By age 40, virtually all individuals with Down Syndrome (DS) will have developed the pathological symptoms of Alzheimer's Disease (AD) (McCarron, McCallion et al. 2017), making it the genetic leading cause of AD worldwide. Our lab developed a specialized behavior-based scale to aid in the diagnosis of AD in DS, the BPSD-DSII (Dekker, Ulgiati et al. 2021). Individuals with DS with or without (questionable) AD (total = 157) were tested with the BPSD-DSII, and subsequently, we also performed immune-based assays (Simoa) to further characterize blood biomarkers in this cohort. Three years after the original BPSD-DSII was administered in this cohort, the individuals were, again, categorized in percentiles based on the BPSD-DSII behavior frequency changes. The outcome of the different sections of the BPSD-DSII at baseline and the levels of several blood-based biomarkers at baseline were put in a statistical prediction model based on linear regression. Linear regression prediction model coded in R with R studio The outcome of several sections of the BPSD-DSII questionnaire, as well as pTau181 levels and GFAP levels, were predictive of percentiles indicating AD in DS. Specific behavioral changes at baseline such as in apathetic behavior, depressive behavior, and eating and drinking behavior, as well as pTau181 and GFAP levels were predictive for the development of AD in DS.

INTRODUCTION: The glymphatic system dysfunction is associated with cognitive decline in neurodegenerative diseases such as Alzheimer's disease (AD). METHODS: We introduce the G-Along Perivascular Space (G-ALPS) index, an optimized version of the ALPS index derived using Genetic Programming, and use it to analyze 217 diffusion tensor imaging (DTI) samples. RESULTS: Compared to the ALPS, the proposed G-ALPS index shows a stronger correlation with cognitive measures, including Mini-Mental State Examination (MMSE, 2.78% improvement), Clinical Dementia Rating (CDR, 5.13% improvement), and Functional Activities Questionnaire (FAQ, 10% improvement), as demonstrated by the analysis of fiber diffusivities in DTI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Furthermore, the G-ALPS exhibits enhanced sensitivity in identifying the effects of aging (94.81% improvement in AD individuals, 105% improvement in patients with mild cognitive impairment [MCI], and 81.25% improvement in normal controls) and sleep-related disorders (21.27% improvement in correlation with MMSE, and 2.53% improvement in correlation with Pittsburgh Sleep Quality Index [PSQI]) using the Human Connectome Project (HCP) dataset. DISCUSSION: Our results suggest that the G-ALPS index may be an indirect metric for assessing the glymphatic system's function or dysfunction.

