Glial reactivity is linked to synaptic dysfunction across the aging and Alzheimer's disease spectrum.

Previous studies have shown that glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease(AD). However, the link between glial and neuronal markers and synaptic abnormalities in the living brain is poorly understood. Here, we investigated the association between biomarkers of astrocyte and microglial reactivity and synaptic dysfunction in 478 individuals across the aging and AD spectrum from two cohorts with available CSF measures of amyloid-ß(Aß), phosphorylated tau(pTau181), astrocyte reactivity(GFAP), microglial activation(sTREM2), and synaptic biomarkers(GAP43 and neurogranin). Elevated CSF GFAP levels were linked to presynaptic and postsynaptic dysfunction, regardless of cognitive status or Aß presence. CSF sTREM2 levels were associated with presynaptic biomarkers in cognitively unimpaired and impaired Aß + individuals and postsynaptic biomarkers in cognitively impaired Aß + individuals. Notably, CSF pTau181 levels mediated all associations between GFAP or sTREM2 levels and synaptic dysfunction biomarkers. These results suggest that neuronal-related synaptic biomarkers could be used in clinical trials targeting glial reactivity in AD.

Omics-derived biological modules reflect metabolic brain changes in Alzheimer's disease.

INTRODUCTION: Brain glucose hypometabolism, indexed by the fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) imaging, is a metabolic signature of Alzheimer's disease (AD). However, the underlying biological pathways involved in these metabolic changes remain elusive. METHODS: Here, we integrated [18F]FDG-PET images with blood and hippocampal transcriptomic data from cognitively unimpaired (CU, n = 445) and cognitively impaired (CI, n = 749) individuals using modular dimension reduction techniques and voxel-wise linear regression analysis. RESULTS: Our results showed that multiple transcriptomic modules are associated with brain [18F]FDG-PET metabolism, with the top hits being a protein serine/threonine kinase activity gene cluster (peak-t(223) = 4.86, P value < 0.001) and zinc-finger-related regulatory units (peak-t(223) = 3.90, P value < 0.001). DISCUSSION: By integrating transcriptomics with PET imaging data, we identified that serine/threonine kinase activity-associated genes and zinc-finger-related regulatory units are highly associated with brain metabolic changes in AD. HIGHLIGHTS: We conducted an integrated analysis of system-based transcriptomics and fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) at the voxel level in Alzheimer's disease (AD). The biological process of serine/threonine kinase activity was the most associated with [18F]FDG-PET in the AD brain. Serine/threonine kinase activity alterations are associated with brain vulnerable regions in AD [18F]FDG-PET. Zinc-finger transcription factor targets were associated with AD brain [18F]FDG-PET metabolism.

15 Years of Longitudinal Genetic, Clinical, Cognitive, Imaging, and Biochemical Measures in DIAN.

This manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.

Influence of Different Diagnostic Criteria on Alzheimer Disease Clinical Research.

