Early-onset Alzheimer's Disease Research Articles

Socioemotional Dysfunction From Temporal Lobe Involvement in Frontotemporal Dementia: A Preliminary Report.

Socioemotional changes, rather than cognitive impairments, are the feature that defines behavioral variant frontotemporal dementia (bvFTD). Investigators have attributed the socioemotional changes in bvFTD and other dementias to frontal lobe dysfunction; however, recent work implies a further contribution from right anterior temporal disease. The authors evaluated relationships between regional brain atrophy and socioemotional changes in both bvFTD and early-onset Alzheimer's disease (EOAD). This study explored the neuroanatomical correlations of performance on the Socioemotional Dysfunction Scale (SDS), an instrument previously shown to document socioemotional changes in bvFTD, among 13 patients with bvFTD not preselected for anterior temporal involvement and 16 age-matched patients with early-onset Alzheimer's disease (EOAD). SDS scores were correlated with volumes of regions of interest assessed with tensor-based morphometric analysis of MRI images. As expected, the bvFTD group had significantly higher SDS scores overall and smaller frontal regions compared with the EOAD group, which in turn had smaller volumes in temporoparietal regions. SDS scores significantly correlated with lateral anterior temporal lobe (ATL) atrophy, and a regression analysis that controlled for diagnosis indicated that SDS scores predicted lateral ATL volume. Within the bvFTD group, higher SDS scores were associated with smaller lateral and right ATL regions, as well as a smaller orbitofrontal cortex. Within the EOAD group, higher SDS scores were associated with a smaller right parietal cortex. This study confirms that, in addition to orbitofrontal disease, there is a prominent right and lateral ATL origin of socioemotional changes in bvFTD and further suggests that right parietal involvement contributes to socioemotional changes in EOAD.

Establishment of a Biorepository for Down Syndrome: Experience of the Inter-Institutional Multidisciplinary BioBank - BioBIM.

Down syndrome, or Trisomy 21, is the leading genetic cause of cognitive disability in children and is associated with a high risk of several comorbidities, particularly congenital heart defects, early onset Alzheimer's disease, leukaemia, and autoimmune disorders. This study describes the design, methods, and operational procedures employed to establish a biobank dedicated to Down syndrome that can support research projects investigating the effects of various genetic and environmental factors on this complex disease. Blood was collected from all recruited subjects, processed, aliquoted and immediately frozen at -80 °C in the Interinstitutional Multidisciplinary BioBank (BioBIM) facilities. A small aliquot of the sample was used to perform blood tests for which analysis would not be feasible at a later date, such as blood cell counts. Each biological sample was coded, assigned a Standard PREanalytical Code, and registered in the oloBIOBANK software connected to a medical card containing all the donor's anamnestic data. All samples were stored under continuous real-time temperature recording using a freezer connected to a T-GUARD alarm system. In addition, a radiofrequency identification tracking system strictly monitored each cryopreservation operation performed throughout the sample lifecycle. Biological samples were collected from 454 individuals with Down syndrome from 2007 to 2023. A total of 2233 biological samples were available for research purposes, including whole blood in different anticoagulants, serum, plasma, and frozen peripheral blood mononuclear cells. The quality of the nucleic acids obtained through specific standard operating procedures demonstrated that these samples were appropriate for clinical and basic research. By establishing this biobank, we have gathered a significant number of biological samples and clinical data from individuals with Down syndrome, thereby fostering collaboration between different research groups in an open and transparent manner. Sharing expertise and resources among scientists will ultimately facilitate the transfer of knowledge to clinical practice, leading to the development of more effective therapeutic treatments to improve the outcomes and quality of life of patients with Down syndrome.

Carvedilol suppresses ryanodine receptor-dependent Ca2+ bursts in human neurons bearing PSEN1 variants found in early onset Alzheimer's disease.

