Plasma neurofilament light chains (pNfL) have shown promise as a biomarker for tracking and predicting neurodegeneration, such as cortical atrophy and hypometabolism, in Alzheimer’s Disease (AD). However, it is still not clear whether neurofilament light chains (NfL) also reflect alterations in the functional connectivity (FC) of the default mode network (DMN), a functional network showing alterations in earlier stages of AD. In this cross-sectional study including 62 cognitively unimpaired (CU) and 47 cognitively impaired (CI) older adults likely due to AD, we measured FC in the posterior midline DMN, and its FC with frontal DMN, temporoparietal DMN, and hippocampus. We also examined whether the previously observed relationships between pNfL and hippocampal volume, as well as memory function, are replicated in our dataset. pNfL showed no association with DMN FC in either the CI or the CU group. However, higher pNfL was associated with lower right hippocampal volume and memory score in the CI group. Our results support the utility of pNfL as a biomarker tracking hippocampal atrophy and memory function but not for predicting DMN FC in older adults with cognitive decline of Alzheimer’s type.

Non-coding RNA species, such as microRNA (miRNA), regulate multiple biological and pathological processes by binding to target mRNAs and facilitating alteration of translation levels via complexes such as RNA-induced silencing complex (RISC). Disrupting this process could contribute to AD pathogenesis by fostering aggregation of hyperphosphorylated microtubule-associated protein tau and amyloid-β (Aβ) peptides, and neuroinflammation. Understanding how these pathological changes are regulated remains our research focus. We report that miR298 plays a vital role in maintaining APP and tau homeostasis and that miR298 imbalances may impact AD progression. Levels of miR298 from non-cognitively impaired (NCI) and AD subject brain tissue samples from different recognized sources were measured by qRT-PCR and assessed for associations with AD risk and potential covariates such as age and APOE genotype. Other biomarkers were assessed in cortical samples from the same subjects, as we previously described. Further, APP, tau, and cytokines were profiled in miR298 mimic- or its antagomiR-expressing human neuronal and astrocyte cultures. Levels of miR298 varied in postmortem temporal lobe between AD patients and age-matched NCI controls. Higher brain miR298 levels were associated with a reduced risk of AD. Subject age and APOE genotype altered this association; specifically, greater age and dose of the APOEε4 allele were associated with an increased risk of AD. However, APOEε4 dose-associated risk reduced as age increased. We identified putative binding sites for miR298 on APP, BACE1, MAPT, IL1α, and IL6 mRNAs to form RISC. We showed that treatment by miR298 reduced tau, APP, and BACE1 proteins and mRNA levels in cell cultures. These studies suggest that miR298 regulates a coordinated network of AD-related proteins APP, BACE1, and tau. Hence, such network regulation may represent a rational therapeutic target for reducing AD risk and disease modification. In addition to late-onset cases, we will profile miR298 in brain tissue samples from early-onset AD cases. Future work involves testing miR298 in AD animal models, such as in human tau-overexpressing transgenic mice. We sincerely thank grant support from NIA/NIH.

Burnout is an occupational challenge to the health, performance, and retention of healthcare personnel. The objective of this cross-sectional study was to further our understanding of the association between burnout, work, coping, and cognitive impairment as it relates to neuroendocrine, inflammatory, and neuroplastic disease mechanisms. One hundred hospital-based registered nurses responded to a validated survey addressing employment and work characteristics, coping, and cognitive impairment, and a one-item, burnout scale. In addition, they all provided blood samples. Nineteen percent of the nurses reported symptoms of evolving burnout and an additional 12% reported established burnout. Severity of burnout was inversely associated with self-rated energy (p<.001), ability to concentrate (p<.001), and positively associated with stressed at work (p<.001), but not with workplace cognitive impairment. The anti-inflammatory and pro-energetic biomarker interleukin-10 was elevated in respondents in the combined two highest burnout categories (mean 2.81, S.E.M. 0.26 pg/mL) vs. a median of 2.09 pg/mL in the no-burnout category (p<.02). When biomarkers in blood were regressed on severity of burnout, concentration of the anabolic hormone dehydroepiandro­sterone­­-sulfate (standardized beta -.73, p=.007) and the neuronal strain biomarker neurofilament light chain (-.79, p=.01) inversely predicted burnout. In contrast, the ability to cope with a tough situation at work was positively associated with burnout (.75, p=.02). The study not only confirms the association between burnout and self-reported individual and work-related adverse outcomes but, importantly, burnout-relevant neuroendocrine, inflammatory, and neuronal biomarkers. Nurses suffering from burnout might exhibit dysfunctional coping resulting in decreased recognition of low energy, which accelerates the burnout process. It is proposed that assessment of biological disease mechanisms should play a larger role in both scholarly and clinical burnout work. ### Competing Interest Statement The authors have declared no competing interest.