BACKGROUND AND OBJECTIVES: Updates in Alzheimer disease (AD) diagnostic guidelines by the National Institute on Aging-Alzheimer's Association (NIA-AA) and the International Working Group (IWG) over the past 11 years may affect clinical diagnoses. We assessed how these guidelines affect clinical AD diagnosis in a cohort of cognitively unimpaired (CU) and cognitively impaired (CI) individuals. METHODS: We applied clinical and biomarker data in algorithms to classify individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort according to the following diagnostic guidelines for AD: 2011 NIA-AA, 2016 IWG-2, 2018 NIA-AA, and 2021 IWG-3, assigning the following generic diagnostic labels: (1) not AD (nAD), (2) increased risk of developing AD (irAD), and (3) AD. Diagnostic labels were compared according to their frequency, convergence across guidelines, biomarker profiles, and prognostic value. We also evaluated the diagnostic discordance among the criteria. RESULTS: A total of 1,195 individuals (mean age 73.2 ± 7.2 years, mean education 16.1 ± 2.7, 44.0% female) presented different repartitions of diagnostic labels according to the 2011 NIA-AA (nAD = 37.8%, irAD = 23.0%, AD = 39.2%), 2016 IWG-2 (nAD = 37.7%, irAD = 28.7%, AD = 33.6%), 2018 NIA-AA (nAD = 40.7%, irAD = 9.3%, AD = 50.0%), and 2021 IWG-3 (nAD = 51.2%, irAD = 8.4%, AD = 48.3%) frameworks. Discordant diagnoses across all guidelines were found in 512 participants (42.8%) (138 [91.4%] occurring in only ß-amyloid [CU 65.4%, CI 34.6%] and 191 [78.6%] in only tau-positive [CU 71.7%, CI 28.3%] individuals). Differences in predicting cognitive impairment between nAD and irAD groups were observed with the 2011 NIA-AA (hazard ratio [HR] 2.21, 95% CI 1.34-3.65, p = 0.002), 2016 IWG-2 (HR 2.81, 95% CI 1.59-4.96, p < 0.000), and 2021 IWG-3 (HR 3.61, 95% CI 2.09-6.23, p < 0.000), but not with 2018 NIA-AA (HR 1.69, 95% CI 0.87-3.28, p = 0.115). DISCUSSION: Over 42% of the studied population presented discordant diagnoses when using the different examined AD criteria, mostly in individuals with a single positive biomarker. Except for 2018 NIA-AA, all guidelines identified asymptomatic individuals at risk of cognitive impairment. Our findings highlight important differences between the guidelines, emphasizing the necessity for updated criteria with enhanced staging metrics, considering clinical, research, therapeutic, and trial design aspects.

Hormone therapy is associated with lower Alzheimer's disease tau biomarkers in post-menopausal females -evidence from two independent cohorts.

BACKGROUND: Females represent approximately 70% of the Alzheimer's disease (AD) cases and the literature has proposed a connection between the decreased estrogen levels during menopause and an increased AD risk. Previous investigations have predominantly focused on assessing how hormone therapy (HT) affects the likelihood of AD development and cognitive deterioration. However, as the research framework has shifted toward a biomarker-defined AD and alterations in specific biomarkers could take place years before cognitive decline becomes discernible, it is crucial to examine how HT influences AD biomarkers. The main goal of this study was to evaluate the impact of HT on AD biomarker-informed pathophysiology in both cognitively unimpaired (CU) and cognitively impaired (CI) post-menopausal females across the aging and AD spectrum. METHODS: This cross-sectional study included post-menopausal females without HT history (HT-) and with HT (HT+) at the time of PET imaging assessment from two cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants underwent magnetic resonance imaging (MRI), positron emission tomography (PET) and biofluid collection. Voxel-based t-tests were performed to assess the differences in amyloid-ß (Aß) and tau neurofibrillary tangles (NFTs) loads between HT- and HT + females. Linear regression models with interaction terms were also conducted to examine the interactive effects of HT and Aß-PET on regional tau-PET. RESULTS: HT + females demonstrated significantly lower tau-PET standardized uptake value ratio (SUVR) in Braak I-II ROIs (P < 0.05, Hedges' g = 0.73), Braak III-IV ROIs (P < 0.0001, Hedges' g = 0.74) and Braak V-VI ROIs (P < 0.0001, Hedges' g = 0.69) compared to HT- females. HT + females also showed significantly lower CSF p-tau181 (P < 0.001) and plasma p-tau181 (P < 0.0001) concentrations. Additionally, results from multivariate linear regression models indicated that HT interacts with cortical Aß and is associated with lower regional NFT load. CONCLUSIONS: Overall, findings from this observational study suggest that HT is associated with lower tau neuroimaging and fluid biomarkers in postmenopausal females. Due to the close link between tau and cognition, this study highlights the need for large randomized controlled trials designed to systemically study the influences of HT on AD biomarkers and disease progression.

In-vivo neuronal dysfunction by Aß and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer's disease.

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 (Aß) and tau deposits in the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aß- 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 Aß 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 Aß-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 Aß and tau. Moreover, cellular vulnerability estimations revealed strong association of microglial expression patterns with Aß 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 Aß-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.

Prediction of future cognitive decline among cognitively unimpaired individuals using measures of soluble phosphorylated tau or tau tangle pathology.