Seizures are increasingly being recognized as the hallmark of Alzheimer's disease (AD). Neuronal hyperactivity can be a consequence of neuronal damage caused by abnormal amyloid β (Aß) depositions. However, it can also be a cell-autonomous phenomenon causing AD by Aß-independent mechanisms. Various studies using animal models have shown that Ca2+ is released from the endoplasmic reticulum (ER) via type 1 inositol triphosphate receptors (InsP3R1s) and ryanodine receptors (RyRs). To investigate which is the main pathophysiological mechanism in human neurons, we measured Ca2+ signaling in neural cells derived from three early-onset AD patients harboring Presenilin-1 variants (PSEN1 p.A246E, p.L286V, and p.M146L). Of these, it has been reported that PSEN1 p.A246E and p.L286V did not produce a significant amount of abnormal Aß. We found all PSEN1-mutant neurons, but not wild-type, caused abnormal Ca2+-bursts in a manner dependent on the calcium channel, Ryanodine Receptor 2 (RyR2). Indeed, carvedilol, an RyR2 inhibitor, and VK-II-86, an analog of carvedilol without the β-blocking effects, sufficiently eliminated the abnormal Ca2+ bursts. In contrast, Dantrolene, an inhibitor of RyR1 and RyR3, and Xestospongin c, an IP3R inhibitor, did not attenuate the Ca2+-bursts. The Western blotting showed that RyR2 expression was not affected by PSEN1 p.A246E, suggesting that the variant may activate the RyR2. The RNA-Seq data revealed that ER-stress responsive genes were increased, and mitochondrial Ca2+-transporter genes were decreased in PSEN1A246E cells compared to the WT neurons. Thus, we propose that aberrant Ca2+ signaling is a key link between human pathogenic PSEN1 variants and cell-intrinsic hyperactivity prior to deposition of abnormal Aß, offering prospects for the development of targeted prevention strategies for at-risk individuals.

Relation between apolipoprotein e in alzheimer's disease and sars-cov-2 and their treatment strategy: A review.

COVID-19, which primarily affects the pulmonary system, turned out to be a global pandemic, whereas the effects on other systems are still unknown. SARS-CoV-2, binds to angiotensin-converting enzyme 2 (ACE2) receptors in the lungs, causing pneumonia-like symptoms. The same ACE receptors are also present in organs other than the lungs. Therefore, there is a need to study the impact of coronavirus on other human body organs. Recently, UK Biobank reports on the genetic risk factor of the virus attack. A double mutation in the apolipoprotein E (APOE4) allele has shown a significant role in COVID-19. The same APOE4 mutation has already been proven to hold a key role in developing early-onset Alzheimer's disease (EOAD). Despite this data, Alzheimer's disease is believed to be a comorbidity of COVID-19. Previous virus attacks on the same viral family, Coronaviridae, produced neurological effects like neurodegeneration, neuronal inflammation, and other central nervous system-related dysfunctions. Since the long-term implications of COVID-19 are unknown, more research into the impact of the virus on the central nervous system is needed. Both COVID-19 and AD share a common genetic factor, so that AD patients may have a greater risk of SARS-CoV-2. Here, in this review, we have briefly discussed the role of APOE4 in the pathogenesis of AD and SARS-CoV-2, along with their treatment strategy, current scenario, and possible future directions.

Alzheimer's Disease: Models and Molecular Mechanisms Informing Disease and Treatments.

Alzheimer's Disease (AD) is a complex neurodegenerative disease resulting in progressive loss of memory, language and motor abilities caused by cortical and hippocampal degeneration. This review captures the landscape of understanding of AD pathology, diagnostics, and current therapies. Two major mechanisms direct AD pathology: (1) accumulation of amyloid β (Aβ) plaque and (2) tau-derived neurofibrillary tangles (NFT). The most common variants in the Aβ pathway in APP, PSEN1, and PSEN2 are largely responsible for early-onset AD (EOAD), while MAPT, APOE, TREM2 and ABCA7 have a modifying effect on late-onset AD (LOAD). More recent studies implicate chaperone proteins and Aβ degrading proteins in AD. Several tests, such as cognitive function, brain imaging, and cerebral spinal fluid (CSF) and blood tests, are used for AD diagnosis. Additionally, several biomarkers seem to have a unique AD specific combination of expression and could potentially be used in improved, less invasive diagnostics. In addition to genetic perturbations, environmental influences, such as altered gut microbiome signatures, affect AD. Effective AD treatments have been challenging to develop. Currently, there are several FDA approved drugs (cholinesterase inhibitors, Aß-targeting antibodies and an NMDA antagonist) that could mitigate AD rate of decline and symptoms of distress.

