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IntroductionEarly-onset Alzheimer's disease (EOAD) shows a higher burden of neuropsychiatric symptoms than late-onset Alzheimer's disease (LOAD). We aim to determine the differences in the severity of neuropsychiatric symptoms and locus coeruleus (LC) integrity between EOAD and LOAD accounting for disease stage.MethodsOne hundred four subjects with AD diagnosis and 32 healthy controls were included. Participants underwent magnetic resonance imaging (MRI) to measure LC integrity, measures of noradrenaline levels in cerebrospinal fluid (CSF) and Neuropsychiatric Inventory (NPI). We analyzed LC-noradrenaline measurements and clinical and Alzheimer's disease (AD) biomarker associations.ResultsEOAD showed higher NPI scores, lower LC integrity, and similar levels of CSF noradrenaline compared to LOAD. Notably, EOAD exhibited lower LC integrity independently of disease stage. LC integrity negatively correlated with neuropsychiatric symptoms. Noradrenaline levels were increased in AD correlating with AD biomarkers.DiscussionDecreased LC integrity negatively contributes to neuropsychiatric symptoms. The higher LC degeneration in EOAD compared to LOAD could explain the more severe neuropsychiatric symptoms in EOAD.HighlightsLC degeneration is greater in early-onset AD (EOAD) compared to late-onset AD. Tau-derived LC degeneration drives a higher severity of neuropsychiatric symptoms. EOAD harbors a more profound selective vulnerability of the LC system. LC degeneration is associated with an increase of cerebrospinal fluid noradrenaline levels in AD.

Background: Practice effects are a well‐known cognitive phenomenon that is reduced in patients with Alzheimer's disease (AD). We aimed to investigate whether cognitively unimpaired (CU) individuals within the Alzheimer's continuum (i.e., positive amyloid‐β biomarker) display decreased practice effects on serial neuropsychological testing. Methods: We included 310 CU from four Spanish research centers, classified into controls (n = 250) or Aβ+ (n = 60). In the main cohort (Cohort A; n = 209), participants underwent neuropsychological assessment at baseline and annually during a 2‐year follow‐up (FU1 and FU2). A "long‐term cohort" (Cohort B; n = 101) was employed to assess practice effects over longer time periods (i.e., two follow‐up sessions at years 3 and 6 from baseline). Practice effects were defined as simple discrepancy scores (SDS) by subtracting Z‐scores at FU2 from Z‐scores at baseline for each neuropsychological variable, and linear mixed effects models (LME) were run to assess the temporal evolution of practice effects according to the two groups. Results: There were no cross‐sectional differences between the control and Aβ+ groups in none of the neuropsychological scores at baseline (Fig. 1). The Aβ+ group displayed lower practice effects than the controls in terms of SDS in several neuropsychological outcomes (Fig. 2). In Cohort A, LME showed negative slopes by the Aβ+ group in verbal memory measures such as the free learning score (β = ‐0.37, SD = 0.12, p = 0.0034), delayed free recall (β = ‐0.43, SD = 0.15, p = 0.0047) and delayed total recall (β = ‐0.46, SD = 0.17, p = 0.0069) from the Free and Cued Selective Reminding Test; as well as in language tasks (Boston Naming Test; β = ‐0.26, SD = 0.087, p = 0.0025) and executive function measures (Trail Making Test; β = ‐0.33, SD = 0.12, p = 0.0094) (Fig. 3A). In Cohort B, similar findings were observed in visual memory measures, such as the Rey‐Osterrieth Complex Figure immediate (β = ‐0.80, SD = 0.35, p = 0.024) and delayed (β = ‐1.25, SD = 0.34, p = 0.00038) recall (Fig. 3B). Conclusions: Individuals with normal cognition who are in the Alzheimer's continuum show decreased practice effects over serial neuropsychological testing. Our findings suggest the reduction of practice effects, particularly in memory measures, as an indicator of subtle cognitive decline in the earliest phase of the Alzheimer's continuum and could be particularly relevant for the design and interpretation of primary prevention trials on disease‐modifying therapies. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant Alzheimer's Disease (ADAD) represents around 0.5% of all AD cases, and is caused by mutations in PSEN1, PSEN2 and APP genes. Gene expression studies can be useful for unravelling the physiopathology of AD and identifying potential biomarkers. However, most studies are focused on late‐onset AD (LOAD), and mainly on brain tissue or immune cells. Preliminary data from our group showed 9 common differentially expressed genes (DEGs) both in brain tissue and lymphoblastoid cell lines in ADAD versus healthy controls (AMMERCR1L, FMR1, FXYD5, PRR3, RNU2.1, SCARNA2, SLC35A1, TCEAL8, TMEM184B). We aim to investigate these DEGs along with 3 AD relevant genes (APP, PSEN1 and MAPT) in whole blood of ADAD with the goal to explore new potential biomarkers. Method: Our cohort (N = 69) consisted of ADAD symptomatic mutation carriers (SMC; N = 19), asymptomatic mutation carriers (AMC; N = 18) and healthy non carriers (CTRL; N = 32). RNA was extracted from whole blood and relative gene expression was determined by RT‐qPCR and ΔΔCt method. Permutation tests were used to determine the differential gene expression between groups. Additionally, a correlation analysis was performed between estimated years of onset (for AMC) or years since onset (for SMC) and relative expression. Result: DEGs were mainly down‐regulated in ADAD with respect to CTRL, except for FXYD5 and MAPT, which were up‐regulated. When comparing ADAD mutation carriers versus CTRL the significant genes were APP (p = 0.045), FXYD5 (p = 0.018), MAPT (p = 0.041), PSEN1 (p = 5e‐4), SCARNA2 (p = 0.042) and TMEM184B (p = 0.0042) (Fig. 1). Then, we compared AMC versus CTRL and SMC versus CTRL and found two DEGs in both comparisons: FXYD5 (p = 0.015; p = 0.033) and MAPT (p = 0.015; p = 0.034). In AMC group we also found these DEGs: FMR1 (p = 0.011), PRR3 (0.029), PSEN1 (p = 2e‐4), SCARNA2 (p = 0.027) and TMEM184B (p = 5e‐4) (Fig. 2). Results showed a significant negative correlation for RNU2.1 (p = 0.016) and PRR3 (p = 0.029) between relative expression and years since onset in SMC (Fig. 3). Conclusion: Mutation carriers show some DEGs in whole blood, even in the asymptomatic stage. FXYD5 and MAPT genes show a consistent up‐regulation in both SMC and AMC, suggesting it could be further validated as a possible genetic biomarker in whole blood of ADAD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Neuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin‐3 (Gal‐3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal‐3 levels in patients with FTD and assess its diagnostic potential. METHODS: We examined Gal‐3 levels in brain, serum, and cerebrospinal fluid (CSF) samples of patients with FTD and controls. Multiple linear regressions between Gal‐3 levels and other FTD markers were explored. RESULTS: Gal‐3 levels were increased significantly in patients with FTD, mainly across brain tissue and CSF, compared to controls. Remarkably, Gal‐3 levels were higher in cases with tau pathology than TAR‐DNA Binding Protein 43 (TDP‐43) pathology. Only MAPT mutation carriers displayed increased Gal‐3 levels in CSF samples, which correlated with total tau and 14‐3‐3. DISCUSSION: Our findings underscore the potential of Gal‐3 as a diagnostic marker for FTD, particularly in MAPT cases, and highlights the relation of Gal‐3 with neuronal injury markers. [ABSTRACT FROM AUTHOR]