Plasma p-tau217 and Tau-PET are strong prognostic biomarkers in Alzheimer's disease (AD), but their relative performance in predicting future cognitive decline among cognitively unimpaired (CU) individuals is unclear. In this head-to-head comparison study including 9 cohorts and 1534 individuals, we found that plasma p-tau217 and medial temporal lobe Tau-PET signal showed similar associations with cognitive decline on a global cognitive composite test (R2 PET=0.32 vs R2 PLASMA=0.32, pdifference=0.812) and with progression to mild cognitive impairment (Hazard ratio[HR]PET=1.56[1.43-1.70] vs HRPLASMA=1.63[1.50-1.77], pdifference=0.627). Combined plasma and PET models were superior to the single biomarker models (R2=0.36, p<0.01). Furthermore, sequential selection using plasma p-tau217 and then Tau-PET reduced the number of participants required for a clinical trial by 94%, compared to a 75% reduction when using plasma p-tau217 alone. We conclude that plasma p-tau217 and Tau-PET showed similar performance for predicting future cognitive decline in CU individuals, and their sequential use (i.e., plasma p-tau217 followed by Tau-PET in a subset with high plasma p-tau217) is useful for screening in clinical trials in preclinical AD.

Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.

INTRODUCTION: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification. HIGHLIGHTS: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

Tau follows principal axes of functional and structural brain organization in Alzheimer's disease.

Alzheimer's disease (AD) is a brain network disorder where pathological proteins accumulate through networks and drive cognitive decline. Yet, the role of network connectivity in facilitating this accumulation remains unclear. Using in-vivo multimodal imaging, we show that the distribution of tau and reactive microglia in humans follows spatial patterns of connectivity variation, the so-called gradients of brain organization. Notably, less distinct connectivity patterns ("gradient contraction") are associated with cognitive decline in regions with greater tau, suggesting an interaction between reduced network differentiation and tau on cognition. Furthermore, by modeling tau in subject-specific gradient space, we demonstrate that tau accumulation in the frontoparietal and temporo-occipital cortices is associated with greater baseline tau within their functionally and structurally connected hubs, respectively. Our work unveils a role for both functional and structural brain organization in pathology accumulation in AD, and supports subject-specific gradient space as a promising tool to map disease progression.

Neuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status.

The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer's disease (AD). They project broadly throughout the brain's white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development.

Plasma p-tau217 predicts cognitive impairments up to ten years before onset in normal older adults.

Importance: Positron emission tomography (PET) biomarkers are the gold standard for detection of Alzheimer amyloid and tau in vivo . Such imaging can identify cognitively unimpaired (CU) individuals who will subsequently develop cognitive impartment (CI). Plasma biomarkers would be more practical than PET or even cerebrospinal fluid (CSF) assays in clinical settings. Objective: Assess the prognostic accuracy of plasma p-tau217 in comparison to CSF and PET biomarkers for predicting the clinical progression from CU to CI. Design: In a cohort of elderly at high risk of developing Alzheimer's dementia (AD), we measured the proportion of CU individuals who developed CI, as predicted by Aß (A+) and/or tau (T+) biomarker assessment from plasma, CSF, and PET. Results from each method were compared with (A-T-) reference individuals. Data were analyzed from June 2023 to April 2024. Setting: Longitudinal observational cohort. Participants: Some 228 participants from the PREVENT-AD cohort were CU at the time of biomarker assessment and had 1 - 10 years of follow-up. Plasma was available from 215 participants, CSF from 159, and amyloid- and tau-PET from 155. Ninety-three participants had assessment using all three methods (main group of interest). Progression to CI was determined by clinical consensus among physicians and neuropsychologists who were blind to plasma, CSF, PET, and MRI findings, as well as APOE genotype. Exposures: Plasma Aß 42/40 was measured using IP-MS; CSF Aß 42/40 using Lumipulse; plasma and CSF p-tau217 using UGOT assay. Aß-PET employed the 18 F-NAV4694 ligand, and tau-PET used 18 F-flortaucipir. Main Outcome: Prognostic accuracy of plasma, CSF, and PET biomarkers for predicting the development of CI in CU individuals. Results: Cox proportional hazard models indicated a greater progression rate in all A+T+ groups compared to A-T-groups (HR = 6.61 [95% CI = 2.06 - 21.17] for plasma, 3.62 [1.49 - 8.81] for CSF and 9.24 [2.34 - 36.43] for PET). The A-T+ groups were small, but also characterized with individuals who developed CI. Plasma biomarkers identified about five times more T+ than PET. Conclusion and relevance: Plasma p-tau217 assessment is a practical method for identification of persons who will develop cognitive impairment up to 10 years later. Key Points: Question: Can plasma p-tau217 serve as a prognostic indicator for identifying cognitively unimpaired (CU) individuals at risk of developing cognitive impairments (CI)?Findings: In a longitudinal cohort of CU individuals with a family history of sporadic AD, almost all individuals with abnormal plasma p-tau217 concentrations developed CI within 10 years, regardless of plasma amyloid levels. Similar findings were obtained with CSF p-tau217 and tau-PET. Fluid p-tau217 biomarkers had the main advantage over PET of identifying five times more participants with elevated tau.Meaning: Elevated plasma p-tau217 levels in CU individuals strongly indicate future clinical progression.