Cultured Rat Hippocampal Neurons Exposed to the Mitochondrial Uncoupler Carbonyl Cyanide Chlorophenylhydrazone Undergo a Rapid, Presenilin-Dependent Change in Neuronal Properties.

Presenilin 1 (PS1) is a transmembrane proteolytic subunit of γ-secretase that cleaves amyloid precursor proteins. Mutations in PS1 (mPS1) are associated with early-onset familial Alzheimer's disease (AD). The link between mutated PS1, mitochondrial calcium regulation, and AD has been studied extensively in different test systems. Despite the wide-ranging role of mPS1 in AD, there is a paucity of information on the link between PS1 and neuronal cell death, a hallmark of AD. In the present study, we employed the selective mitochondrial uncoupler carbonyl cyanide chlorophenylhydrazone (CCCP) and compared the reactivity of mPS1-transfected cultured rat hippocampal neurons with PS1 and control neurons in a situation of impaired mitochondrial functions. CCCP causes a slow rise in cytosolic and mitochondrial calcium in all three groups of neurons, with the mPS1 neurons demonstrating a faster rise. Consequently, mPS1 neurons were depolarized by CCCP and measured with TMRM, a mitochondrial voltage indicator, more than the other two groups. Morphologically, CCCP produced more filopodia in mPS1 neurons than in the other two groups, which were similarly affected by the drug. Finally, mPS1 transfected neurons tended to die from prolonged exposure to CCCP sooner than the other groups, indicating an increase in vulnerability associated with a lower ability to regulate excess cytosolic calcium.

Alterations of Structural Network Efficiency in Early-Onset and Late-Onset Alzheimer's Disease.

Early- and late-onset Alzheimer's disease (EOAD and LOAD, respectively) share the same neuropathological hallmarks of amyloid and neurofibrillary tangles but have distinct cognitive features. We compared structural brain connectivity between the EOAD and LOAD groups using structural network efficiency and evaluated the association of structural network efficiency with the cognitive profile and pathological markers of Alzheimer's disease (AD). The structural brain connectivity networks of 80 AD patients (47 with EOAD and 33 with LOAD) and 57 healthy controls were reconstructed using diffusion-tensor imaging. Graph-theoretic indices were calculated and intergroup differences were evaluated. Correlations between network parameters and neuropsychological test results were analyzed. The correlations of the amyloid and tau burdens with network parameters were evaluated for the patients and controls. Compared with the age-matched control group, the EOAD patients had increased global path length and decreased global efficiency, averaged local efficiency, and averaged clustering coefficient. In contrast, no significant differences were found in the LOAD patients. Locally, the EOAD patients showed decreases in local efficiency and the clustering coefficient over a wide area compared with the control group, whereas LOAD patients showed such decreases only within a limited area. Changes in network parameters were significantly correlated with multiple cognitive domains in EOAD patients, but only with Clinical Dementia Rating Sum-of-Boxes scores in LOAD patients. Finally, the tau burden was correlated with changes in network parameters in AD signature areas in both patient groups, while there was no correlation with the amyloid burden. The impairment of structural network efficiency and its effects on cognition may differ between EOAD and LOAD.

Enhancing of cerebral Abeta clearance by modulation of ABC transporter expression: a review of experimental approaches.

Clearance of amyloid-beta (Aβ) from the brain is impaired in both early-onset and late-onset Alzheimer's disease (AD). Mechanisms for clearing cerebral Aβ include proteolytic degradation, antibody-mediated clearance, blood brain barrier and blood cerebrospinal fluid barrier efflux, glymphatic drainage, and perivascular drainage. ATP-binding cassette (ABC) transporters are membrane efflux pumps driven by ATP hydrolysis. Their functions include maintenance of brain homeostasis by removing toxic peptides and compounds, and transport of bioactive molecules including cholesterol. Some ABC transporters contribute to lowering of cerebral Aβ. Mechanisms suggested for ABC transporter-mediated lowering of brain Aβ, in addition to exporting of Aβ across the blood brain and blood cerebrospinal fluid barriers, include apolipoprotein E lipidation, microglial activation, decreased amyloidogenic processing of amyloid precursor protein, and restricting the entrance of Aβ into the brain. The ABC transporter superfamily in humans includes 49 proteins, eight of which have been suggested to reduce cerebral Aβ levels. This review discusses experimental approaches for increasing the expression of these ABC transporters, clinical applications of these approaches, changes in the expression and/or activity of these transporters in AD and transgenic mouse models of AD, and findings in the few clinical trials which have examined the effects of these approaches in patients with AD or mild cognitive impairment. The possibility that therapeutic upregulation of ABC transporters which promote clearance of cerebral Aβ may slow the clinical progression of AD merits further consideration.

