The Second International Conference on Unconventional Animal Models of Alzheimer's Disease and Aging (UAMAA 2026) was held February 9 through 11, 2026, in Irvine, California. Building upon the inaugural meeting in Santiago, Chile (2023), this conference expanded an international effort to develop, characterize, and rigorously evaluate non-traditional animal models with enhanced translational relevance for Alzheimer's disease (AD) and aging research. The meeting convened leading investigators across genomics, systems neuroscience, comparative biology, and pathology to discuss naturally occurring and engineered models including degu (Octodon degus), dog (Canis lupus familiaris), marmoset (Callithrix jacchus), rhesus macaque (Macaca mulatta), naked mole-rat (Heterocephalus glaber), and emerging large animal species including elephants and whales. A central theme was the need for cross-species integration of multimodal and multi-scale approaches to interrogate cellular vulnerability, gene regulatory programs, and age-associated neuropathology and circuit alterations across species. UAMAA 2026 emphasized cross-species comparison, human brain atlas integration, and translational alignment with National Institutes of Health priorities. The conference highlighted growing momentum toward a diversified model ecosystem aimed at accelerating mechanistic insight and therapeutic discovery in AD and aging research. A special journal issue associated with the conference has been announced to extend these themes into peer-reviewed scientific discourse.

We present a novel approach for endoscopic calcium imaging in the marmoset extrastriate visual cortex, combining a chronically implanted microprism lens with an integrated injection cannula. This method achieved stable, longitudinal imaging of visually responsive GCaMP-expressing neurons over multiple weeks. Using a head-mounted miniscope in two subjects, we repeatedly presented naturalistic visual stimuli and longitudinally tracked the activity of more than one hundred neurons across sessions within an 800-μm2 field of view. Stably monitored neurons in cortical areas V3 and MT responded reliably to visual images and movies over periods up to 3 weeks. Cells having different visual response preferences were spatially intermixed. These results demonstrate the feasibility of longitudinal calcium imaging in the primate visual cortex using a single-surgery, integrated lens-cannula approach, and provide initial insights into single neuron response stability and diversity to naturalistic stimuli in mid-level cortical visual areas.

Abstract Permutation-based methods such as the spin test, Brain Surrogate Maps with Autocorrelated Spatial Heterogeneity (BrainSMASH), and the simple permutation-based intermodal correspondence (SPICE) test are widely used to assess correspondence between brain maps while accounting for their spatial autocorrelation. However, these methods define and evaluate correspondence in fundamentally different ways, making their results difficult to compare or interpret jointly. We address these limitations by introducing a two-factor mixed-effects model that decomposes brain map variability into components arising from inter-subject variability and spatial variability across brain locations. This formulation provides a principled way to characterize distinct sources of variability in brain maps and to formally link each correspondence test to the specific component it targets. Within this framework, we further provide the analytical expressions of the null distributions of the spin test, BrainSMASH, and SPICE in terms of model parameters. This unified framework clarifies the fundamental distinctions among the permutation tests, reveals their implicit assumptions, and provides a principled way to compare and interpret their results. Beyond clarifying existing methods, the modeling framework naturally motivates a bootstrap-based method that enables simultaneous inference of multiple forms of correspondence arising from different components of brain map variability. Through extensive simulations and empirical analyses of both structural (cortical thickness vs. sulcal depth) and functional (language vs. motor contrast) brain maps, we demonstrate that the bootstrap-based method achieves well-calibrated type I error, substantially higher statistical power, and provides a robust and comprehensive characterization of different forms of brain map correspondence.

