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Sedation and topical anesthetics in audiology and speech-language pathology. Ad Hoc Committee on Advances in Clinical Practice. American Speech-Language-Hearing Association.

Audiologists and speech-language pathologists who participate in or perform procedures on patients who have been medicated for sedation or topical anesthesia should appreciate the complex factors which may expose their patients to risk or harm. Administration of medications to achieve a desired patient state is a medical procedure requiring physician or dentist prescription, physician or dentist approval on the conditions of administration and monitoring, and physician or dentist availability for provision of emergency care that may be required. For these reasons, audiologists and speech-language pathologists should address issues of scope of practice as defined by state licensing boards and institutional regulatory committees, professional liability, and patient and practitioner safety before engaging in procedures on individuals medicated for sedation or topical anesthesia. These issues should be defined in specific, written protocols that the audiologist and speech-language pathologist develop in collaboration with physicians, dentists, and other medical professionals who are responsible for patient care. The protocols should specify responsibility for each aspect of care and limit procedures to professional settings with immediate access to emergency medical care. In all instances, both in development of written protocols and in actual professional practice, the comfort and safety of the patient must be paramount.

Administration, Topical

Alzheimer disease and the dementia of Parkinson disease: comparative investigations.

Intellectual abnormalities are common in Parkinson disease (PD), occurring in a majority of patients and exhibiting a spectrum of severity from mild to severe. Alzheimer disease (AD) has been posited as the cause of dementia in PD. Comparative neuropsychological studies, however, show differences in memory, language, and frontal lobe functions between AD and PD patients even when the two groups have comparably severe dementia syndromes. The AD-type neuropathology occurs in 10-60% of PD patients, and dementia is usually overt when AD pathology is identified at autopsy. The AD changes are less frequent than intellectual deterioration in PD, and dementia has been observed in PD patients without AD pathology. Therefore, concurrent AD cannot be the cause of all cases of dementia in PD. Cholinergic deficits occur in some PD patients, but cholinergic deficits have been described in patients without dementia and dementia has been documented in patients without cholinergic system abnormalities. Dopaminergic disturbances contribute to the dementia of PD. Differences in neuropeptide concentrations, electrophysiologic responses, and cerebral metabolism also support pathophysiologic distinctions between AD and the dementia of PD. Genetic investigations suggest a role for heredity in AD, whereas PD appears to be an acquired, nongenetic disorder. These studies indicate that despite areas of overlap in clinical symptoms and neuropathology, AD and the dementia of PD are largely distinct.

Aged

Tyrosine phosphorylation systems in Alzheimer's disease pathology.

Immunohistochemical techniques have been used to assess the distribution of phosphotyrosine-containing compartments in Alzheimer's disease (AD) pathology. Elevated levels of phosphotyrosine are apparent in the somatodendritic compartment of tangle-bearing neurons, in the neuritic plaque (NP) and in dystrophic neurites coursing through the neuropil. The only neuronal staining observed in non-AD tissue is in developing neurites. This suggests that some neuronal elements involved in AD pathology may be recapitulating a developmental profile or, alternately, that elevated phosphotyrosine levels may reflect a role for tyrosine kinase/phosphatase systems in the degeneration process directly. Cells in the neuritic plaque which strongly resemble microglia also contain elevated levels of phosphotyrosine compared to non-activated ramified microglia in the same tissue section. Thus, tyrosine phosphorylation systems may be involved in the response of microglia to degeneration in AD pathology. Implications of these results are discussed.

Aged

Protein kinase C alteration is an early biochemical marker in Alzheimer's disease.

Neuritic (senile) plaques are a hallmark of the pathology found in the brain of patients afflicted with Alzheimer's disease (AD). Neuritic plaques have been considered to be composed of an amyloid core surrounded by dilated neurites, although the use of anti-beta/A4-protein antibody revealed the presence of diffuse plaques without a nuclear-like central mass or surrounding paired helical filament (PHF)-containing neuritic components. The presence of diffuse plaques without PHF-containing neuritic components strongly suggests that the formation of amyloid precedes the degeneration of neurites that surround amyloid. Diffuse plaques are thus considered to be an early marker of AD pathology. In this article, we report that diffuse plaques, possible markers of early AD pathology, are immunostained with anti-protein kinase C(beta II) [anti-PKC(beta II)] antibodies. The PKC(beta II)-immunoreacting components of the diffuse plaques extend from neurons embedded in the plaques. Immunoelectron microscopy of diffuse and mature neuritic plaques shows that PKC(beta II)-like immunoreactivity in the plaques is closely associated with membranous structures of fine neuronal processes apposed to the amyloid fibers. These fine neuronal processes are distinct from classical neurites found typically in mature neuritic plaques. Furthermore, biochemical analysis demonstrates that PKC abnormalities, but not other AD markers (ubiquitin and A68), were found in the neocortex of clinically nondemented individuals with cortical plaques. Therefore, the PKC alteration in neurons might be involved in the early pathophysiology of AD.