BACKGROUND:Heterozygous de novo variants in the transcription factor Activity-Dependent Neuroprotective Protein (ADNP) cause a severe neurodevelopmental disorder, termed Helsmoortel-Van der Aa syndrome (HVDAS), characterised by autism, intellectual disability, and multisystem involvement. The ADNP gene is essential for embryonic development and interacts with components of several chromatin remodelling complexes. However, the precise pathophysiological mechanisms underlying the disorder remain incompletely understood. METHODS:We used CRISPR/Cas9 genome editing to create a 14-base pair deletion c.2463_2476del (p.Leu822Hisfs∗6) in the murine Adnp gene to establish a disease-relevant mouse model. Only male mice were used in this study to reduce variability associated with sex-specific differences. Molecular, transcriptomic (RNA-seq), chromatin accessibility (ATAC-seq), proteomic (mass spectrometry), and 3D genome architecture (Hi-C) analyses were performed in cortical brain tissue. Neuroanatomical and behavioural phenotyping, including Morris water maze, elevated plus maze, marble burying, social interaction testing, and the Live Mouse Tracker were conducted to assess cognitive and autism-related phenotypes. FINDINGS:Heterozygous mice are viable and fertile. Introduction of the 14-base pair deletion reduced cellular Adnp levels in the brain (p = 0.0008) and decreased its chromatin association (p = 0.001), parallelled by a genome-wide increase in chromatin accessibility. Morphological analyses revealed mild neuroanatomical alterations in regions associated with cognition, memory, learning, and motor function (p < 0.05). Behavioural testing confirmed cognitive impairment in the Morris water maze (p < 0.05), increased anxiety-like behaviour in the elevated plus maze (p = 0.0035), repetitive behaviour in the marble burying assay (p = 0.045), and impaired social interactions (p < 0.05). Transcriptome sequencing of the frontal cortex, an essential region involved in executive functions, cognition, and motor control, revealed predominant downregulation of the Wnt signalling pathway (p = 0.03). Cytoskeletal abnormalities were further coupled to synaptic plasticity deficits, dysregulation of transcription factors implicated in lineage specification, and alterations in neuronal cell numbers. Adnp directly regulated mechanisms of synaptic plasticity through interaction with Camk2a and Dbn1. In heterozygous mice, these protein interactions were disrupted, resulting in aberrant Camk2a phosphorylation at synapses (p = 0.012). Mass spectrometry identified changes in multiple chromatin-interacting proteins and cytoskeletal components, corroborating nuclear and cytoskeletal dysregulation observed at the transcriptomic level. Hi-C analysis detected locus-specific alterations in 3D genome architecture associated with transcriptional changes. INTERPRETATION:We generated a disease-relevant heterozygous Adnp mouse model that recapitulates key molecular and behavioural features observed in patients with Helsmoortel-Van der Aa syndrome. Our findings demonstrate a role for Adnp in chromatin regulation and Wnt signalling, coupled to aberrant expression of cytoskeletal components and synaptic dysfunction. This mouse model provides a mechanistic framework linking chromatin dysregulation to autism-related behaviours and represents a valuable platform for future preclinical studies. FUNDING:This work was supported by the Marguerite-Marie Delacroix Foundation (FFP240064 to C.P.D.), the Research Fund of the University of Antwerp (Methusalem grant "GENOMED" to R.F.K.), ERA-NET NEURON ("ADNPinMED"), and the European E-RARE programme ("IMPACT"). Additional support was provided by a crowdfunding initiative from the German ADNP parent community to support C.P.D.; E.P. was supported by the FWO grant G0A1Z24N. C.A.M. received support from the Marguerite-Marie Delacroix fellowship. D.S. was supported by an EMBO fellowship (ALTF 1564-2025). F.P. was supported by a Human Frontier Science Program Long-Term Fellowship (LT000111/2021-L) and an EMBO Long-Term Fellowship (ATLF 716-2020). W.V.B. acknowledges support from the University of Antwerp (ID46420/48076/50799) and COST Action CA18127 (International Nucleosome Consortium 5INC). W.V.B., F.K., E.P., and C.P.D. acknowledge the IMPULS BOF 2024. Infrastructure support was provided by FWO (including IRI grant I000123N, GOH4216N).

We recently developed a CD8 T cell-induced mouse model that recapitulates definitive hallmarks of Alzheimer's disease (AD) and allowed prediction of previously unknown properties of human sporadic AD (DOI: 10.1073/pnas.2401420121). Identification of a peptide antigen to which the inducing T cells respond in this model (a non-Aβ epitope on Amyloid Precursor Protein [APP]) allowed us to quantify analogous T cells in human brain and blood, using an APP 471-479 /Human Leukocyte Antigen(HLA)-A2 multimer (pHLA) and flow cytometry on blood. Blood levels of these T cells distinguished AD and related MCI from normal aging controls with high accuracy (AUC: 0.883-0.892), but the assay is currently suitable only for HLA-A2-positive (about half of all) patients due to HLA subtype-restricted binding. CD8 T cell binding to a non-self ( ALIAPVHAV /HLA-A0201) multimer correlated with APP multimer binding in HLA-A2-positive patients (0.42-0.58x relative to APP/HLA-A2; r = 0.81; P  < 0.001). Surprisingly, the same non-self multimer bound at similar levels to HLA-A2-negative patients’ Tcells. We thus quantified levels of age-related, KLRG1 + CD8 T cells binding to this multimer in HLA-A2-positive ( n  = 79) and -negative ( n  = 44) subjects by flow cytometry from Alzheimer's disease (AD) and normal aging control cohorts, and assessed their correspondence to disease status. As with the APP pHLA reagent, levels of T cells binding to the non-self pHLA multimer were significantly diminished in AD irrespective of HLA subtype ( P  < 0.015 by 2-sided T-Test). In receiver operating characteristic (ROC) analysis of the HLA-negative cohort, area under the curve (AUC) was 0.878 for AD ( P  < 0.00001) with 79.4% sensitivity and 98.6% specificity, nearly identical to the APP-specific CD8 T cells in HLA-A2-positive individuals (AUC 0.88; 72.2% sensitivity, 97.2 specificity). Moreover, disease correspondence of the non-self pHLA-reactive T cells was improved in HLA-A2-positive patients as well (AUC 0.912). Subtype-independent pHLA binding by CD8 T cells strongly corresponds to AD status in HLA-A2-negative and HLA-positive individuals, providing a working basis for expanding our AD biomarker assay to all patients. Ongoing work will focus on increasing the sensitivity of HLA-independent multimer binding to further increase assay utility.