Translational neuroscience requires consistent anatomical frameworks to compare brain organization across species despite differences in size and specialization. Existing atlases are species-specific, limiting cross-species analyses. Here we constructed population-averaged minimal deformation templates for rodents, nonhuman primates, and humans, and developed a hierarchical common atlas delineating homologous cortical and subcortical gray matter regions through landmark-guided boundaries and multimodal nonlinear registration. Validation against species-specific atlases confirmed strong regional correspondence and revealed systematic volumetric scaling, with humans showing expanded associative cortices and rodents emphasizing limbic and sensorimotor areas. This freely available atlas provides a unified coordinate system supporting comparative imaging, developmental analyses, and cross-species connectomics, facilitating investigations into conserved and divergent brain organization across species.

Schizophrenia is thought to arise from disrupted postnatal maturation of prefrontal circuits, but the developmental events linking early vulnerability to adult cortical dysfunction remain unclear. Here, we tested whether the primate medial pulvinar, a higher-order thalamic nucleus interconnected with prefrontal cortex, contributes to prefrontal maturation. Bilateral medial pulvinar lesions in neonatal marmosets altered adolescent prefrontal diffusion trajectories and produced adult working memory deficits, the latter of which did not follow comparable lesions in adulthood. Early-life lesioned animals showed reduced thalamocortical input to layer 3 parvalbumin interneurons, diminished prefrontal gamma power, reduced parvalbumin expression, and immature-like physiology in fast-spiking interneurons. These findings reveal a developmental window in which thalamic input shapes prefrontal inhibitory maturation, suggesting that some forms of cortical dysfunction in psychiatric disease originate not in the cortex itself, but in its thalamic inputs.

Schizophrenia, major depressive disorder (MDD), and Alzheimer's disease (AD) involve dysfunction of distributed cortical-subcortical networks that support complex cognitive processes and emotion regulation. Convergent evidence identifies the dorsolateral prefrontal cortex (dlPFC) as a critical site of molecular, cellular, and circuitry alterations in these disorders. The primate dlPFC contains recurrent, excitatory microcircuits in layer III that sustain working memory and top-down control through specialized forms of neurotransmission and intracellular signaling. Specifically, NMDA receptor and cholinergic modulation, as well as tightly regulated calcium-cAMP signaling within dendritic spines, support task-specific firing of layer III pyramidal neurons, but may also increase vulnerability to genetic risk, stress, inflammation and aging. This review integrates findings from human postmortem studies, neuroimaging, and genetics to examine how dlPFC circuitry is altered in these disease states. In schizophrenia, layer III pyramidal neurons exhibit altered synaptic and cytoskeletal signaling, lower dendritic spine density, and compensatory shifts in inhibitory inputs that likely weaken recurrent excitation and network synchrony. In MDD, dysfunction of dlPFC pathways regulating subgenual cingulate cortex contributes to impaired top-down control of emotion and motivation. In AD and frontotemporal lobar degeneration, tau pathology and neurodegeneration target association cortices, including layer III dlPFC circuits, contributing to progressive cognitive decline and impaired executive function. The review also highlights how studies in rhesus macaques and genetically engineered marmosets have provided important insight into the organization, physiology, and disease vulnerability of primate dlPFC circuits. Together, these findings inform the development of emerging therapeutic strategies aimed at strengthening prefrontal network function.

INTRODUCTION:The slow, age-related development of Alzheimer's disease (AD) and inaccessibility of early-stage brain tissue necessitates model studies to understand its origins and progression. Non-human primate models can provide a platform for linking molecular changes to translatable phenotypes. Here, we assess fibroblast lines derived from marmosets with engineered variants in the PSEN1 gene. METHODS:Fibroblast cultures were obtained from 10 animals and assayed using a NanoString AD gene expression panel and label-free proteomics. We compared mutant expression changes to human AD signatures in human iPSC-derived neurons and postmortem brains to assess disease relevance. RESULTS:Gene products involved in amyloid-beta interaction and regulation were differentially expressed, providing evidence for the functional relevance of the engineered fibroblasts. Both gene and protein expression changes in the undifferentiated fibroblasts correlated with human iPSCs from AD donors reprogrammed into neuronal lineages, as well as postmortem brains derived from case-control cohorts. Altered expression profiles were noted based on marmoset donor sex and mutation status, highlighting underlying sex-specific biology relevant to Alzheimer's disease. DISCUSSION:These findings demonstrate that disease-relevant pathways and processes are altered in fibroblasts from mutant marmosets, emphasize the complementarity of transcriptomic and proteomic profiling in AD, and provide a roadmap for more advanced molecular studies of AD in aging marmosets and marmoset-derived cell models.