Background and purpose: How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker‐confirmed early‐onset (EOAD) and late‐onset (LOAD) Alzheimer's disease (AD) was assessed. Method: Eighty‐seven cerebrospinal fluid (CSF) biomarker‐confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non‐carriers (–EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non‐carriers (–LOAD). Grey matter (GM) volume differences were analyzed using voxel‐based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition. Results: Significantly more mammillary body atrophy in +EOAD compared to –EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to –LOAD. Medial temporal GM volume loss was also found in +EOAD compared to –LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in –LOAD. Conclusions: Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to –LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset. [ABSTRACT FROM AUTHOR]

Background and Objectives: Pathogenic variants in the GRN gene cause frontotemporal dementia (FTD- GRN ) with marked brain asymmetry. This study aims to assess whether the disease progression of FTD- GRN depends on the initial side of the atrophy. We also investigated the potential use of brain asymmetry as a biomarker of the disease., Methods: Retrospective examination of data from the prospective Genetic Frontotemporal Initiative (GENFI) cohort study that recruits individuals who carry or were at risk of carrying a pathogenic variant causing FTD. GENFI participants underwent a standardized clinical and neuropsychological assessment, MRI, and a blood sample test yearly. We generated an asymmetry index for brain MRI to characterize brain asymmetry in participants with or at risk of FTD- GRN . Depending on the side of the asymmetry, we classified symptomatic GRN patients as right- GRN or left- GRN and compared their clinical features and disease progression. We generated generalized additive models to study how the asymmetry index evolves in carriers and noncarriers and compare its models with others created with volumetric values and plasma neurofilament light chain., Results: A total of 399 participants (mean age 49.7 years, 59% female) were included (63 symptomatic carriers, 177 presymptomatic carriers, and 159 noncarriers). Symptomatic carriers showed higher brain asymmetry (11.6) than noncarriers (1.0, p < 0.001) and presymptomatic carriers (1.0, p < 0.001), making it possible to classify most of them as right- GRN (n = 21) or left- GRN (n = 36). Patients with right- GRN showed more disease severity at baseline ( β = 6.9, 95% CI 2.4-11.0, p = 0.003) but a lower deterioration by year ( β = -1.5, 95% CI -2.7 to -0.31, p = 0.015) than patients with left- GRN . Brain asymmetry could be found in GRN carriers 10.4 years before the onset of the symptoms (standard difference 0.85, CI 0.01-1.68)., Discussion: FTD- GRN affects the brain hemispheres asymmetrically and causes 2 anatomical asymmetry patterns depending on the side of the disease onset. We demonstrated that these 2 anatomical asymmetry patterns present different symptoms, severity at the time of the first visit, and different disease courses. Our results also suggest brain asymmetry as a possible biomarker of conversion in GRN carriers.

Introduction: Neuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin-3 (Gal-3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal-3 levels in patients with FTD and assess its diagnostic potential., Methods: We examined Gal-3 levels in brain, serum, and cerebrospinal fluid (CSF) samples of patients with FTD and controls. Multiple linear regressions between Gal-3 levels and other FTD markers were explored., Results: Gal-3 levels were increased significantly in patients with FTD, mainly across brain tissue and CSF, compared to controls. Remarkably, Gal-3 levels were higher in cases with tau pathology than TAR-DNA Binding Protein 43 (TDP-43) pathology. Only MAPT mutation carriers displayed increased Gal-3 levels in CSF samples, which correlated with total tau and 14-3-3., Discussion: Our findings underscore the potential of Gal-3 as a diagnostic marker for FTD, particularly in MAPT cases, and highlights the relation of Gal-3 with neuronal injury markers., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)