Substantial numbers of individuals who contract COVID-19 experience long-lasting cognitive symptoms such as brain fog. Yet research to date has not compared these patients with healthy controls with a history of laboratory-confirmed COVID-19 infection, making it difficult to understand why certain COVID patients develop post-COVID cognitive symptoms while others do not. The objective of this pilot study was to compare two groups of laboratory-confirmed post-COVID patients, with and without cognitive symptoms, on measures of cognitive and psychological functioning, self-reported perceptions of functional status and quality of life, and biomarkers of stress, inflammation, and neuroplasticity. Using a case-control design, 17 participants were recruited from a healthcare system in western Michigan, USA in 2022-2024. All participants were aged 25-65 and had a positive polymerase chain reaction (PCR) test confirming previous COVID-19 infection. Ten participants reported cognitive symptoms (long COVID group) while seven were fully recovered with no residual symptoms (controls). All participants underwent an interview on their self-rated health and quality of life, a battery of neurocognitive tests, and blood draw for biomarker analysis. No group differences were detected for neuropsychological test measures except for letter fluency where the long COVID group scored significantly lower (p < .05). The long COVID group had significantly lower ratings than controls on quality of life, physical health, emotional functioning, and psychological well-being. Serum levels of nerve growth factor (NGF), a biomarker of brain plasticity, were significantly lower in the long COVID group, which was significantly more likely than controls to have serum levels of inflammatory marker (interleukin (IL)-10) values greater than or equal to the median (p = 0.015). Biomarker analyses suggest possible prolonged inflammatory processes in long COVID patients compared to fully recovered patients. Results of decreased neuroplastic functioning give credence to patients' reports of post-COVID changes in brain function.

INTRODUCTION:Small non-coding microRNAs (miRNAs) play essential roles in Alzheimer's disease (AD) pathogenesis. Repressor element 1-silencing transcription factor (REST) is involved in AD, though its regulation remains unclear. METHODS:We performed real-time quantitative polymerase chain reaction (qPCR) in autopsied brain tissues to determine miR-153-3p and AD associations. A reporter-based assay measured the activity of REST mRNA 3'-untranslated region (3'-UTR). Induced pluripotent stem cells (iPSC)-derived neurons and human cell lines were applied to determine miR-153-3p regulation of endogenous proteins. RESULTS:Elevation of miR-153-3p is associated with a reduced probability of AD, while elevated REST is associated with a greater probability of AD. The 3'-UTR functional assay pinpointed the miR-153-3p binding sites. miR-153-3p treatment reduced REST, amyloid precursor protein (APP), and α-synuclein (SNCA) 3'-UTR activities and protein levels. miR-153-3p treatment altered REST and neuronal differentiation in iPSC-derived neuronal stem cells. RNA-sequencing and proteomics revealed miR-153-3p-associated networks. DISCUSSION:miR-153-3p reduces REST, APP, and SNCA expression, pointing toward its therapeutic and biomarker potential in neurodegenerative diseases. HIGHLIGHTS:With the increased emphasis on comorbidities of Alzheimer's disease (AD) and other neurodegenerative diseases, we identified that miR-153-3p, as a master regulator, reduced a group of neurodegeneration related proteins: REST, amyloid precursor protein (APP) and α-synuclein (SNCA) levels. The elevation of miR-153-3p levels is associated with reduced probability of AD in posterior cingulate cortex (PCC), while REST, by contrast, is associated with a greater probability of AD. miR-153-3p treatment alters REST protein levels and neuronal differentiation in induced pluripotent stem cells (iPSC) derived neuronal cells. RNA sequencing proteomics and interactome analysis revealed the role of miR-153-3p in axonal guidance.