Alzheimer Disease

Transcriptome-wide association analysis of Alzheimer's disease: construction and clinical validation of transcriptomic risk scores.

Early identification of individuals at high risk for Alzheimer's disease (AD) is crucial for disease prevention and intervention. This study aims to develop AD-specific transcriptomic risk scores (TRSs) through multi-tissue transcriptome-wide association study (TWAS) and to evaluate its clinical utility in AD diagnosis and risk prediction. Using GWAS summary statistics combined with expression quantitative trait loci (eQTL) data from 14 tissues, a multi-tissue TWAS approach was applied to identify AD-associated genes. Peripheral blood RNA expression data from the ADNI and GEO databases were used to construct the AD-specific TRSs. The associations of TRSs with AD pathological features and cognitive function were assessed in two independent cohorts. Furthermore, the diagnostic performance, differential diagnostic capability, and risk prediction efficiency of TRSs were evaluated. The TWAS identified 131 genes significantly associated with AD. The TRSs were significantly elevated in patients with AD and mild cognitive impairment (MCI) compared to cognitively normal (CN) individuals, and showed significant correlations with AD pathological markers and cognitive performance. When combined with APOE4 status, the TRSs demonstrated robust diagnostic ability for AD and MCI. When combined with age, the TRSs showed good diagnostic performance in distinguishing AD from frontotemporal dementia (FTD) (AUC = 0.86). Additionally, the TRSs effectively predicted the risk of progression to AD in non-AD individuals (HR = 1.74). The AD-specific TRSs developed in this study shows promising clinical utility in AD diagnosis, differential diagnosis, and risk prediction, providing valuable translational medical evidence for early screening and precision prevention of Alzheimer's disease.

Humans

Entorhinal neurofibrillary tangles in Alzheimer disease with Lewy bodies.

Entorhinal cortex is the major source of hippocampal afferents. Its neurons, especially in layer 2, develop neurofibrillary tangles (NFTs) in Alzheimer disease (AD). We quantified entorhinal NFTs in cases of AD, elderly controls, and in brains with both AD pathology and subcortical and neocortical Lewy bodies, (a Lewy body variant, LBV). A nosologic controversy hinges on whether LBVs are a form of AD or a different disease, since they have few neocortical NFTs and their neuritic plaques often lack paired helical filament immunoreactivity. The LBVs had more entorhinal NFTs than controls (P less than 0.001), but fewer than ADs (P less than 0.02), despite comparable numbers of neuritic plaques. AD pathology in LBVs is of moderate severity, or perhaps in an earlier developmental stage.

Aged

Consensus meta-analysis of genome-wide association studies for Alzheimer's disease and related dementias.

To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.

Humans

Aberrant localization of MAP5 immunoreactivity in the hippocampal formation in Alzheimer's disease.

Immunocytochemistry was used to examine MAP5 immunoreactivity in the hippocampal formation obtained postmortem from five elderly, normal individuals, six individuals with Alzheimer's disease (AD), and two "transition" cases that did not have a history of dementia but did exhibit significant AD pathology. In all of the cases examined, axonal staining was restricted to the mossy fibers and their terminal field in CA3 stratum lucidum. In control cases, MAP5 immunoreactivity was observed in the neuronal cytoplasm and the proximal portion of the apical dendrites of pyramidal and granule cells. In both AD and transition cases, increased intensity of immunostaining was observed in CA3 pyramidal, subicular, and dentate gyrus granule cell neurons. Within individual neurons, immunoreactivity filled the neuronal perikarya, including the nuclear region, and the apical dendrite. Punctate staining was observed in neuritic plaques, but neurofibrillary tangles and neuropil threads were not immunostained. The increase and altered distribution of MAP5 immunoreactivity in both vulnerable and nonvulnerable neurons in AD may reflect an aberrant sprouting response. The increased expression of early cytoskeletal proteins may be tolerated in some regions such as CA3, but not in others including CA1 where the increased expression appear to precede aberrant phosphorylation, proteolysis, and incorporation of cytoskeletal proteins into AD pathology. Alternatively, the results could reflect sprouting in response to the neuronal loss and degeneration.

