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Positron Emission Tomography (PET) ligands have advanced Alzheimers disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.

Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence in humans remains scarce, requiring improved non-invasive techniques and integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators and incorporating resting-state functional MRI, amyloid-β (Aβ) and tau-PET from 132 individuals in the AD spectrum to evaluate the direct impact of toxic protein deposition on neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) and grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show the hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aβ-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental activation phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

The molecular mechanisms underlying neuronal dysfunction in Alzheimer's disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aβ and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant's real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aβ-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aβ and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aβ and tau's synergistic impact on neuronal activity (q

ImportanceNeuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms.ObjectiveTo evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum.Design, setting, and participantsThis cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions.Main outcomes and measuresAll individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-β ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET).ResultsOf the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-β PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β = 7.37; 95% CI, 1.34-13.41; P = .01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (β = 6.86; 95% CI, 1.77-11.95; P = .008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (β = 5.72; 95% CI, 0.33-11.10; P = .03).Conclusions and relevanceIn this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-β- and microglia-targeted therapies could have an impact on relieving these symptoms.

Background: Alzheimer's disease (AD) is classically viewed as a predominantly amnestic syndrome, with other cognitive and neuropsychiatric symptoms (NPS) being non‐integral associations. Emerging Evidence suggests that within typical AD, these symptoms are core features from the onset. Methods: We employed K‐modes clustering on 2483 cognitively impaired (CI) individuals (CDR ≥ 0.5), excluding participants diagnosed with atypical AD, non‐amnestic MCI, or CI due to non‐AD dementias from five cohorts: TRIAD, ADNI, BICWALZS, OASIS‐III, and Pittsburgh. Cluster‐specific clinical and pathological profiles were established through comparison with 2670 cognitively unimpaired (CU) participants across plasma biomarkers (Ptau‐181, Ptau‐217, GFAP, Nfl, AB42/40 ratio) and neuroimaging (amyloid and tau PET, white matter hyperintensity, MRI‐derived degeneration maps). The rate of functional decline, modeled by increase in CDR‐SB, was assessed using a Cox‐proportional hazards model and a linear mixed‐effect model. Results: We identified five distinct clinical phenotypes within typical AD: 'Pure Amnestic' (30.2%), 'Linguistic‐Hyperactive' (14.7%), 'Visuospatial‐Affective' (14.7%), 'Frontal' (27.6%), and 'Global' (19.3%) (Figure 1, Figure 3). These phenotypes demonstrated consistency regardless of amyloid status or cohort. Each phenotype exhibited a unique neuropathological signature and a distinct pattern of neurodegeneration (Figure 2). A critical aspect of our findings is the differential rate of functional decline across these phenotypes. The 'Pure Amnestic' group showed the slowest decline, followed by 'Linguistic‐Hyperactive' (HR = 1.39; B = 0.2), 'Visuospatial‐Affective' (HR = 2.13; B = 1), 'Frontal' (HR = 2.23; B = 1.53), and the 'Global' phenotype showing the fastest decline (HR = 3.52; B = 2.66) (Figure 2, Figure 3). Conclusion: Our results challenge the concept of "typical" AD by uncovering five robust clinical phenotypes with divergent neuropathological profiles and clinical characteristics. These results mark an important advancement toward personalized medicine in the landscape of emerging AD treatments. [ABSTRACT FROM AUTHOR]

Background and purpose: This study was undertaken to compare the performance of plasma p‐tau181 with that of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in the identification of early biological Alzheimer disease (AD). Methods: We included 533 cognitively impaired participants from the Alzheimer's Disease Neuroimaging Initiative. Participants underwent PET scans, biofluid collection, and cognitive tests. Receiver operating characteristic analyses were used to determine the diagnostic accuracy of plasma p‐tau181 and [18F]FDG‐PET using clinical diagnosis and core AD biomarkers ([18F]florbetapir‐PET and cerebrospinal fluid [CSF] p‐tau181) as reference standards. Differences in the diagnostic accuracy between plasma p‐tau181 and [18F]FDG‐PET were determined by bootstrap‐based tests. Correlations of [18F]FDG‐PET and plasma p‐tau181 with CSF p‐tau181, amyloid β (Aβ) PET, and cognitive performance were evaluated to compare associations between measurements. Results: We observed that both plasma p‐tau181 and [18F]FDG‐PET identified individuals with positive AD biomarkers in CSF or on Aβ‐PET. In the MCI group, plasma p‐tau181 outperformed [18F]FDG‐PET in identifying AD measured by CSF (p = 0.0007) and by Aβ‐PET (p = 0.001). We also observed that both plasma p‐tau181 and [18F]FDG‐PET metabolism were associated with core AD biomarkers. However, [18F]FDG‐PET uptake was more closely associated with cognitive outcomes (Montreal Cognitive Assessment, Mini‐Mental State Examination, Clinical Dementia Rating Sum of Boxes, and logical memory delayed recall, p < 0.001) than plasma p‐tau181. Conclusions: Overall, although both plasma p‐tau181 and [18F]FDG‐PET were associated with core AD biomarkers, plasma p‐tau181 outperformed [18F]FDG‐PET in identifying individuals with early AD pathophysiology. Taken together, our study suggests that plasma p‐tau181 may aid in detecting individuals with underlying early AD. [ABSTRACT FROM AUTHOR]