Advancements and Challenges in Antiamyloid Therapy for Alzheimer's Disease: A Comprehensive Review.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by the accumulation of amyloid-beta (Aβ) proteins and neurofibrillary tangles in the brain. There have been recent advancements in antiamyloid therapy for AD. This narrative review explores the recent advancements and challenges in antiamyloid therapy. In addition, a summary of evidence from antiamyloid therapy trials is presented with a focus on lecanemab. Lecanemab is the most recently approved monoclonal antibody that targets Aβ protofibrils for the treatment of patients with early AD and mild cognitive impairment (MCI). Lecanemab was the first drug shown to slow cognitive decline in patients with MCI or early onset AD dementia when administered as an infusion once every two weeks. In the Clarity AD trial, lecanemab was associated with infusion-site reactions (26.4%) and amyloid-related imaging abnormalities (12.6%). The clinical relevance and long-term side effects of lecanemab require further longitudinal observation. However, several challenges must be addressed before the drug can be routinely used in clinical practice. The drug's route of administration, need for imaging and genetic testing, affordability, accessibility, infrastructure, and potential for serious side effects are some of these challenges. Lecanemab's approval has fueled interest in the potential of other antiamyloid therapies, such as donanemab. Future research must focus on developing strategies to prevent AD; identify easy-to-use validated plasma-based assays; and discover newer user-friendly, and cost-effective drugs that target multiple pathways in AD pathology.

The Molecular Efficacy of CRISPR-Cas9 in TreatingAlzheimer’s Disease

Alzheimer’s disease (AD), a highly complicated type of neurodegenerative diseases is the brain ailment characterized by the progressive decline in mental function influencing millions of people globally. In spite the developments in molecular biology, it is not fully understood what causes this disease. Mutations in APP, PSEN1, and PSEN2 symptomize AD by building amyloid-beta, a plaque formed in the brains by which neurons communication is hindered triggering cognitive decline, neuronal impairment, and death. Current advances in gene editing have provided new insights into the significant genetic factors take part in the progress of AD. CRISPR-Cas9 is a cutting-edge genome-editing tool used to provide sincere efforts to target and silence infective proteins linked with AD. The main goal of this research is to assess the potential of CRISPR Cas9, as a treatment for Alzheimer’s disease (AD) in addition to reviewing genes for both early and late onset AD.

Presenilin2 D439A Mutation Induces Dysfunction of Mitochondrial Fusion/Fission Dynamics and Abnormal Regulation of GTPase Activity

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disease, and approximately 10% of AD cases are early-onset familial AD (EOFAD), which is mainly linked to point mutations in genes encoding presenilins (PS1 and PS2). Mutations in PS2 are extremely rare and have not received enough attention. Recently, studies have found that Rho GTPase activity is closely related to the pathogenesis of AD. In this study, we used transcriptome sequencing in PS2 siRNA-transfected SH-SY5Y cells and found a group of differentially expressed genes (DEGs) related to the regulation of GTPase activity. Among those DEGs, the most significantly downregulated was Rho guanine nucleotide exchange factor 5 (ARHGEF5). GTPase activity in PS2 siRNA-transfected cells was significantly decreased. Then, we found that the expression of ARHGEF5 and the GTPase activity of Mitochondrial Rho GTPase 2 (Miro2) in PS2 D439A mutant SH-SY5Y cells were significantly decreased. We found for the first time that PS2 can bind to Miro2, and the PS2 D439A mutation reduced the binding between PS2 and Miro2, reduced the expression of Miro2, and resulted in an imbalance in mitochondrial fusion/fission dynamics. In conclusion, PS2 gene knockdown may participate in the pathogenesis of AD through the regulation of GTPase activity. The imbalance in mitochondrial dynamics mediated by the PS2 D439A mutation through regulation of the expression and GTPase activity of Miro2 may be a potential pathogenic mechanism of AD.