The common marmoset is a New World monkey widely used to study primate evolution and human disease. We present a telomere-to-telomere (T2T) reference assembly for the species, plus three near-T2T haplotypes. These resolve previously inaccessible regions, including the centromeres, sex chromosomes, subterminal satellites, acrocentric chromosomes, and the major histocompatibility complex (MHC). We find marmoset centromeres carry dimeric alpha satellites with chromosomal specificity, flanked by inactive layers interpreted as ancestral centromere remnants. We assemble gene-poor, satellite-rich short arms of the acrocentrics and find that most can harbor rDNA and all share pseudo-homolog regions (PHRs). PHR-sharing chromosomes also share closely related centromeric satellites, consistent with a model of ongoing rDNA-facilitated recombinational exchange between heterologous chromosomes. We further identify over 500 marmoset-lineage-specific transcribed genes with previously unknown transcript models or expansions. These resources, along with a preliminary pangenome, improve the utility of the marmoset as a model organism and address gaps in primate genome evolution.

The common marmoset (Callithrix jacchus) is an important animal model in neuroscience and neurological diseases, presenting primate-specific evolutionary features such as an expanded frontal cortex. We established a new consortium with funding support from the National Institute on Aging to generate, characterize, and validate MArmosets as Research MOdels of AD (MARMO-AD). This consortium develops and studies gene-edited marmoset models carrying genetic risk for AD, comparing them against wild-type aging marmosets from birth throughout their lifespan, using non-invasive longitudinal assessments. Here, we aim to characterize healthy aging trajectories by investigating their resting state functional connectivity in a population of marmosets. We imaged a cohort of 25 marmosets (17 males, 8 females) across the lifespan (8 to 150 months) using a dedicated 9.4T/30cm Bruker MRI scanner. The animals were acclimated to restrainers and head-fixation helmets and imaged awake. EPI images (500 µm isotropic) were acquired for 1 hour and 20 minutes, yielding 2400 whole-brain volumes. The images were pre-processed for fMRI using AFNI and FSL. For each run, the first ten time points were removed for magnetization to reach a steady state. The images were despiked, and spatially aligned. Slice timing was corrected, and phase-encoding distortion was corrected using FSL. Subsequently, brain images were registered to the Marmoset Brain Mapping V3 template, and brain-wide connectomics were calculated using the GRETNA toolbox. Our group has shown through structural investigations (voxel-based morphometry and white matter tractography) that several cortical clusters are affected by aging (Figure 1, Top Left). Here, with resting state fMRI, we show that many brain regions that change size with aging also show accompanying changes in their functional connectivity strength (Figure 1, Right). Integrating resting-state fMRI with structural investigations will allow us to understand how these affected structures work together in a dynamic network. Our work is the first to thoroughly describe the changes in resting state functional connectivity in the marmoset brain during normal aging, a valuable model for AD. This research will establish normative baselines for changes in marmoset brain connectivity with aging to evaluate our genetically engineered marmoset models of AD.

We present a new clustering-enabled regression approach to investigate how functional connectivity (FC) of the entire brain changes from childhood to old age. By applying this method to resting-state functional magnetic resonance imaging data aggregated from three Human Connectome Project studies, we cluster brain regions that undergo identical age-related changes in FC and reveal diverse patterns of these changes for different region clusters. While most brain connections between pairs of regions show minimal yet statistically significant FC changes with age, only a tiny proportion of connections exhibit practically significant age-related changes in FC. Among these connections, FC between region clusters from the same functional network tends to decrease over time, whereas FC between region clusters from different networks demonstrates various patterns of age-related changes. Moreover, our research uncovers sex-specific trends in FC changes. Females show much higher FC mainly within the default mode network, whereas males display higher FC across several more brain networks. These findings underscore the complexity and heterogeneity of FC changes in the brain throughout the lifespan.