INTRODUCTION:MicroRNA (miRNA) activity is increasingly appreciated as a key regulator of pathophysiologic pathways in Alzheimer's disease (AD). However, the role of miRNAs during the progression of AD, including resilience and prodromal syndromes such as mild cognitive impairment (MCI), remains underexplored. METHODS:We performed miRNA-sequencing on samples of posterior cingulate cortex (PCC) obtained post mortem from Rush Religious Orders Study participants diagnosed ante mortem with no cognitive impairment (NCI), MCI, or AD. NCI subjects were subdivided as low pathology (Braak stage I/II) or high pathology (Braak stage III/IV), suggestive of resilience. Bioinformatics approaches included differential expression, messenger RNA (mRNA) target prediction, interactome modeling, functional enrichment, and AD risk modeling. RESULTS:We identified specific miRNA groups, mRNA targets, and signaling pathways distinguishing AD, MCI, resilience, ante mortem neuropsychological test performance, post mortem neuropathological burden, and AD risk. DISCUSSION:These findings highlight the potential of harnessing miRNA activity to manipulate disease-modifying pathways in AD, with implications for precision medicine. HIGHLIGHTS:MicroRNA (MiRNA) dysregulation is a well-established feature of Alzheimer's disease (AD). Novel miRNAs also distinguish subjects with mild cognitive impairment and putative resilience. MiRNAs correlate with cognitive performance and neuropathological burden. Select miRNAs are associated with AD risk with age as a significant covariate. MiRNA pathways include insulin, prolactin, kinases, and neurite plasticity.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by memory impairment that significantly interferes with daily life. Therapeutic options for AD that substantively modify disease progression remain a critical unmet need. In this regard, the gut microbiota is crucial in maintaining human health by regulating metabolism and immune responses, and increasing evidence suggests that probiotics, particularly beneficial bacteria, can enhance memory and cognitive functions. Recent studies have highlighted the positive effects of Bifidobacterium breve MCC1274 (B. breve MCC1274) on individuals with mild cognitive impairment (MCI) and schizophrenia. Additionally, oral supplementation with B. breve MCC1274 has been shown to effectively prevent memory decline in AppNL-G-F mice. In relation to Alzheimer's pathology, oral supplementation with B. breve MCC1274 has been found to reduce amyloid-β (Aβ) accumulation and tau phosphorylation in both AppNL-G-F and wild-type (WT) mice. It also decreases microglial activation and increases levels of synaptic proteins. In this review, we examine the beneficial effects of B. breve MCC1274 on AD, exploring potential mechanisms of action and how this probiotic strain may aid in preventing or treating the disease. Furthermore, we discuss the broader implications of B. breve MCC1274 for improving overall host health and provide insights into future research directions for this promising probiotic therapy.