Extensive evidence suggests overlapping pathological mechanisms in the brain of individuals with Parkinson’s disease dementia, Down syndrome dementia, and Alzheimer’s disease. For these neurodegenerative dementias, we observed that the chronological age did not align with their biological age, which was determined based on hippocampal transcript levels (i.e., transcriptional age). Subsequently, we performed a transcriptomic analysis that corrected for the transcriptional age in the hippocampus of affected individuals, highlighting common underlying pathogenic mechanisms. There were 45 common differentially expressed genes (DEGs), whereas enriched functional terms were related to lysine N-methyltransferase activity and intermediate filament. Co-expression network analysis displayed a module that was significantly downregulated in the non-demented control group only. This module identified EHMT2 and LMNB2 as hub genes, which were also common DEGs. Overall, these findings uncover shared functional insights in the hippocampus, while specifically highlighting EHMT2 and LMNB2 as potential universal biomarkers or disease-altered targets across neurodegenerative dementias.

Dual Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) has been implicated in Alzheimer's disease (AD) pathology. Using Meso Scale Discovery (MSD) technology, we previously demonstrated that individuals with AD, Down syndrome with AD (DS-AD), or tauopathies exhibit reduced plasma DYRK1A levels compared to controls (Delabar et al., 2023). To further evaluate DYRK1A as a potential biomarker, we developed and optimized a homebrew DYRK1A immunoassay using the ultrasensitive Single Molecule Array (Simoa HD-X platform). This assay was applied to measure DYRK1A levels in plasma and brain homogenates from AD mouse models and plasma samples from individuals with DS and DS-AD. To assess the impact of DYRK1A overexpression in the context of AD-related biomarkers, we analyzed DYRK1A levels using Simoa in wild-type controls and AD mouse models (APP23 or P301S), with or without DYRK1A overexpression. Additionally, EDTA plasma from healthy controls and age-matched individuals with DS, with or without AD, was analyzed using the developed immunoassay. The limit of detection (LOD) and limit of quantification (LOQ) for the assay were 0.021 pg/mL and 0.069 pg/mL, respectively. DYRK1A levels in both plasma and brain homogenates from mouse models exhibited a dose-dependent change, with significantly higher levels in DYRK1A-overexpressing mice compared to non-overexpressing counterparts. The assay was also successfully applied to human cohorts, demonstrating its potential clinical utility. Ongoing experiments aim to quantify longitudinal changes in DYRK1A levels in AD mouse models to further evaluate its biomarker potential. This study strengthens the evidence for DYRK1A as a potential biomarker for AD and DS-AD, utilizing ultrasensitive Simoa technology for detection. Future investigations will determine whether longitudinal DYRK1A level changes correlate with AD progression and aging, aiding in early biomarker discovery and potential therapeutic targeting.

Short-term caloric restriction (CR) and resveratrol (Rsv) supplementation have shown potential in preserving brain function in aging and neurodegenerative diseases such as AD. However, there is a lack of knowledge regarding the potential benefits of long-term CR or Rsv on brain health in context of AD. Therefore, we aimed to assess the effects of short-term (1 month) CR and Rsv administration on resting-state functional connectivity (rs-FC), as well as the effect of long-term (8 months) CR or Rsv supplementation on rs-FC, spatial memory, amyloid burden, and neuroinflammation in male and female TgF344-AD (Tg) and wild-type (WT) rats. In Tg rats, short-term CR decreased rs-FC in female rats, while long-term CR decreased rs-FC and modestly improved spatial memory in male rats. Long-term CR and Rsv altered regional amyloid burden, and CR decreased IBA-1 in males without affecting GFAP. Overall, long-term CR and Rsv failed to mitigate FC loss and cognition, underscoring the potentially limited impact of these dietary interventions in AD.