The common marmoset (Callithrix jacchus) is an important animal model in neuroscience and neurological diseases (e.g., Alzheimer’s disease - AD), as they present primate-specific evolutionary features such as an expanded frontal cortex. We established a new consortium with funding support from the National Institute on Aging to generate, characterize, and validate MArmosets as Research MOdels of AD (MARMO-AD). This consortium develops and studies gene-edited marmoset models carrying genetic risk for AD, comparing them against wild-type aging marmosets from birth throughout their lifespan, using non-invasive longitudinal assessments. Here, we aim to characterize healthy aging trajectories of regional brain volume in a population of marmosets. We imaged a cohort of 59 marmosets (45 males, 14 females) across the lifespan (8 to 150 months) using a dedicated 9.4T 30cm bore MRI scanner (Bruker BioSpin Corp, Billerica). The animals were anesthetized under isoflurane and maintained under normal physiological conditions. High-resolution (250 µm isotropic) T1-, T2-, and diffusion-weighted structural MRI were acquired. The brain images were aligned and registered to the Marmoset Brain Mapping V3 template. The brain was segmented into cortical (CTX) and subcortical (SUB CTX) grey matter, white matter (WM), and cerebral spinal fluid (CSF), and voxel-based-morphometry was used to quantify regional brain volume in the left and right hemispheres. We discovered a decrease in grey matter volume in both males and females with age (Figure 1), reflected by the reduction in several cortical and subcortical brain regions in both sexes. Overall, we discovered that age affects female marmoset brains (38 CTX and 5 SUB CTX regions) more than males (15 CTX and 2 SUB CTX regions). We found no significant age-dependent changes in WM and CSF. Our work is the first to thoroughly describe the normal aging of the marmoset brain, a valuable model for age-related neuropathologies (e.g., AD). This research will establish normative baselines for changes in regional marmoset brain volume with aging that will be used to evaluate our genetically engineered marmoset models of AD, which is the goal of the MARMO-AD consortium.

The common marmoset (Callithrix jacchus) is an important animal model in neuroscience and neurological diseases (e.g., Alzheimer’s disease - AD), as they present primate-specific evolutionary features such as an expanded frontal cortex. We established a new consortium with funding support from the National Institute on Aging to generate, characterize, and validate MArmosets as Research MOdels of AD (MARMO-AD). This consortium develops and studies gene-edited marmoset models carrying genetic risk for AD, comparing them against wild-type aging marmosets from birth throughout their lifespan, using non-invasive longitudinal assessments. Here, we aimed to characterize the structural cortical connectivity (white matter fibers) in a population of marmosets across the lifespan to establish healthy aging trajectories against which we will compare our genetically engineered marmoset models of AD. We performed high-resolution (500 µm isotropic) diffusion-weighted MRI (dMRI) in a cohort of 19 marmosets (13 males, 6 females) aged 8 to 89 months using a dedicated 9.4T 30cm bore MRI scanner (Bruker BioSpin Corp, Billerica). The animals were anesthetized under isoflurane and maintained at normal physiological conditions. The brain images were aligned and registered to the Marmoset Brain Mapping (MBM) V2 template. The brain was segmented using the MBM white matter atlas, and voxel-based morphology (VBM) was used to quantify regional white matter volume in the left and right hemispheres. Furthermore, we used DSI STUDIO to perform the whole-brain tractogram, calculate network-based statistics (NBS), and correlate them with age. We measured decreases in the NBS properties of Assortativity, Small Worldliness, and Hierarchy with age but an increase in Efficiency, showing the maturation processes of white matter across development. We are actively working on increasing our sample size to identify the entire marmoset age trajectory and its impact on white matter connectivity. Our work is the first to thoroughly describe the healthy aging trajectories of the marmoset brain, a valuable model for age-related neuropathologies (e.g., AD). This research will establish normative baselines for changes in marmoset brain connectivity with aging that will be used to evaluate our genetically engineered marmoset models of AD, which is the goal of the MARMO-AD consortium.

