics suggest that even a 30% inhibition may be sufficient to protect from Alzheimer's disease. Aside from AßPP, BACE1 cleaves many other substrates in the brain that may be contributing to the cognitive worsening. It is important to know what the cause of cognitive worsening is, and if a lower level of inhibition would sufficiently slow the progress of pathology while preventing these unwanted side effects. Should these side effects be mitigated, BACE inhibitors could rapidly move forward in clinical trials either as a primary prevention strategy in individuals that are at risk or biomarker positive, or as a maintenance therapy following amyloid clearance with an anti-amyloid antibody.

Amyloid deposition and its association with depressive symptoms and cognitive functions in late-life depression: a longitudinal study using amyloid-ß PET images and neuropsychological measurements.

BACKGROUND: Although depression is linked to an increased risk of dementia, the association between late-onset depression (LOD) and amyloid burden remains unclear. This study aimed to determine amyloid deposition in patients with LOD compared to healthy controls (HC) using amyloid-beta (Aß) positron emission tomography (PET) images and neuropsychological assessments. METHODS: Forty patients first diagnosed with major depressive disorder after the age of 60 (LOD) and twenty-one healthy volunteers (HC) were enrolled. Depression and anxiety were evaluated using the 17-item Hamilton Depression Scale, Hamilton Anxiety Rating Scale, and Clinical Global Impression Scale. Cognitive function was assessed using the Korean versions of the Mini-Mental Status Examination, Montreal Cognitive Assessment, and Seoul Neuropsychological Screening Battery at baseline and 3-month follow-up. 18F-florbetapir PET images were co-registered with T1-weighted magnetic resonance images. RESULTS: There was no significant difference in Aß deposition between LOD and HC groups. No significant correlation between Aß burden and depressive symptom severity was found in LOD patients. Higher somatic anxiety was correlated with lower Aß burden in multiple brain regions, including the left inferior frontal lobe (p = 0.009), right anterior cingulate (p = 0.003), and right superior frontal lobe (p = 0.009). Despite cognitive recovery in areas such as attention (Digit Span Forward, p = 0.026), memory (Auditory Verbal Learning Test Recall Total, p = 0.010; Rey Complex Figure Test Delayed Recall, p = 0.039), and frontal executive function (Contrasting Program, p = 0.033) after three months of antidepressant treatment, cognitive improvement showed no association with amyloid deposition. CONCLUSIONS: These findings suggest distinct mechanisms may underlie amyloid deposition in neurodegenerative changes associated with depression. While amyloid burden in specific brain regions negatively correlated with somatic anxiety, it showed no significant correlation with the severity of depression or overall cognitive function.

Non-rapid eye movement sleep slow-wave activity features are associated with amyloid accumulation in older adults with obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer's disease pathology. Non-rapid eye movement slow-wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants ≥60 years old with OSA (mean baseline age = 72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least 2 consecutive Amyloid Pittsburgh Compound B (PiB)-PET scans and a polysomnographic study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation [global ΔPiB(log)/year] was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included in SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO: 0.5-0.9 Hz) and delta (1-3.9 Hz) frequency bands and by their downslopes (SO-slope and delta-slope, respectively) during the diagnostic portion of polysomnography. We fit linear regression models to test for associations among global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ɛ4 and baseline amyloid positivity. For 1 SD increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI: 0.0001; 0.0064, P = 0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P = 0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by -0.0082 (95% CI: -0.0143; -0.0021, P = 0.009). Sleep apnoea severity was not associated with amyloid accumulation. Regional associations were stronger in the pre-frontal region. Both slow-wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slope, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength, and/or hyper-excitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology.

Exploring the Relationship Between Amyloid Burden and Depression in Pre-clinical Alzheimer's Disease.

Background Alzheimer's disease (AD) is a form of dementia, marked by amyloid-ß plaques, neurofibrillary tangles, and neuronal loss. The amyloid burden has been associated with cognitive impairment and depression, suggesting a potential link between these conditions. Objective This study investigates the relationships between amyloid burden, cognitive impairment, and depression in the preclinical stages of AD. Methods Data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study, involving 4486 cognitively unimpaired individuals aged 65-85, was analyzed. The amyloid burden was assessed using positron emission tomography (PET) standardized uptake value ratio (SUVR), cognitive function via cognitive function index (CFI) and tests, and depression via the short-form geriatric depression scale. Mediation analyses, adjusted for age, sex, and education, were employed to measure the impact of amyloid deposition on depression into direct and cognition-mediated indirect effects. Results No significant direct correlation between amyloid burden and depression was found (p=0.2935). Significant indirect effects were observed in cognition measures: CFI (0.3203, 95% CI: (0.2382, 0.4010)), digit symbol substitution test (0.0401, 95% CI: (0.0180, 0.0683)), and immediate recall (0.0169, 95% CI: (0.0014, 0.0354)). However, free and cued selective reminding (0.0056, 95% CI: (-0.0078, 0.0268)) and delayed recall (0.0105, 95% CI: (-0.0009, 0.0259)) showed no significant indirect effects. Conclusions The findings indicate significant mediation by CFI, digit symbol substitution test, and immediate recall in the relationship between amyloid burden and depression while free and cued selective reminding and delayed recall showed no significant mediation. These results underscore the importance of further research using longitudinal data and a broader range of confounders to fully understand cognition's mediating role.

Japanese Subgroup Analyses from EMERGE and ENGAGE, Phase 3 Clinical Trials of Aducanumab in Patients with Early Alzheimer's Disease.

BACKGROUND: Global prevalence and incidence of dementia continue to rise at a rapid rate. There is a need for new Alzheimer's disease (AD) treatments globally. Aducanumab is a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils. In June 2021, aducanumab was approved by the US Food and Drug Administration for the treatment of AD under the accelerated approval pathway. OBJECTIVES: We evaluated the efficacy, safety, biomarker and pharmacokinetics (PK) of aducanumab in Japanese subgroups in EMERGE and ENGAGE studies. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early AD (mild cognitive impairment due to AD or mild AD dementia). SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants enrolled in Japan included 121 (7.4% of total 1638 in EMERGE) and 100 (6.1% of total 1647 in ENGAGE) patients (aged 50-85 years with confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to AD or mild AD dementia. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (6 or 10 mg/kg target dose) or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to Week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; biomarker endpoints (amyloid PET and plasma p-tau181); serum PK profiles and immunogenicity. RESULTS: Results from the Japanese subgroup analyses were generally consistent with those of the overall study population across endpoints, while a lower mean body weight (kg) and a smaller proportion of ApoE ε4 carriers were observed in the Japanese subgroup population. A treatment effect was observed in favor of aducanumab on the primary and secondary efficacy endpoints at Week 78 in EMERGE, but not ENGAGE. The incidence and type of adverse events in the Japanese subgroups were generally comparable to those observed in the overall study population; amyloid related imaging abnormalities (ARIA) were common treatment-related adverse events that appeared to be related to the aducanumab dose. ARIA incidence was generally lower in the Japanese subgroup compared with the overall population. Consistent with the overall data set, a robust dose-dependent decrease in amyloid beta levels as assessed with amyloid-PET and plasma p-tau181 was observed. Serum PK profiles and immunogenicity of aducanumab in Japanese population were consistent with the non-Japanese population. CONCLUSION: Efficacy, safety, biomarker, and PK profiles of aducanumab were consistent between the Japanese subgroup and the overall population. A positive treatment effect of aducanumab on efficacy endpoints was observed in EMERGE, but not in ENGAGE.