Multiple sclerosis (MS) is a chronic neurological disorder involving immune-mediated demyelination and neurodegeneration in the central nervous system (CNS). Current therapies primarily target inflammation, with limited strategies to promote remyelination or neural repair. This study explores the therapeutic potential of Brain-Derived Neurotrophic Factor (BDNF) delivered via an adeno-associated virus (AAV) vector to enhance remyelination and improve cognitive function in a subchronic cuprizone (CPZ)-induced demyelination mouse model. Sixty female C57BL/6 mice were used, with half receiving a 7-week CPZ diet to induce oligodendrocyte loss. After demyelination, mice were treated with AAV-BDNF, AAV-eGFP, or saline injections into the corpus callosum (CC), followed by a 5-week recovery phase. Behavioral assessments revealed improved cognitive performance with BDNF treatment, demonstrated by increased latency in passive avoidance tests. Immunofluorescence analysis showed increased proliferation and maturation of oligodendrocyte progenitor cells, with higher PDGFRα and CC1 markers, alongside elevated MBP. Transmission electron microscopy (TEM) indicated thicker myelin sheaths and a higher percentage of myelinated axons in AAV-BDNF-treated mice. Mitochondrial analyses revealed that BDNF treatment preserved mitochondrial integrity, with reduced swelling and improved structural regularity. Inflammatory markers showed no differences in Iba1 but indicated a trend of reduced astrocytic activation with BDNF. These results demonstrate that AAV-BDNF therapy enhances remyelination, myelin integrity, mitochondrial structure, and cognitive function in a CPZ model, underscoring its potential for treating MS. BDNF-based strategies may offer innovative avenues to improve neurological recovery and address unmet needs in MS management.

BACKGROUND:The locus coeruleus (LC) and its noradrenergic projections are among the earliest sites displaying pathology in Alzheimer's disease (AD) and Parkinson's disease (PD). In vivo measures of norepinephrine transporter (NET) availability with [11C]methylreboxetine ([11C]MRB) positron emission tomography (PET) and structural magnetic resonance imaging (MRI) indices of LC integrity provide complementary, but rarely integrated biomarkers. METHODS:13 Healthy controls (HC), individuals with 12 AD or amnestic mild cognitive impairment due to AD (AD/aMCI), and 5 patients with PD underwent [11C]MRB PET and high-resolution T1-weighted MRI. NET availability was quantified using [11C]MRB PET SUV-ratio-based binding potential (SUVr-BP) in the LC and projection regions (hippocampus, amygdala, thalamus, and prefrontal cortex). LC structural integrity was indexed by LC MRI contrast-to-noise ratio (CNR), and projection region volumes were extracted with FreeSurfer. Group differences were assessed with Kruskal-Wallis tests, and PET-MRI associations were examined using Pearson correlations with Yeo-Johnson transformation to reduce outlier influence. RESULTS:No significant group-level differences in [11C]MRB PET SUVr-BP or MRI measures were observed across HC, AD/aMCI, and PD. However, LC [11C]MRB PET SUVr-BP correlated with LC MRI-CNR (r = 0.429, 95 % CI [0.082-0.684], p = 0.018). In contrast, PET-MRI associations in projection regions were weak and non-significant. Exploratory analyses confirmed expected differences in cognition, neuropsychiatric symptoms, and functional measures, most pronounced in AD/aMCI participants. CONCLUSIONS:This proof-of-concept study demonstrates convergent multimodal assessment of LC integrity using [11C]MRB PET and LC MRI-CNR, whereas projection regions showed divergent or absent associations. These findings highlight the potential of the LC as a target for multimodal biomarker development and support further investigation of these imaging strategies in larger, longitudinal cohorts to delineate their role in detecting noradrenergic vulnerability in neurodegeneration. SIGNIFICANCE STATEMENT:This study integrates [11C]MRB PET and MRI to examine noradrenergic integrity in Alzheimer's and Parkinson's disease. Results demonstrate strong PET-MRI convergence in the locus coeruleus, but not in projection regions, highlighting the locus coeruleus as a sensitive biomarker target and supporting multimodal imaging approaches for early detection of neurodegenerative vulnerability.