Vascular pathology associated with small vessel disease (SVD), such as microinfarcts and microbleeds, are common in elderly populations and significant contributors to cognitive impairment and dementia. Autosomal dominant cerebral arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL), caused by mutations in the Notch3 gene, is the most prominent inheritable SVD, with a common etiology of subcortical strokes and dementia. This study aimed to investigate additive or synergistic effects of CADASIL-related vascular alterations and familial Alzheimer’s disease (FAD)-related amyloid pathology on cerebral metabolism of glucose and disease progression in a novel FAD-CADASIL mouse model. We bred 5xFAD mice to CADASIL mice carrying the Notch3 C456R mutation to create the novel FAD-CADASIL mouse model. To investigate progressive alterations in cerebral glucose metabolism, 18 F-FDG was delivered to awake mice via a tail vein injection, with an average dose of 18.5 MBq. The mice were fasted for a minimum of 2 hours before 18 F-FDG administration. PET and CT acquisitions were completed after a 30-minute 18 F-FDG circulation period using a Bruker Si78 instrument. Static datasets were analyzed for standard uptake values relative to the brainstem (SUV r ) and corrected for glucose levels (SUV glc ). Statistical tests included unpaired t-tests and 1- & 2-way ANOVA using GraphPad Prism 9. Whole brain SUV r values were decreased across age groups in 5xFAD, Notch3 C456R , and 5xFAD/Notch3 C456R mice compared to age-matched WT controls. Blood glucose levels collected before ligand injection indicated an age-dependent decrease in glucose levels across all genotypes. 5xFAD/Notch3 C456R mice showed distinct reductions in whole brain SUV glc values compared to aged-matched 5xFAD and Notch3 C456R mice. ROI analysis of 3-month-old 5xFAD/Notch3 C456R shows significantly decreased SUV glc levels in several cortical regions such as the striatum, cortex, hippocampus, hypothalamus, and thalamus when individually compared to WT, 5xFAD, and Notch3 C456R mice (Figure 1). We observed a significant synergistic effect of CADASIL on accelerating increased amyloid accumulation and reducing cerebral glucose metabolism in the novel FAD-CADASIL mouse model. These results provide further key evidence of an association between cortical vascular pathology and Alzheimer’s Disease progression. This research was funded by NIH/NINDS grant RF1NS117486.

Brain commissures are antiparallel white matter fiber bundles that connect both hemispheres across the midsagittal plane at different anatomical levels. In the mammalian brain, the best-known commissures are the corpus callosum, the anterior and the posterior commissures. Recent studies have identified a new white matter pathway, the thalamic commissures (TCs), that connect the cortex to the contralateral thalamus in rodents and primates. However, the specific cortical regions that project via the TCs and their target thalamic nuclei are still unknown. To thoroughly and accurately map this projectome, we utilized the mouse Allen Brain Institute connectivity atlas. Our results indicate that not all cortical regions project via the TCs, with most of these regions concentrated in the rostral portion of the brain. In addition, our data suggest that the TCs projections are very numerous, although less robust than the ipsilateral counterpart. Furthermore, these projections had a high degree of bilateral symmetry. We did not find any projections from the thalamus to the contralateral cortex, suggesting that the TCs are not reciprocal. Our findings reinforce the concept of the thalamus as an interhemispheric connectivity hub and suggest that the TCs might play a role in interhemispheric functional modulation.