Functional magnetic resonance imaging faces inherent challenges when applied to deep-brain areas in rodents, e.g. entorhinal cortex, due to the signal loss near the ear cavities induced by susceptibility artifacts and reduced sensitivity induced by the long distance from the surface array coil. Given the pivotal roles of deep brain regions in various diseases, optimized imaging techniques are needed. To mitigate susceptibility-induced signal losses, we introduced baby cream into the middle ear. To enhance the detection sensitivity of deep brain regions, we implemented inductively coupled ear-bars, resulting in approximately a 2-fold increase in sensitivity in entorhinal cortex. Notably, the inductively coupled ear-bar can be seamlessly integrated as an add-on device, without necessitating modifications to the scanner interface. To underscore the versatility of inductively coupled ear-bars, we conducted echo-planner imaging-based task functional magnetic resonance imaging in rats modeling Alzheimer's disease. As a proof of concept, we also demonstrated resting-state-functional magnetic resonance imaging connectivity maps originating from the left entorhinal cortex-a central hub for memory and navigation networks-to amygdala hippocampal area, Insular Cortex, Prelimbic Systems, Cingulate Cortex, Secondary Visual Cortex, and Motor Cortex. This work demonstrates an optimized procedure for acquiring large-scale networks emanating from a previously challenging seed region by conventional magnetic resonance imaging detectors, thereby facilitating improved observation of functional magnetic resonance imaging outcomes.

The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer's disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an ante-mortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to AD pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak Stages III/IV compared with Stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small non-coding micro-RNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak Stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs are significantly associated (rho > 0.38, P < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak Stages I-II and 47 miRNAs were associated with higher Braak Stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak Stages I/II versus Braak Stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and post-mortem neuropathological AD diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (pre-clinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.

Linear regression is one of the most used statistical techniques in neuroscience, including the study of the neuropathology of Alzheimer’s disease (AD) dementia. However, the practical utility of this approach is often limited because dependent variables are often highly skewed and fail to meet the assumption of normality. Applying linear regression analyses to highly skewed datasets can generate imprecise results, which lead to erroneous estimates derived from statistical models. Furthermore, the presence of outliers can introduce unwanted bias, which affect estimates derived from linear regression models. Although a variety of data transformations can be utilized to mitigate these problems, these approaches are also associated with various caveats. By contrast, a robust regression approach does not impose distributional assumptions on data allowing for results to be interpreted in a similar manner to that derived using a linear regression analysis. Here, we demonstrate the utility of applying robust regression to the analysis of data derived from studies of human brain neurodegeneration where the error distribution of a dependent variable does not meet the assumption of normality. We show that the application of a robust regression approach to two independent published human clinical neuropathologic data sets provides reliable estimates of associations. We also demonstrate that results from a linear regression analysis can be biased if the dependent variable is significantly skewed, further indicating robust regression as a suitable alternate approach.

Examination of early phases of synucleinopathy when inclusions are present, but long before neurodegeneration occurs, is critical to both understanding disease progression and the development of disease modifying therapies. The rat alpha-synuclein (α-syn) preformed fibril (PFF) model induces synchronized synucleinopathy that recapitulates the pathological features of Parkinson’s disease (PD) and can be used to study synucleinopathy progression. In this model, phosphorylated α-syn (pSyn) inclusion-containing neurons and reactive microglia (major histocompatibility complex-II immunoreactive) peak in the substantia nigra pars compacta (SNpc) months before appreciable neurodegeneration. However, it remains unclear which specific genes are driving these phenotypic changes. To identify transcriptional changes associated with early synucleinopathy, we used laser capture microdissection of the SNpc paired with RNA sequencing (RNASeq). Precision collection of the SNpc allowed for the assessment of differential transcript expression in the nigral dopamine neurons and proximal glia. Transcripts upregulated in early synucleinopathy were mainly associated with an immune response, whereas transcripts downregulated were associated with neurotransmission and the dopamine pathway. A subset of 29 transcripts associated with neurotransmission/vesicular release and the dopamine pathway were verified in a separate cohort of males and females to confirm reproducibility. Within this subset, fluorescent in situ hybridization ( FISH ) was used to localize decreases in the Syt1 and Slc6a3 transcripts to pSyn inclusion-containing neurons. Identification of transcriptional changes in early synucleinopathy provides insight into the molecular mechanisms driving neurodegeneration.