Aged

Elevated plasma GFAP levels in MCI link APOE ε4 allele with impaired gait speed.

The presence of at least one copy of the apolipoprotein ε4 allele (APOE ε4) is a known predictor of gait impairment risk among older adults. However, the mechanisms by which APOE ε4 affects gait performance remain unclear. This cross-sectional study aimed to reveal underlying pathological mechanisms linking APOE ε4 carriage to slow gait. This secondary analysis used baseline assessments from the J-MINT multicenter intervention trial, focusing on older adults with mild cognitive impairment. Gait speed was measured at baseline, with slow gait (SG) defined as speeds one standard deviation below the age- and sex-specific mean. APOE phenotype and plasma biomarkers related to Alzheimer's disease (AD), including amyloid-β composite biomarker, phosphorylated Tau 181, neurofilament light, and glial fibrillary acidic protein (GFAP), were also measured. The analysis included 236 non-APOE ε4 carriers and 84 carriers of at least one APOE ε4. APOE ε4 carriers exhibited significantly slower gait speed than non-carriers (1.20 m/s [SD = 0.22] vs 1.26 m/s [SD = 0.23], p = 0.042). Significant interaction between APOE ε4 carriage and SG was observed only in plasma GFAP levels (F1, 312 = 7.17, p = 0.008), indicating that individuals with APOE ε4 and SG had significantly higher plasma GFAP levels. Elevated plasma GFAP levels fully mediated the association between APOE ε4 carriage and gait speed (partially standardized indirect effect = -0.059: -0.12 to -0.013]). No other AD-related biomarkers mediated this association. Our results suggest that APOE ε4-related gait changes may reflect AD pathology, as indicated by elevated GFAP levels, and could potentially accelerate dementia symptoms.

Aged

Early oligodendrocyte dysfunction signature in Alzheimer's disease: Insights from DNA methylomics and transcriptomics.

Much research into the aetiology of Alzheimer's disease (AD) has focused on neuronal cell types, while studies on the contribution of glial cells, particularly oligodendrocytes (OLGs), are only starting to emerge. Altered brain DNA methylation, an epigenetic modification that provides the interplay between genetics and environmental cues to tightly regulate gene expression, is well documented in AD. Yet, cell-type-specific investigations remain limited. Here, we examine the role of DNA methylation and OLGs in AD, and how such changes may impact gene expression. We performed weighted-gene correlation network analysis (WGCNA) on multiple brain omics AD datasets across species: human DNA methylation data from 4 brain regions, human brain single-nuclei RNA sequencing data and mouse brain RNA sequencing data. We compared AD-associated network modules enriched for OLG genes across AD brain regions, as well as with other neurodegenerative disease DNA methylation datasets. We identified a DNA methylation signature associated with AD, enriched for OLGs, and preserved across brain regions representing early and late AD pathology stages. Genes within this signature showed altered expression in AD OLGs, confirming cell-type specificity and relevance to AD. This OLG signature was also preserved in transgenic mice with early Aβ pathology and in other neurodegenerative diseases without Aβ pathology. We reveal a consistent pattern of OLG dysfunction spanning early to late stages of AD, across DNA methylation and gene expression. Our findings highlight OLG-associated DNA methylation changes as important in AD pathogenesis, and possibly in other neurodegenerative diseases, opening new avenues for therapeutic development.