Our limited understanding of the mechanisms that trigger the emergence of Alzheimer’s disease (AD) has contributed to the lack of interventions that stop, prevent, or fully treat this disease. We believe that developing a nonhuman primate model of AD will be an essential step toward overcoming the limitations of other model systems and is crucial for investigating primate-specific mechanisms underlying the cellular and molecular root causes of the pathogenesis and progression of AD. The consortium successfully generated viable founders carrying PSEN1 mutations. in C410Y and A426P using CRISPR/Cas9 approaches, with germline transmission demonstrated in the C410Y line. Longitudinal characterization of these models, their germline offspring, and normal aging outbred marmosets is ongoing. All data and resources from this consortium will be shared with the greater AD research community. The consortium successfully generated viable founders carrying PSEN1 mutations. in C410Y and A426P using CRISPR/Cas9 approaches, with germline transmission demonstrated in the C410Y line. Longitudinal characterization of these models, their germline offspring, and normal aging outbred marmosets is ongoing. All data and resources from this consortium will be shared with the greater AD research community. By establishing marmoset models of AD, we will be able to investigate primate-specific cellular and molecular root causes that underlie the pathogenesis and progression of AD, overcome limitations of other model organisms, and support future translational studies to accelerate the pace of bringing therapies to patients.

INTRODUCTION:Marmosets spontaneously develop pathological hallmarks of Alzheimer's disease (AD) including amyloid beta plaques. However, tau expression in the marmoset brain has been understudied. METHODS:Isoforms of tau were examined by western blot, mass spectrometry, immunofluorescence, and immunohistochemical staining. RESULTS:3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. Mass spectrometry analysis revealed that tau peptides in marmoset corresponded to the 3R and 4R peptides in human brain, with 3R predominating at birth and an ≈40%:60% 3R:4R ratios in adolescents and adults; tau was distributed widely in neurons, with localization in the soma and synaptic regions. Phosphorylation residues were observed on Threonine (Thr) Thr181, Thr217, Thr231, Serine (Ser) Ser202/Thr205, and Ser396/Ser404. DISCUSSION:Our results confirm both 3R and 4R tau isoform expression and phosphorylation residues in the marmoset brain, and emphasize the significance of marmosets with natural expression of AD-related hallmarks as important translational models for AD. Highlights We report comprehensive characterization of tau isoform expression in marmoset brains across the lifespan. 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. These data emphasize the significance of marmosets with natural expression of primate-specific traits that are important for the study of Alzheimer's disease.

The corpus callosum (CC), the largest brain commissure and the primary white matter pathway for interhemispheric cortical connectivity, was traditionally viewed as a predominantly homotopic structure, connecting mirror areas of the cortex. However, new studies verified that most callosal commissural fibers are heterotopic. Recently, we reported that ~75% of the callosal connections in the brains of mice, marmosets, and humans are heterotopic, having an essential role in determining the global properties of brain networks. In the present study, we leveraged high-resolution diffusion-weighted imaging and graph network modeling to investigate the relationship between heterotopic and homotopic callosal fibers in human subjects and in a spontaneous mouse model of Corpus Callosum Dysgenesis (CCD), a congenital developmental CC malformation that leads to widespread whole-brain reorganization. Our results show that the CCD brain is more heterotopic than the normotypical brain, with both mouse and human CCD subjects displaying highly variable heterotopicity maps. CCD mice have a clear heterotopicity cluster in the anterior CC, while hypoplasic humans have strongly variable patterns. Graph network-based connectivity profile showed a direct impact of heterotopic connections on CCD brains altering several network-based statistics. Our collective results show that CCD directly alters heterotopic connections and brain connectivity.