SOURCES OF BURDEN IN CAREGIVERS OF PERSONS WITH EARLY- AND LATE-ONSET ALZHEIMER’S DISEASE

Abstract Functional impairment and neuropsychiatric symptoms (NPS) are common in Alzheimer’s disease (AD) and contribute to caregiver burden. Persons with early-onset AD (EOAD) on average experience greater functional impairment and NPS compared to late-onset AD (LOAD), yet their contribution to caregiver burden have not been explored. Objectives were to: 1) compare functional impairment, NPS, and caregiving burden in EOAD and LOAD; 2) identify sources of caregiver burden including functional impairment and NPS in EOAD and LOAD. Caregivers of 85 persons with EOAD (n=63) and LOAD (n=22) completed questionnaires [Functional Activities Questionnaire, Neuropsychiatric Inventory, Zarit Burden Inventory]. T-tests compared group differences in function, NPS, and caregiver burden. Persons with EOAD had greater NPS frequency than LOAD (t= 2.275, p=0.026). There were no significant differences between groups in function or caregiver burden. Multivariate regression analyses were performed in AD groups, with function and NPS frequency as predictors of caregiver burden covarying for age, caregiver sex, and global cognitive function (MMSE). In the total AD sample, the model explained 12.6% of the variance in caregiver burden [F(5,52)=2.64, adjusted R2=0.126; p=0.033] and poor function was a significant predictor (standardized B=0.42, p=0.003) of caregiver burden. In EOAD, the model explained 17% of the variance in caregiver burden [F(5,35)=2.64, adjusted R2=0.17; p=0.04], and poor function was a significant (standardized B=0.42, p=0.015) predictor of caregiver burden; however this was not the case in LOAD. Results suggest poor function predicts caregiver burden in EOAD. Although NPS in EOAD are more frequent, this was not a predictor of caregiver burden.

CIRCADIAN CLOCK DISRUPTION: SEX-SPECIFIC EFFECTS ON METABOLISM & COGNITION IN AN ALZHEIMER’S MODEL

Abstract Preclinical studies have been largely performed on transgenic murine models of early-onset AD, which only accounts for a small fraction of AD cases. A number of confounds have impacted and limited the translatability of these mouse models, including potential off-target genetic effects, artifacts resulting from ultra-physiological overexpression of specific gene products, and overblown pathologies in non-fully developed brains. The objective of this study is to leverage a new microtubule-associated protein tau knockin (MAPT H1-GR) mouse model to assess the effects of an understudied environmental factor associated with AD, a disturbed circadian rhythm, on whole body and brain metabolism, tauopathy, neuroinflammation, neurodegeneration, and cognition. For the experimental design, a cohort of 32 mice was divided into two groups, normal light conditions (NLC) and chronic jet lag (CJL). The CJL mice have a regulated light schedule which shifts 4 hours ahead every 3 days while the NLC mice have a continuous 12 hours of light and 12 hours of dark schedule. Non-fasted and overnight-fasted glucose, ketones, and lactose levels were measured. CJL led to a sex-dependent disruption of fuel utilization during fasting conditions with males displaying more dramatic phenotypes than females. CJL also led to sex-specific changes in body composition, assessed via qMRI testing every other month, specifically at the level of fat mass in males. Cognitive assessment through the Barnes Maze test revealed a disruption of spatial memory in males, while females seemed to be protected from the deleterious effects of CJL on cognition.

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.