Alzheimer Disease

Diagnostic value of blood p-tau subtypes in Alzheimer's disease progression and pathology: systematic review and meta-analysis.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease and the most likely to lead to dementia. With the availability of the latest therapies, the need for Alzheimer's disease diagnosis is now gradually increasing. Whereas blood phosphorylated-tau (p-tau) has demonstrated excellent performance in the prediction and diagnosis of disease progression and A&#x3b2; positivity in AD, there are differences between different p-tau subtypes. Therefore, a pooled analysis of different blood p-tau subtypes is of more important clinical value. METHOD: Relevant literature was screened by complete search in four databases, Pubmed, Embase, Cochrane Library and Scopus. Relevant data and AUC and their confidence intervals of the included literature were extracted and analyzed by classification according to p-tau subtypes. Quality assessment was performed using the QUADAS-2 tool. RESULT: Our results reveal that p-tau217 performs better in the diagnostic performance in most stages of AD, which is consistent with the guidelines. However, our results concluded that p-tau217 has poorer diagnostic performance in the stages of cognitive unimpaired or less cognitively impaired, especially in the A&#x3b2; positivity diagnosis of SCD and CU. Head-to-head meta-analyses formally confirmed that p-tau217 significantly outperforms p-tau181 across AD dementia, A&#x3b2; positivity, tau positivity, and biological staging (all P&#x2009;<&#x2009;0.05), whereas no significant difference was observed between p-tau231 and p-tau181. CONCLUSION: By integrating single-arm pooled AUC estimates with formal head-to-head statistical comparisons, our study provides evidence-based support for plasma p-tau217 as the subtype with the most robust diagnostic performance across AD pathology and biological staging. Head-to-head analyses formally confirmed that p-tau217 significantly outperforms p-tau181 in A&#x3b2; positivity, Tau positivity, and biological staging.

Humans

Inverse relationship between education and parietotemporal perfusion deficit in Alzheimer's disease.

A higher prevalence of dementia in individuals with fewer years of education has suggested that education may protect against Alzheimer's disease (AD). We tested whether individuals with more years of education have a more advanced AD before it is clinically evident. As a measure of pathophysiological severity, we quantified regional cerebral blood flow (rCBF), by the 133Xenon inhalation technique; a specific pattern of flow reduction in the parietotemporal cortex corresponds to AD pathology. In 3 groups of patients with probable AD, matched for clinical measures of dementia severity but with varying levels of education, whole-cortex mean flows were comparable. However, the parietotemporal perfusion deficit was significantly greater in the group with the highest level of education, indicating that AD was more advanced in this group. We conclude that education or its covariates or both may provide a reserve that compensates for the neuropathological changes of AD and delays the onset of its clinical manifestations.

Alzheimer Disease

Brain stem serotonin-synthesizing neurons in Alzheimer's disease: a clinicopathological correlation.

The location and number of brain stem serotonin-synthesizing neurons were analyzed in 11 patients with Alzheimer's disease (AD) and 5 age-matched controls using immunohistochemical techniques. In addition, the number of neuritic plaques and neurofibrillary tangles in the cortex and brain stem raphe was evaluated, as was the number of Nissl-stained raphe neurons. AD patients could be classified into two groups based on their raphe pathology; patients with such pathology (AD+) and those without (AD-). The number of large raphe neurons correlated significantly with the number of serotonin-synthesizing neurons in control material, indicating that all large neurons were serotonergic. This relationship was not apparent in AD+ patients, in whom the number of serotonin-synthesizing neurons correlated with the number of neurofibrillary tangles in the raphe of these patients. This indicates that in AD+ patients the serotonin-synthesizing neurons were selectively affected. There was no correlation between raphe and cortical pathology or raphe pathology and patient sex, age, mini-mental score or depression score, even when such scores were weighted for the interval between testing and death. There was a trend for the raphe pathology to correlate with the age of onset and duration of dementia and the Blessed dementia score in AD+ patients. Most AD+ patients with severe raphe lesions had clinical dementia only, while AD- patients had additional clinical features. The raphe lesions were more dramatic in AD+ patients with a rapid progression of symptoms.

Aged

DeepPlaque: a scalable multimodal platform for A&#x3b2; pathology and cell analysis in Alzheimer's disease.