The neuropathological hallmarks of Alzheimer’s Disease (AD) are characterized by the accumulation of beta-amyloid (Ab) plaques and neurofibrillary tangles (NFTs) of a hyperphosphorylated form of the microtubule-associated protein tau (MAPT) in the brain. However, Ab and tau accumulate in the brain decades before the clinical symptoms emerge and the biological basis for the relationship between abnormal aggregation of AD-related proteins and neuronal deterioration remains unknown. Cell models play an imperative role in understanding the pathogenesis of the disorder. For this, the present studies aimed to establish a marmoset induced neurons directly converted from fibroblasts (induced neurons; iNs) as well as induced neural stem cells (iNSCs) that are further differentiated into neurons to quantify the spontaneous presence of AD-related pathology in marmoset cell cultures in vitro. Marmoset fibroblasts were cultured from skin biopsies and reprogrammed into iNSCs by transfection with episomal reprogramming vectors carrying the Oct4, Sox2, Nanog, Lin28, Klf4, and L-Myc and culture in the presence of small molecule inhibitors CHIR99021 and SB431542. The iNSCs were subsequently differentiated into neurons. Direct neuronal conversion from the marmoset fibroblast was performed by co-overexpression of Ngn2 and Ascl1 under the control of the doxycycline-inducible tetOn promoter and supplementation of medium containing doxycycline in combination with a defined cocktail of small molecule-based pathway modulators. Highly proliferative marmoset iNSCs were established and expressed neural stem cell markers, including Sox2 and Pax6 when detected by immunofluorescence. iNSCs were differentiated into neurons and stained the neuron-specific markers such as Tuj1, Map2, and NeuN. The Ngn2 and Ascl1 overexpressed marmoset fibroblasts underwent a morphological change into a neuron-like structure within a few hours of neuronal induction and the resultant iNs were expressed the pan-neuronal markers in the neurite-like projection and cell bodies. The directly reprogrammed iNSC and iNs have been shown to have neuronal characteristics and offer a cellular model system to quantify the natural incidence of AD-related pathology in marmosets. The marmoset cellular system of AD will provide mechanistic insight into the etiology of the disease and may serve as a beneficial tool for drug discovery to treat the disorder.

Alzheimer’s Disease (AD) is a progressive disease that presents as a continuum evolution from preclinical AD to mild cognitive impairment and, ultimately, dementia. The phenotypic characterization of AD was unified under a biological construct research framework supported by the National Institutes on Aging and Alzheimer’s Association (NIA-AA). This framework, referred to as ATN, is based on the presence of biomarkers for amyloid (Aβ, A), pathologic tau (T), and neurodegeneration (N). The present studies aimed to establish normative values of these biomarkers in our colony of outbred marmosets from infancy through aged individuals and compare them to the values from our population of marmosets genetically engineered with early onset familial mutations in the PSEN1 gene. Plasma (EDTA) and fibroblast media from skin biopsies were evaluated using MesoScale Discovery (MSD) Aβ peptide panel 4G8 ELISA and Human Neurofilament L (NfL) per the manufacturer’s protocols for each kit. There was a significant increase in the plasma Aβ42:40 ratio in PSEN1 mutation carriers relative to age- and sex-matched wild-type (WT) controls, which was also observed in culture media generated from fibroblasts of the same individuals. Longitudinal analysis of plasma Aβ revealed consistent levels in WT controls across multiple samplings with persistent increases in PSEN1 carriers. An increase in Nfl was observed in aging WT marmosets relative to young subjects. We have optimized the detection of plasma biomarkers for amyloid and NfL in marmosets and established normative values within our colony. Importantly, these results demonstrate the sensitivity and validity of these reagents for tracking plasma Aβ longitudinally across the marmoset lifespan. Other clinically utilized commercially available reagents are in the process of being optimized and validated to enable an analogous marmoset ATN. Pilot studies are ongoing evaluating the potential of pTau plasma biomarkers as part of the longitudinal assessments. The application of the NIA-AA Research Framework to marmosets will attain a more accurate characterization and understanding of the etiological sequence of events that lead to AD development, in line with the currently used framework in AD patients.

Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In six animals followed with multisequence 7 T MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in four of six marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.