Down syndrome (DS, trisomy 21) is the most frequent genetic cause of intellectual disability (ID), prevalent in approximately 1 in 900 live births (Loane et al., 2013). People with DS are at high risk to develop Alzheimer’s disease dementia (AD) (Lott & Head, 2001). Onset of clinical symptoms varies substantially in time. Consequently, predicting and monitoring decline and onset of dementia is a diagnostic challenge, while it is of essence in daily care and support. Behavioral and Psychological Symptoms of Dementia are an important and easily accessible tool for the prediction of dementia onset in the DS population. The BPSD-DSII scale was developed to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior in an (AD-)DS population. Changes are assessed with the use of different behavior-specific questions (items) which are categorized in different clusters (sections) (Dekker et al., 2018). We used the BPSD-DSII to assess these symptoms and predict a potential diagnosis of dementia. BPSD-DSII results are correlated with the serum levels of monoaminergic (epinephrine, norepinephrine, dopamine, serotonin and their metabolic products) and classical biomarkers, such as Ab40, Ab42, total tau, phosphorylated tau and neurofilament light chain. We used reversed-phase ultra-high performance liquid chromatography with electrochemical detection to determine the levels of epinephrine, norepinephrine, dopamine, serotonin and their metabolic products in serum. The Simoa platform was applied to detect the levels of Ab40, Ab42, total tau, phosphorylated tau and neurofilament light chain. Finally, we worked together with the caregivers of the (AD-)DS individuals for the collection of BPSD-DSII data. Preliminary data suggests correlations between different sections of the BPSD-DSII questionnaire and serotonin levels, as well as correlations between different sections of the BPSD-DSII questionnaire and classical biomarker levels. In addition, complementary data regarding the correlation between the different items of the BPSD-DSII questionnaire and the different serum-based biomarkers will be presented at the conference. The results per section of the BPSD-DSII correlate with the levels of monoamines and classical biomarkers in (AD-)DS individuals. And could therefore be used as potential biomarkers for the development of AD within the population of DS patients.

INTRODUCTION:The locus coeruleus (LC), the brain's primary source of noradrenaline (NA), undergoes early neurodegeneration in Parkinson's disease (PD), Alzheimer's diseases (AD), and Down syndrome (DS); however, differences have not been examined in parallel. METHODS:Post mortem brains (n = 67) from individuals with AD, DS-AD, and PD without and with dementia (PD-D) and controls were analyzed for amyloid beta (Aβ), phosphorylated tau (pTau), α-synuclein, endo-lysosomal alterations, biogenic amines, and selective biomarkers. RESULTS:LC degeneration correlated with age, peaking in AD and PD-D, while NA and dopaminergic metabolites were significantly reduced only in PD-D. DS-AD, the youngest group, showed the highest Aβ and pTau levels but the least noradrenergic neuron loss. We demonstrated for the first time that endosomal alterations were present in AD, lysosomal changes were present in PD-D/DS-AD, and DYRK1A, a key protein from chromosome 21, was elevated only in DS-AD. DISCUSSION:Loss of noradrenergic neurons may occur independently of amyloid and tau pathologies. HIGHLIGHTS:We provide the first analysis of neuropathological and biochemical features including biogenic amines of the LC in AD, DS, and PD. Loss of noradrenergic neurons was most severe in AD and PD. Only in DS, levels of DYRK1A - a kinase encoded on chromosome 21 and implicated in neurodegenerative processes - were elevated and negatively correlated to biogenic amine levels. Although individuals with DS having AD were the youngest group, they had the highest levels of amyloid and tau pathologies, but less noradrenergic neurons loss compared to other disease groups.