TRIM22 facilitates autophagosome-lysosome fusion by mediating the association of GABARAPs and PLEKHM1

ABSTRACT Tripartite motif (TRIM) proteins are a large family of E3 ubiquitin ligases implicated in antiviral defense systems, tumorigenesis, and protein quality control. TRIM proteins contribute to protein quality control by regulating the ubiquitin-proteasome system, endoplasmic reticulum-associated degradation, and macroautophagy/autophagy. However, the detailed mechanisms through which various TRIM proteins regulate downstream events have not yet been fully elucidated. Herein, we identified a novel function of TRIM22 in the regulation of autophagy. TRIM22 promotes autophagosome-lysosome fusion by mediating the association of GABARAP family proteins with PLEKHM1, thereby inducing the autophagic clearance of protein aggregates, independent of its E3 ubiquitin ligase activity. Furthermore, a TRIM22 variant associated with early-onset familial Alzheimer disease interferes with autophagosome-lysosome fusion and autophagic clearance. These findings suggest TRIM22 as a critical autophagic regulator that orchestrates autophagosome-lysosome fusion by scaffolding autophagy-related proteins, thus representing a potential therapeutic target in neurodegenerative diseases. Abbreviations: AD: Alzheimer disease; ADAOO: AD age of onset; AICD: APP intracellular domain; APP: amyloid beta precursor protein; BSA: bovine serum albumin; cDNAs: complementary DNAs; CQ: chloroquine; CTF: carboxyl-terminal fragment; EBSS: Earle’s balanced salt solution; GABARAP: GABA type A receptor-associated protein; GST: glutathione S-transferase; HA: hemagglutinin; HOPS: homotypic fusion and protein sorting; IFN: interferon; IL1A/IL-1α: interleukin 1 alpha; KO: knockout; MTORC1: mechanistic target of rapamycin kinase complex 1; NFKBIA/IκBα: NFKB inhibitor alpha; NFE2L2/NRF2: NFE2 like bZIP transcription factor; PBS: phosphate-buffered saline; PI3K: class I phosphoinositide 3-kinase; PLA: proximity ligation assay; PLEKHM1: pleckstrin homology and RUN domain containing M1; PSEN1: presenilin 1; SEM: standard errors of the means; SNAREs: soluble N-ethylmaleimide-sensitive factor attachment protein receptors; SNCA: synuclein alpha; SNP: single nucleotide polymorphism; TBS: tris-buffered saline; TNF/TNF-α: tumor necrosis factor; TRIM: tripartite motif; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type

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.

Clinical Manifestations.

Perturbations in immune pathways are strongly associated with Alzheimer's disease. A positive association between autoimmune diseases and frontotemporal dementia has been reported. We explored whether early onset Alzheimer's disease (EOAD) would associate with autoimmune diseases. We compared 313 patients with EOAD from the Mayo Clinic Florida, Alzheimer's Disease Research Center (ADRC) Registry with matched cognitively normal controls (NC) based on age (+/- 2 years) and gender at 1:2 ratio. NC were derived from Mayo Clinic Biobank Project, Rochester (N = 313) and the Mayo Clinic Study of Aging (N = 313). Data abstraction was performed by trained statisticians using ICD 9&10 codes corresponding to 40 specified autoimmune diseases and/or documentation of specified immunomodulatory treatment. Data was also abstracted via retrospective record review. We further reviewed clinical records from EOAD patients with neuropathologically confirmed Alzheimer's disease patients enrolled in the ADRC (n = 10). Each autoimmune disease type was compared between cases and controls using Fisher's exact test. All tests were two-sided with alpha level set at 0.05 for statistical significance. Continuous variables were summarized as median (range) while categorical variables were reported as frequency (percentage). The prevalence of autoimmune disease in the general population was based off Hayter & Cook, 2012 and Roberts & Erdei, 2020. All data abstraction was done blinded to the clinical diagnosis and baseline demographics. Autoimmune disease history was abstracted from 949 patient records (313 EOAD, 10 pathologically-confirmed EOAD, 626 NCI). The median age was 57 years-old. (EOAD range 28,65 yrs.; NC 30,66 yrs.). Autoimmune thyroiditis (p = 0.0008), ulcerative colitis (p = 0.011, psoriasis (<0.0001), rheumatoid arthritis (p = 0.0005), and Raynaud's syndrome (p = 0.0021) were less prevalent in patients with EOAD compared to NC. Furthermore, patients with EOAD had a lower prevalence of immune mediated hematologic disorders. Patients with EOAD have a lower prevalence of autoimmune diseases than NC. Immune activation identified in early onset AD patients may be unrelated to autoimmunity. Findings should be explored in late onset AD patients.