Histological analysis is essential for understanding disease pathology and the microenvironment, particularly in Alzheimer's disease (AD), characterized by beta-amyloid (A&#x3b2;) plaques that exist as diffuse, fibrillar, and core species, with distinct toxicity levels. However, accurate classification of A&#x3b2; plaque types in postmortem brain tissues and profiling of surrounding cells present significant challenges. To address these challenges, we developed "DeepPlaque", an integrated system featuring "PlaqueNet", a deep learning model for automated classification of A&#x3b2; plaque species from diverse imaging platforms. DeepPlaque includes automated workflows for cellular phenotyping and proteomic profiling through targeted laser microdissection. PlaqueNet achieves expert-level accuracy (AUC&#x2009;>&#x2009;90%) in classifying the 3 major A&#x3b2; plaque species, supporting consistent and large-scale annotation. By integrating spatial cellular phenotyping with laser microdissection, DeepPlaque enables high-throughput proteomic analysis of A&#x3b2; plaque niches, revealing that microglia are more abundant around core and fibrillar A&#x3b2; plaques, with increased expression of apolipoprotein E and amyloid precursor protein in core A&#x3b2; plaques. This customizable platform enhances the molecular and cellular characterization of A&#x3b2; plaque-associated environments, providing critical insights into AD pathology.

Alzheimer Disease

[Affected siblings with Alzheimer's disease had missense mutation of codon 717 in amyloid precursor protein gene].

Using reverse genetic techniques, the gene responsible for familial Alzheimer's disease (FAD) is one of the clues to identify the pathogenesis of Alzheimer's disease (AD). Recently a missense mutation in the APP (amyloid precursor protein) gene (generally this mutation was called APP717) was detected in 2 Caucasian AD families and the same mutation was found in 3 Japanese AD families. We experienced brother's cases who were diagnosed as AD. Both of them and one normal person of the next generation had APP717. The first symptom of the elder brother (case 1) was forgetfulness at 52 years old, then dementia was advanced. In his clinical course there were characteristic findings such as the mirror sign, pseudodialog and jargon which has been rarely described in the Japanese literature. Finally he died of pneumonia at 57 years old. He was diagnosed as AD pathologically and physical findings of brain CT, SPECT (single photon emission computed tomography) and EEG supported this diagnosis clinically. The first symptom of the younger brother (case 2) was also forgetfulness at 45 years old, then severe dementia was advanced, at last he died of pneumonia at age 53 old. On the other hand the mother of the brothers died of severe dementia, so it was suspected that brothers died of severe dementia, so it was suspected that she had had AD. The clinical courses and pathological findings were thought to be typical of AD, namely there were no significant differences in comparison with other cases of FAD and sporadic AD.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer's disease.

BACKGROUND: A significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. METHODS: This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n&#x2009;=&#x2009;631 individuals) and multiregional single-nucleus RNA sequencing (n&#x2009;=&#x2009;48 individuals). Subjects were categorized into AD, resilient, and control based on &#x3b2;-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. RESULTS: Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+&#x2009;and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+&#x2009;inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. CONCLUSIONS: We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Humans

Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre-neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-&#x3b3; signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.

Animals

The Effect of APOE &#x3b5;4 Allele on Dynamic Local Spontaneous Brain Activity and Functional Integration in Alzheimer's Disease.

The apolipoprotein E (APOE) &#x3b5;4 allele is the most important genetic risk factor for sporadic Alzheimer's disease (AD), yet its mechanisms in AD pathology and cognitive decline remain unclear. Using a sliding-time window approach to directly quantify the instantaneous fluctuations of various local metrics based on continuous time series and calculate voxel-wise concordance of these metrics, we explored the impact of APOE &#x3b5;4 on dynamic local brain activity and functional integration in AD, and its interrelations with plasma biomarkers and cognition. Results showed that APOE &#x3b5;4 widely affected dALFF, dReHo, dGSCorr, and voxel-wise concordance. For AD patients, APOE &#x3b5;4 carriers uniquely exhibited correlations between dALFF in the right angular gyrus/supramarginal gyrus and MoCA scores and orientation function, and between voxel-wise concordance in the right caudate nucleus (CAU) and general cognition, attention, language function, orientation function, plasma A&#x3b2;42. Critically, APOE &#x3b5;4-related altered voxel-wise concordance in the right CAU mediated the relationship between plasma A&#x3b2; and language cognition in AD. Moreover, the combined model incorporating dynamic metrics, plasma AD biomarkers, and demographic data effectively distinguished AD from NC (AUC&#x2009;=&#x2009;0.94, sensitivity&#x2009;=&#x2009;87.69%, specificity&#x2009;=&#x2009;86.84%). In conclusion, the APOE &#x3b5;4 allele might play a pivotal role in modulating brain dynamic functional activities in AD, which may contribute to the association between A&#x3b2; pathology and cognitive decline. Our findings may provide imaging markers and targets for the diagnosis and treatment of AD.

Humans