Background: The newly proposed criteria by the AA working group incorporates both biological and clinical stages to characterize the progression of AD. In this study, we aim to evaluate the agreement between these two complementary systems. Methods: Using 188 participants from McGill TRIAD and 139 from the HEAD cohorts, we categorized participants into biological (0‐4) and clinical (0‐4) stages using amyloid PET, tau PET(MK‐6240), and clinical measures as described by the working group. Participants were then stratified into three categories: congruent (clinical = biological), higher in the biological stage (clinical < biological), and higher in the clinical stage (clinical > biological). In the TRIAD cohort, we further compared these groups for age, sex, years of education, vascular burden (WMH), microglial activation (PBR scan), Astrocyte reactivity (GFAP), amyloid load, tau load, and NPI‐Q scores using Welch two‐sided t‐test with FDR multiple comparison correction. Results: In the TRIAD cohort, 34% of participants were congruent, 24.5% had a higher clinical stage, and 41.5% had a higher biological stage. Meanwhile in the HEAD cohort 68.2% were congruent, 20.7% had a higher clinical stage, and 17% had a higher biological stage. TRIAD participants with a higher clinical stage had lower education (P = 0.02), more neuropsychiatric symptoms (P = 0.03), and a higher vascular burden (P = 0.03) (Table 1). As expected, people with higher biological stage had more amyloid(P<0.001), tau(P<0.001), and astrocyte reactivity(P<0.001) (Table 1, Figure 2). Conclusions: Our findings highlight important discordance between clinical and biological stages, which could be partially explained by cognitive reserve. This was supported by the protective effects of educational attainment in participants with a higher biological stage. Vascular burden played a major role in the cognitive impairment of individuals with higher clinical stages. Future studies should replicate these findings in larger more representative population‐based cohorts. [ABSTRACT FROM AUTHOR]

Background: Classical literature has pointed at lateralization of the relationship between memory scores and cerebral hemisphere injury. Epilepsy studies have suggested an association between left hippocampal damage and verbal memory deficits, and between right hippocampal damage and visual memory deficits. We aimed to explore this concept in the context of tauopathy due to Alzheimer's disease. Method: we assessed 132 cognitively unimpaired (CU) older adults, and 44 cognitively impaired (CI), amyloid‐β positive individuals from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. All participants had amyloid‐PET with [18F]AZD4694 and tau‐PET with [18F]MK6240, verbal memory assessments with Rey Auditory Verbal Learning Test (RAVLT), and visual memory assessments with Aggie Figures Learning Test (AFLT). We conducted voxel‐wise analyses to explore the relationship between tau PET and memory modality. In addition, we run regression models with right or left tau temporal metaROI as predictor and memory scores as outcome variables. We entered global amyloid (PET), sex, age, years of education, ApoE status, grey matter volume and handedness as covariates. Finally, we used the laterality index (LI) to investigate correlations with memory modality. Right laterality is indicated by an LI below 0, while left laterality would be signaled by an LI above 0. Result: voxel‐wise analyses suggested a lateralized relationship between tau and visual memory scores on the right hemisphere, whereas tau and verbal memory scores were bilaterally associated. Regression analyses showed a trend towards a stronger relationship between temporal tau on the right and visual memory scores. The LI was significantly associated with visual memory performance. Further analyses showed that this relationship seems to be driven by tau positive individuals. Conclusion: visual memory performance might be more prominently affected by tau load on the right hemisphere in Alzheimer's disease. Furthermore, a hemispheric imbalance in the amount of tau is related to visual, but not verbal, memory scores. [ABSTRACT FROM AUTHOR]

The molecular mechanisms underlying neuronal dysfunction in Alzheimer's disease (AD) remain uncharacterized. Here, we identify genes, molecular pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- and tau-PET for 47 cognitively unimpaired and 16 AD participants from the Translational Biomarkers in Aging and Dementia cohort. Adverse neuronal activity impacts by Aβ and tau were quantified with personalized dynamical models by fitting pathology-mediated computational signals to the participant's real rs-fMRIs. Then, we detected robust brain-wide associations between the spatial profiles of Aβ-tau impacts and gene expression in the neurotypical transcriptome (Allen Human Brain Atlas). Within the obtained distinctive signature of in-vivo neuronal dysfunction, several genes have prominent roles in microglial activation and in interactions with Aβ and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aβ and tau's synergistic impact on neuronal activity (q < 0.001). These results further support the central role of the immune system and neuroinflammatory pathways in AD pathogenesis. Neuronal dysregulation by AD pathologies also associated with neurotypical synaptic and developmental processes. In addition, we identified drug candidates from the vast LINCS library to halt or reduce the observed Aβ-tau effects on neuronal activity. Top-ranked pharmacological interventions target inflammatory, cancer and cardiovascular pathways, including specific medications undergoing clinical evaluation in AD. Our findings, based on the examination of molecular-pathological-functional interactions in humans, may accelerate the process of bringing effective therapies into clinical practice. [ABSTRACT FROM AUTHOR]