Are noradrenergic and orexinergic systems contributing to sleep‐wake patterns in early and late‐onset Alzheimer’s Disease?

AbstractBackgroundNeuropsychiatric symptoms, including sleep‐wake disturbances, are more common in Early‐onset Alzheimer’s disease (EOAD) than in Late‐onset AD (LOAD)(Falgàs, EurJNeurol2022). The pattern of tau‐related degeneration of wake and sleep‐promoting neurons determine sleep‐wake profiles in neurodegenerative disorders (Oh, JAMANeurol2022). We hypothesize that distinct patterns of noradrenergic (locus coeruleus‐LC) and orexigenic (hypothalamus‐HT) degeneration contribute for the differential sleep‐wake patterns between EOAD and LOAD.MethodA group of 21 participants (7 EOAD, 18 LOAD) with a diagnosis of AD confirmed by cerebrospinal fluid biomarkers (CSF) were recruited from Hospital Clínic de Barcelona. Participants underwent sleep questionnaires (Pittsburg Sleep Quality Inventory‐PSQI and Epworth Sleepiness Scale‐ESS), 2‐week actigraphy (MotionWatch8, CamnTech) and 3T‐neuromelanin‐sensitive MRI to measure locus coeruleus (LC) and hypothalamus (HT) volumes. Sleep, napping, and circadian parameters were obtained (MotionWare).ResultThe preliminary results showed no differences in sex (71vs.61% women) or disease stage (CDR 0.5: 85% vs.72%). The amnestic phenotype was prevalent (100 vs.78%). EOAD had longer daytime napping (93.2±74 vs. 58.2±28min, p&lt;0.05), later fell asleep times (0:42am vs. 11:30pm, p&lt;0.05) and higher central phase measure (4.4±0.5 vs. 3.5±1 h, p&lt;0.05, midpoint between fell asleep and wake‐up) than LOAD. Daytime napping correlated with ESS (r = 0.53, p&lt;0.01). Other parameters such as actual sleep time, sleep efficiency, sleep latency, or fragmentation index showed no differences. PSQI did not correlate to any measures. LC‐volumes were lower in EOAD than in LOAD (24.4±7mm3 vs. 33.3±6 p&lt;0.01). In contrast, HT‐ trended towards higher volumes in EOAD (416.8±38 vs. 392.9±36, p = 0.09), being inversely correlated to the age at onset (r = ‐0.47, p&lt;0.05). The central phase measure was inversely correlated to LC‐volumes (r = ‐0.47, p&lt;0.05) but not to HT. Further analyses with increased sample size, CSF noradrenaline and orexin will be performed.ConclusionGreater daytime sleepiness and circadian dysfunction could be main differing traits regarding sleep‐wake patterns between EOAD and LOAD. An opposite pattern of degeneration within wake‐promoting systems consisting of higher degeneration of the LC‐noradrenergic system and relative preservation of the HT‐orexigenic in EOAD in contrast to LOAD might underlie differing sleep‐wake phenotypes. Age‐related hypothalamic volume loss can be adding to AD driven loss resulting in higher volumes in EOAD.

Sex‐associated differences in plasma and cerebrospinal fluid biomarkers in Early‐onset Alzheimer’s disease