Genetic variation in Transmembrane protein 106B (TMEM106B) is known to influence the risk and presentation in several neurodegenerative diseases and modifies healthy aging. While evidence from human studies suggests that the risk allele is associated with higher levels of TMEM106B, the contribution of elevated levels of TMEM106B to neurodegeneration and aging has not been assessed and it remains unclear how TMEM106B modulates disease risk. To study the effect of increased TMEM106B levels, we generated Cre-inducible transgenic mice expressing human wild-type TMEM106B. We evaluated lysosomal and neuronal health using in vitro and in vivo assays including transmission electron microscopy, immunostainings, behavioral testing, electrophysiology, and bulk RNA sequencing. We created the first transgenic mouse model that successfully overexpresses TMEM106B, with a 4- to 8-fold increase in TMEM106B protein levels in heterozygous (hTMEM106B(+)) and homozygous (hTMEM106B(++)) animals, respectively. We showed that the increase in TMEM106B protein levels induced lysosomal dysfunction and age-related downregulation of genes associated with neuronal plasticity, learning, and memory. Increased TMEM106B levels led to altered synaptic signaling in 12-month-old animals which further exhibited an anxiety-like phenotype. Finally, we observed mild neuronal loss in the hippocampus of 21-month-old animals. Characterization of the first transgenic mouse model that overexpresses TMEM106B suggests that higher levels of TMEM106B negatively impacts brain health by modifying brain aging and impairing the resilience of the brain to the pathomechanisms of neurodegenerative disorders. This novel model will be a valuable tool to study the involvement and contribution of increased TMEM106B levels to aging and will be essential to study the many age-related diseases in which TMEM106B was genetically shown to be a disease- and risk-modifier.

Setting: Dementia with Lewy bodies (DLB) remains poorly understood and frequently misdiagnosed, complicated by co-pathology with other dementia forms. DLB patients often present with autonomic dysfunction and peripheral Lewy body pathology alongside central lesions. Monoaminergic neurotransmitter systems seem an early target for DLB pathology, especially the noradrenergic system. Noradrenaline analogue 123I-metaiodobenzylguanidine (MIBG) is considered an indicative biomarker for peripheral noradrenergic sympathetic denervation. Objectives: Our aim was to measure paired monoaminergic levels and MIBG scintigraphy values in DLB patients, exploring a possible link between noradrenergic neurotransmission and peripheral denervation. Design: 44 patients with a possible DLB diagnosis entered the study. Peripheral uptake of 123I-MIBG was determined by the heart-to-mediastinum (H/M) ratio, as a measure for noradrenergic sympathetic denervation. In cerebrospinal fluid (CSF), serum and plasma samples, monoamines ((nor)adrenaline ((N)A), 5-hydroxytryptamin (5-HT, serotonin), dopamine (DA)) and respective metabolites (3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC)), were measured by means of reversed-phase ultrahigh-performance liquid chromatography with electrochemical detection. Results: We found significant correlations between the H/M ratio and serum 5-HIAA, plasma 5-HT, plasma 5-HIAA/5-HT and plasma HVA/5-HIAA, but no further correlations with the noradrenergic system. CSF-serum MHPG, CSF-serum DOPAC, CSF-serum HVA, CSF-plasma MHPG, CSF plasma NA, CSF-plasma DOPAC, CSF-plasma MHPG/NA and CSF-plasma DOPAC/DA were significantly correlated. Conclusions: These results show an association between the H/M ratio and serotonergic system, but not between peripheral noradrenergic denervation and circulating noradrenergic levels.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder and the most common cause of dementia. While the amyloid cascade hypothesis has long dominated AD research, emerging evidence suggests that neuroinflammation may play a more central role in disease onset and progression. Increasingly, AD is recognized as a multifactorial disorder influenced by systemic inflammation and immune dysregulation, shifting focus toward peripheral immune mechanisms as potential contributors to neurodegeneration. This review explores the hypothesis that inflammaging, the age-related increase in pro-inflammatory mediators, combined with lifelong exposure to infections, injuries, metabolic changes, and chronic diseases, among others, may prime the immune system, amplifying neuroinflammation and influencing the progression and exacerbation of AD pathology. To this end, we examined how systemic immune disturbances, including chronic pain, post-operative cognitive dysfunction, viral and bacterial infections, gut microbiome dysregulation, and cardiovascular disease, may act as risk factors for AD. Overall, evidence suggests that modulating peripheral inflammation, accompanied by early diagnosis, could significantly reduce the risk of developing AD. Furthermore, we highlight key immune signaling pathways involved in both central and peripheral immune responses, such as the NLRP3 inflammasome and TREM2, which represent promising therapeutic targets for modulating inflammation while preserving protective immune functions. Strategies aimed at reducing systemic inflammation, identifying early biomarkers, and intervening before significant neurodegeneration occurs may provide novel approaches to delay or prevent AD onset. In conclusion, this review underscores the crucial role of systemic inflammation in AD pathogenesis and progression. By targeting peripheral immune dysfunction, we may advance our understanding of AD mechanisms and develop more effective therapeutic interventions to mitigate disease risk and progression.