Personalized whole-brain neural mass models reveal combined Aß and tau hyperexcitable influences in Alzheimer's disease.

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-ß (Aß) 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 Aß 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 Aß-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 effect of harmonization on the variability of PET radiomic features extracted using various segmentation methods.

PURPOSE: This study aimed to examine the robustness of positron emission tomography (PET) radiomic features extracted via different segmentation methods before and after ComBat harmonization in patients with non-small cell lung cancer (NSCLC). METHODS: We included 120 patients (positive recurrence = 46 and negative recurrence = 74) referred for PET scanning as a routine part of their care. All patients had a biopsy-proven NSCLC. Nine segmentation methods were applied to each image, including manual delineation, K-means (KM), watershed, fuzzy-C-mean, region-growing, local active contour (LAC), and iterative thresholding (IT) with 40, 45, and 50% thresholds. Diverse image discretizations, both without a filter and with different wavelet decompositions, were applied to PET images. Overall, 6741 radiomic features were extracted from each image (749 radiomic features from each segmented area). Non-parametric empirical Bayes (NPEB) ComBat harmonization was used to harmonize the features. Linear Support Vector Classifier (LinearSVC) with L1 regularization For feature selection and Support Vector Machine classifier (SVM) with fivefold nested cross-validation was performed using StratifiedKFold with 'n_splits' set to 5 to predict recurrence in NSCLC patients and assess the impact of ComBat harmonization on the outcome. RESULTS: From 749 extracted radiomic features, 206 (27%) and 389 (51%) features showed excellent reliability (ICC ≥ 0.90) against segmentation method variation before and after NPEB ComBat harmonization, respectively. Among all, 39 features demonstrated poor reliability, which declined to 10 after ComBat harmonization. The 64 fixed bin widths (without any filter) and wavelets (LLL)-based radiomic features set achieved the best performance in terms of robustness against diverse segmentation techniques before and after ComBat harmonization. The first-order and GLRLM and also first-order and NGTDM feature families showed the largest number of robust features before and after ComBat harmonization, respectively. In terms of predicting recurrence in NSCLC, our findings indicate that using ComBat harmonization can significantly enhance machine learning outcomes, particularly improving the accuracy of watershed segmentation, which initially had fewer reliable features than manual contouring. Following the application of ComBat harmonization, the majority of cases saw substantial increase in sensitivity and specificity. CONCLUSION: Radiomic features are vulnerable to different segmentation methods. ComBat harmonization might be considered a solution to overcome the poor reliability of radiomic features.

Dynamic neuroreceptor positron emission tomography in non-anesthetized rats using point source based motion correction: A feasibility study with [11C]ABP688.

To prevent motion artifacts in small animal positron emission tomography (PET), animals are routinely scanned under anesthesia or physical restraint. Both may potentially alter metabolism and neurochemistry. This study investigates the feasibility of fully awake acquisition and subsequent absolute quantification of dynamic brain PET data via pharmacokinetic modelling in moving rats using the glutamate 5 receptor radioligand [11C]ABP688 and point source based motion correction. Five male rats underwent three dynamic [11C]ABP688 PET scans: two test-retest awake PET scans and one scan under anesthesia for comparison. Specific radioligand binding was determined via the simplified reference tissue model (reference: cerebellum) and outcome parameters BPND and R1 were evaluated in terms of stability and reproducibility. Test-retest measurements in awake animals gave reliable results with high correlations of BPND (y = 1.08 × -0.2, r = 0.99, p < 0.01) and an acceptable variability (mean over all investigated regions 15.7 ± 2.4%). Regional [11C]ABP688 BPNDs under awake and anesthetized conditions were comparable although in awake scans, absolute radioactive peak uptakes were lower and relative blood flow in terms of R1 was higher. Awake small animal PET with absolute quantification of neuroreceptor availability is technically feasible and reproducible thereby providing a suitable alternative whenever effects of anesthesia are undesirable, e.g. in sleep research.