AbstractBackgroundFemale sex is associated with greater atrophy, amyloid and tau burden in Early‐onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE‐ε4 non‐carrier‐status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE‐ε4 on plasma and cerebrospinal fluid (CSF) biomarkers of AD. Plasma markers included: neurofilament light chain (NfL), plasma glial fibrillary acidic protein (GFAP), Aβ 42/40, and pTau231. CSF markers included: Aβ 42/40, neurogranin, tTau, pTau181, synaptosomal‐associated protein‐25 (SNAP25), YKL‐40, and visinin‐like protein‐1 (VILIP1).MethodWe included 201 amyloid‐positive EOAD, 64 amyloid‐negative Early‐onset cognitively impaired (EOnonAD), and 86 Cognitively Normal (CN) LEADS participants with plasma biomarker data. Of these 100 EOAD, 35 EOnonAD, and 38 CN participants also had CSF data. Participants were stratified by sex and APOE‐ε4 genotype. Demographics (age, education, APOE‐ε4, MMSE) and biomarker differences were compared using ANOVA within each diagnostic group. ANCOVAs were run to control for the effects of age and education on biomarkers.ResultCompared to men, EOAD women showed greater levels of plasma NfL (p = .03), and GFAP (p&lt;.001) while Aβ 42/40, and pTau231 were comparable. In CSF, EOAD women showed higher levels of neurogranin (p = .01), tTau (p = .01), pTau181 (p = .01) and VILIP1 (p = .02). EOnonAD women showed significantly greater plasma GFAP levels (p = .02). In the CN cohort, women had greater CSF SNAP25 levels (p = .03) while men showed a trend for higher plasma pTau231 levels (p = .05). APOE‐ε4 carrier‐status was not associated with differences in levels of plasma or CSF biomarkers in either sex.ConclusionAs highly selective and specific AD fluid biomarkers emerge, understanding sex‐based differences in CSF and plasma is imperative. Female sex is associated with higher levels of neurodegeneration (NfL, tTau, pTau181, neurogranin, VILIP1) in EOAD and astrogliosis (GFAP) in both EOAD and EOnonAD.This data supports our previous findings that greater pathology burden is associated with female sex. This paves the way for further examination of sex and APOE‐ε4 genotype‐based differences in imaging and fluid biomarkers, their associations, and utility in early diagnosis.

Sex‐associated differences in plasma and cerebrospinal fluid biomarkers in Early‐onset Alzheimer’s disease

AbstractBackgroundFemale sex is associated with greater atrophy, amyloid and tau burden in Early‐onset Alzheimer’s Disease (EOAD) in the Longitudinal EOAD Study (LEADS). APOE‐e4 non‐carrier‐status was found to be a further predictor of EOAD pathology. We expanded the analyses by examining the impact of sex and APOE‐e4 on plasma and cerebrospinal fluid (CSF) biomarkers of AD. Plasma markers included: neurofilament light chain (NfL), plasma glial fibrillary acidic protein (GFAP), Aß 42/40, and pTau231. CSF markers included: Aß 42/40, neurogranin, tTau, pTau181, synaptosomal‐associated protein‐25 (SNAP25), YKL‐40, and visinin‐like protein‐1 (VILIP1).MethodWe included 201 amyloid‐positive EOAD, 64 amyloid‐negative Early‐onset cognitively impaired (EOnonAD), and 86 Cognitively Normal (CN) LEADS participants with plasma biomarker data. Of these 100 EOAD, 35 EOnonAD, and 38 CN participants also had CSF data. Participants were stratified by sex and APOE‐e4 genotype. Demographics (age, education, APOE‐e4, MMSE) and biomarker differences were compared using ANOVA within each diagnostic group. ANCOVAs were run to control for the effects of age and education on biomarkers.ResultCompared to men, EOAD women showed greater levels of plasma NfL (p = .03), and GFAP (p&lt;.001) while Aß 42/40, and pTau231 were comparable. In CSF, EOAD women showed higher levels of neurogranin (p = .01), tTau (p = .01), pTau181 (p = .01) and VILIP1 (p = .02). EOnonAD women showed significantly greater plasma GFAP levels (p = .02). In the CN cohort, women had greater CSF SNAP25 levels (p = .03) while men showed a trend for higher plasma pTau231 levels (p = .05). APOE‐e4 carrier‐status was not associated with differences in levels of plasma or CSF biomarkers in either sex.ConclusionAs highly selective and specific AD fluid biomarkers emerge, understanding sex‐based differences in CSF and plasma is imperative. Female sex is associated with higher levels of neurodegeneration (NfL, tTau, pTau181, neurogranin, VILIP1) in EOAD and astrogliosis (GFAP) in both EOAD and EOnonAD. This data supports our previous findings that greater pathology burden is associated with female sex. This paves the way for further examination of sex and APOE‐e4 genotype‐based differences in imaging and fluid biomarkers, their associations, and utility in early diagnosis.