Early-onset neurodegeneration leads to cognitive and behavioral symptoms in frontotemporal dementia (FTD) and motor disturbances in amyotrophic lateral sclerosis (ALS). Despite distinct clinical profiles, more than half of FTD patients experience ALS-related symptoms and vice versa. Spinal cord monoamine neurotransmitter alterations were reported in ALS, but not yet in FTD. Therefore, we compared monoaminergic turnover across the FTD-ALS continuum. Reversed-phase, ultra-high-performance liquid chromatography with electrochemical detection was used to measure levels of the monoamines (nor)adrenaline ((N)A), dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) and their metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in five cervical and thoracic spinal cord regions in 10 FTD, 14 ALS, 6 mixed FTD-ALS, 14 early-onset Alzheimer's disease (EOAD), and 7 control (CONTR) individuals. At the cervical level, NA levels were lower in FTD-ALS versus CONTR, whereas the HVA/5-HIAA ratio was higher in ALS versus EOAD in the lateral funiculus. In the dorsal horn-intermediate gray matter, DA levels were decreased in FTD-ALS compared to FTD. At the thoracic level, DOPAC was lower in ALS than in FTD-ALS patients in the ventral and lateral funiculus, ventral horn, and dorsal horn-intermediate gray matter, as was the DOPAC/DA ratio in the lateral funiculus and dorsal horn-intermediate gray matter. Contrarily, HVA/DA turnover was lower in FTD-ALS than in FTD in the dorsal and ventral funiculus. We observed lower NA levels in FTD-ALS than in FTD in the ventral funiculus, and lower MHPG/NA turnover in the dorsal horn-intermediate gray matter. A levels were lower in ALS versus FTD. This study indicates differences in monoaminergic turnover across the FTD-ALS continuum, at the cervical and thoracic levels, with primarily a decrease in dopaminergic activity in ALS. Characterizing disease-specific neurochemical profiles for FTD, ALS, or FTD-ALS could contribute to the identification of novel interesting pharmacological targets.

People with Down Syndrome (DS) are at high risk of developing Alzheimer’s disease dementia (AD) and cerebral amyloid angiopathy, which is a critical factor contributing to dementia in sporadic AD. Predicting and monitoring the decline and onset of dementia is a diagnostic challenge and of essence in daily care and support for people with DS. In this literature scoping review, we first summarize the different blood-based biomarkers for AD in DS. Next, we describe urine-based biomarkers for AD in DS and finally, we explore various blood-based biomarkers in the general AD population. Apart from the classic amyloid beta and Tau biomarkers, we also discuss more out-of-the-box biomarkers such as neurofilament light chain, Dual-specificity tyrosine-regulated kinase 1A, and monoaminergic biomarkers. These potential biomarkers could be a valuable addition to the established panel of fluid biomarkers.

Long considered to fluctuate between pro- and anti-inflammatory states, it has now become evident that microglia occupy a variegated phenotypic landscape with relevance to aging and neurodegeneration. However, whether specific microglial subsets converge in or contribute to both processes that eventually affect brain function is less clear. To investigate this, we analyzed microglial heterogeneity in a tauopathy mouse model (K18-seeded P301L) and an accelerated aging model (Senescence-Accelerated Mouse-Prone 8, SAMP8) using cellular indexing of transcriptomes and epitopes by sequencing. We found that widespread tau pathology in K18-seeded P301L mice caused a significant change in the number and morphology of microglia, but only a mild overrepresentation of disease-associated microglia. At the cell population-level, we observed a marked upregulation of the calprotectin-encoding genes S100a8 and S100a9. In 9-month-old SAMP8 mice, we identified a unique microglial subpopulation that showed partial similarity with the disease-associated microglia phenotype and was additionally characterized by a high expression of the same calprotectin gene set. Immunostaining for S100A8 revealed that this population was enriched in the hippocampus, correlating with the cognitive impairment observed in this model. However, incomplete colocalization between their residence and markers of neuronal loss suggests regional specificity. Importantly, S100A8-positive microglia were also retrieved in brain biopsies of human AD and tauopathy patients as well as in a biopsy of an aged individual without reported pathology. Thus, the emergence of S100A8-positive microglia portrays a conspicuous commonality between accelerated aging and tauopathy progression, which may have relevance for ensuing brain dysfunction.

Cerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer’s disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aβ/pTau, however, appears to vary depending on the animal model. Our prior work suggested that antigen-specific memory CD8 T (“ hi T”) cells act upstream of Aβ/pTau after brain injury. Here, we examine whether hi T cells influence sporadic AD-like pathophysiology upstream of Aβ/pTau. Examining neuropathology, gene expression, and behavior in our hi T mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. We identify an age-related factor acting upstream of Aβ/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.

ImportanceAmbient air pollution is a worldwide problem, not only related to respiratory and cardiovascular diseases but also to neurodegenerative disorders. Different pathways on how air pollutants could affect the brain are already known, but direct evidence of the presence of ambient particles (or nanoparticles) in the human adult brain is limited.ObjectiveTo examine whether ambient black carbon particles can translocate to the brain and observe their biodistribution within the different brain regions.Design, Setting, and ParticipantsIn this case series a label-free and biocompatible detection technique of nonincandescence-related white light generation was used to screen different regions of biobanked brains of 4 individuals from Belgium with neuropathologically confirmed Alzheimer disease for the presence of black carbon particles. The selected biological specimens were acquired and subsequently stored in a biorepository between April 2013 and April 2017. Black carbon measurements and data analysis were conducted between June 2020 and December 2022.Main Outcomes and MeasuresThe black carbon load was measured in various human brain regions. A Kruskal-Wallis test was used to compare black carbon loads across these regions, followed by Dunn multiple comparison tests.ResultsBlack carbon particles were directly visualized in the human brain of 4 individuals (3 women [75%]; mean [SD] age, 86 [13] years). Screening of the postmortem brain regions showed a significantly higher median (IQR) number of black carbon particles present in the thalamus (433.6 [289.5-540.2] particles per mm3), the prefrontal cortex including the olfactory bulb (420.8 [306.6-486.8] particles per mm3), and the hippocampus (364.7 [342.0-448.7] particles per mm3) compared with the cingulate cortex (192.3 [164.2-277.5] particles per mm3), amygdala (217.5 [147.3-244.5] particles per mm3), and the superior temporal gyrus (204.9 [167.9-236.8] particles per mm3).Conclusions and RelevanceThis case series provides evidence that ambient air pollution particles are able to translocate to the human brain and accumulate in multiple brain regions involved in cognitive functioning. This phenomenon may contribute to the onset and development of neurodegenerative disorders.

Exposure to an acute stressor triggers a complex cascade of neurochemical events in the brain. However, deciphering their individual impact on stress-induced molecular changes remains a major challenge. Here, we combine RNA sequencing with selective pharmacological, chemogenetic, and optogenetic manipulations to isolate the contribution of the locus coeruleus-noradrenaline (LC-NA) system to the acute stress response in mice. We reveal that NA release during stress exposure regulates a large and reproducible set of genes in the dorsal and ventral hippocampus via β-adrenergic receptors. For a smaller subset of these genes, we show that NA release triggered by LC stimulation is sufficient to mimic the stress-induced transcriptional response. We observe these effects in both sexes, and independent of the pattern and frequency of LC activation. Using a retrograde optogenetic approach, we demonstrate that hippocampus-projecting LC neurons directly regulate hippocampal gene expression. Overall, a highly selective set of astrocyte-enriched genes emerges as key targets of LC-NA activation, most prominently several subunits of protein phosphatase 1 (Ppp1r3c, Ppp1r3d, Ppp1r3g) and type II iodothyronine deiodinase (Dio2). These results highlight the importance of astrocytic energy metabolism and thyroid hormone signaling in LC-mediated hippocampal function and offer new molecular targets for understanding how NA impacts brain function in health and disease.