Contactin 5 and Apolipoproteins Interplay in Alzheimer's Disease.

Background: Apolipoproteins and contactin 5 are proteins associated with Alzheimer's disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment. Objective: To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage. Methods: Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink's proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of cognitively unimpaired participants (n = 93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (n = 57) and control subjects (n = 31) and in the hippocampi of mice following entorhinal cortex lesions. Results: Contactin 5 positively correlated with apolipoproteins B (p = 5.4×10-8), D (p = 1.86×10-4), E (p = 2.92×10-9), J (p = 2.65×10-9), and with cholesterol (p = 0.0096) in the CSF, and with cholesterol (p = 0.02), HDL (p = 0.0143), and LDL (p = 0.0121) in the plasma. Negative correlations were seen between CNTN5, APOB (p = 0.034) and APOE (p = 0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (p <  0.05), while apob (p = 0.023) and apod (p = 0.006) increased in the deafferentation stage. Conclusions: Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage.

Reduction in Constitutively Activated Auditory Brainstem Microglia in Aging and Alzheimer's Disease.

Background: Alzheimer's disease (AD) pathology is considered to begin in the brainstem, and cerebral microglia are known to play a critical role in AD pathogenesis, yet little is known about brainstem microglia in AD. Translocator protein (TSPO) PET, sensitive to activated microglia, shows high signal in dorsal brainstem in humans, but the precise location and clinical correlates of this signal are unknown. Objective: To define age and AD associations of brainstem TSPO PET signal in humans. Methods: We applied new probabilistic maps of brainstem nuclei to quantify PET-measured TSPO expression over the whole brain including brainstem in 71 subjects (43 controls scanned using 11C-PK11195; 20 controls and 8 AD subjects scanned using 11C-PBR28). We focused on inferior colliculi (IC) because of visually-obvious high signal in this region, and potential relevance to auditory dysfunction in AD. We also assessed bilateral cortex. Results: TSPO expression was normally high in IC and other brainstem regions. IC TSPO was decreased with aging (p = 0.001) and in AD subjects versus controls (p = 0.004). In cortex, TSPO expression was increased with aging (p = 0.030) and AD (p = 0.033). Conclusions: Decreased IC TSPO expression with aging and AD-an opposite pattern than in cortex-highlights underappreciated regional heterogeneity in microglia phenotype, and implicates IC in a biological explanation for strong links between hearing loss and AD. Unlike in cerebrum, where TSPO expression is considered pathological, activated microglia in IC and other brainstem nuclei may play a beneficial, homeostatic role. Additional study of brainstem microglia in aging and AD is needed.

Biomarker-based staging of Alzheimer disease: rationale and clinical applications.

Disease staging, whereby the spatial extent and load of brain pathology are used to estimate the severity of Alzheimer disease (AD), is pivotal to the gold-standard neuropathological diagnosis of AD. Current in vivo diagnostic frameworks for AD are based on abnormal concentrations of amyloid-ß and tau in the cerebrospinal fluid or on PET scans, and breakthroughs in molecular imaging have opened up the possibility of in vivo staging of AD. Focusing on the key principles of disease staging shared across several areas of medicine, this Review highlights the potential for in vivo staging of AD to transform our understanding of preclinical AD, refine enrolment criteria for trials of disease-modifying therapies and aid clinical decision-making in the era of anti-amyloid therapeutics. We provide a state-of-the-art review of recent biomarker-based AD staging systems and highlight their contributions to the understanding of the natural history of AD. Furthermore, we outline hypothetical frameworks to stage AD severity using more accessible fluid biomarkers. In addition, by applying amyloid PET-based staging to recently published anti-amyloid therapeutic trials, we highlight how biomarker-based disease staging frameworks could illustrate the numerous pathological changes that have already taken place in individuals with mildly symptomatic AD. Finally, we discuss challenges related to the validation and standardization of disease staging and provide a forward-looking perspective on potential clinical applications.

Comparison of two plasma p-tau217 assays to detect and monitor Alzheimer's pathology.

BACKGROUND: Blood-based biomarkers of Alzheimer's disease (AD) have become increasingly important as scalable tools for diagnosis and determining clinical trial eligibility. P-tau217 is the most promising due to its excellent sensitivity and specificity for AD-related pathological changes. METHODS: We compared the performance of two commercially available plasma p-tau217 assays (ALZpath p-tau217 and Janssen p-tau217+) in 294 individuals cross-sectionally. Correlations with amyloid PET and tau PET were assessed, and Receiver Operating Characteristic (ROC) analyses evaluated both p-tau217 assays for identifying AD pathology. FINDINGS: Both plasma p-tau217 assays were strongly associated with amyloid and tau PET. Furthermore, both plasma p-tau217 assays identified individuals with AD vs other neurodegenerative diseases (ALZpath AUC = 0.95; Janssen AUC = 0.96). Additionally, plasma p-tau217 concentrations rose with AD severity and their annual changes correlated with tau PET annual change. INTERPRETATION: Both p-tau217 assays had excellent diagnostic performance for AD. Our study supports the future clinical use of commercially-available assays for p-tau217. FUNDING: This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR), Canadian Consortium on Neurodegeneration in Aging, the Alzheimer's Association, Brain Canada Foundation, the Fonds de Recherche du Québec - Santé and the Colin J. Adair Charitable Foundation.

Predicting functional decline in aging and Alzheimer's disease with PET-based Braak staging.

The progression of PET-based Braak stages correlates with cognitive deterioration in aging and Alzheimer's disease. Here, we investigate the association between PET-based Braak stages and functional impairment and assess whether PET-based Braak staging predicts a longitudinal decline in the performance of activities of daily living. In this cohort study, we evaluated cognitively unimpaired individuals and individuals with mild cognitive impairment or Alzheimer's disease dementia. Participants underwent [18F]MK6240 tau-PET, were assigned a PET-based Braak stage at baseline and were followed for a mean (SD) of 1.97 (0.66) years. Functional performance was evaluated with the Functional Activities Questionnaire, Everyday Cognition and functional Clinical Dementia Rating sum of boxes. Multiple linear regressions assessed the association of PET-based Braak stages with baseline functionality and with the longitudinal rate of change in functional scores, adjusting for age, sex and amyloid-ß load. We employed voxel-based regression models to investigate the association between functionality and tau-PET signal and assessed the voxel overlap with Braak regions of interest. We included 291 individuals (181 cognitively unimpaired, 56 amyloid-ß+ mild cognitive impairment and 54 amyloid-ß+ Alzheimer's disease) aged 70.60 (7.48) years. At baseline, PET-based Braak stages III-IV (ß = 0.43, P = 0.03) and V-VI (ß = 1.20, P < 0.0001) showed associations with poorer Functional Activities Questionnaire scores. Similarly, stages III-IV (ß = 0.43, P = 0.02) and V-VI (ß = 1.15, P < 0.0001) were associated with worse Everyday Cognition scores. Only stages V-VI were associated with higher functional Clinical Dementia Rating sum of boxes (ß = 1.17, P < 0.0001) scores. Increased tau-PET signals in all Braak regions of interest were linked to worse performance in all tools. The voxelwise analysis showed widespread cortical associations between functional impairment and tau-PET and high voxel overlap with Braak regions of interest. Baseline PET-based Braak stages V-VI predicted significant longitudinal functional decline as assessed by the Functional Activities Questionnaire (ß = 1.69, P < 0.0001), the Everyday Cognition (ß = 1.05, P = 0.001) and the functional Clinical Dementia Rating sum of boxes (ß = 1.29, P < 0.0001). Our results suggest that functional impairment increases with the severity of tau accumulation. These findings also indicate that PET-based Braak staging is a good predictor of functional impairment in the Alzheimer's disease continuum. Finally, our study provides evidence for the clinical significance of the PET-based Braak staging framework.