Several proteins play critical roles in vulnerability or resistance to neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and frontotemporal dementia (FTD). Regulation of these proteins is critical to maintaining healthy neurohomeostasis. In addition to transcription factors regulating gene transcription and microRNAs regulating mRNA translation, natural antisense transcripts (NATs) regulate mRNA levels, splicing, and translation. NATs’ roles are significant in regulating key protein-coding genes associated with neurodegenerative disorders. Elucidating the functions of these NATs could prove useful in treating or preventing diseases. NAT activity is not restricted to mRNA translation; it can also regulate DNA (de)methylation and other gene expression steps. NATs are noncoding RNAs (ncRNAs) encoded by DNA sequences overlapping the pertinent protein genes. These NATs have complex structures, including introns and exons, and therefore bind their target genes, precursor mRNAs (pre-mRNAs), and mature RNAs. They can occur at the 5’- or 3’-ends of a mRNA-coding sequence or internally to a parent gene. NATs can downregulate translation, e.g., microtubule-associated protein tau (MAPT) antisense-1 gene (MAPT-AS1), or upregulate translation, e.g., β-Amyloid site Cleaving Enzyme 1 (BACE1) antisense gene (BACE1-AS). Regulation of NATs can parallel pathogenesis, wherein a “pathogenic” NAT (e.g., BACE1-AS) is upregulated under pathogenic conditions, while a “protective” NAT (e.g., MAPT-AS1) is downregulated under pathogenic conditions. As a relatively underexplored endogenous control mechanism of protein expression, NATs may present novel mechanistic targets to prevent or ameliorate aging-related disorders.

Alzheimers disease (AD) is a progressive degenerative disease characterized by a significant loss of neurons and synapses in cognitive brain regions and is the leading cause of dementia worldwide. AD pathology comprises extracellular amyloid plaques and intracellular neurofibrillary tangles. However, the triggers of this pathology are still poorly understood. Repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF), a transcription repressor of neuronal genes, is dysregulated during AD pathogenesis. How REST is dysregulated is still poorly understood, especially at the post-transcriptional level. MicroRNAs (miRNAs), a group of short non-coding RNAs, typically regulate protein expression by interacting with target mRNA transcript 3-untranslated region (UTR) and play essential roles in AD pathogenesis. Herein, we demonstrate that miR-153-3p reduces REST 3-UTR activities, mRNA, and protein levels in human cell lines, along with downregulating amyloid β precursor protein (APP) and α-synuclein (SNCA). We determine by mutational analyses that miR-153-3p interacts with specific targets via the seed sequence present within the respective mRNA 3-UTR. We show that miR-153-3p treatment alters the expression of these specific proteins in human neuronally differentiated cells and human induced pluripotent stem cells and that miR-153-3p is itself dysregulated in AD. We further find that single nucleotide polymorphisms (SNPs) within 5kb of the MIR153-1 and MIR153-2 genes are associated with AD-related endophenotypes. Elevation of miR-153-3p is associated with reduced AD probability, while elevated REST may associate with a greater AD probability. Our work suggests that a supplement of miR-153-3p would reduce levels of toxic protein aggregates by reducing APP, SNCA, and REST expression, all pointing towards a therapeutic and biomarker potential of miR-153-3p in AD and related dementias.

This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age-related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid-related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA-related inflammation (CAA-ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid β (Aβ) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy.

MicroRNA (miRNA) dysregulation is linked to Alzheimer’s disease (AD) pathophysiology. We recently reported a role for miR-298 and miR-20b in AD risk and amyloid and tau metabolism. To examine the extent to which miRNAs are dysregulated during the earliest stages of AD, we quantified miRNA transcript levels in postmortem samples of posterior cingulate cortex (PCC), a default mode network (DMN) hub that underlies autobiographical memory, in normal subjects and those who died within the AD continuum. PCC samples were obtained from Rush ROS/MAP participants who came to autopsy with a diagnosis of a) no cognitive impairment and low pathology (NCI-LP, Braak stage I/II, n = 12), b) NCI with high pathology (NCI-HP, Braak stage IV, representing cognitive resilience, n = 8), c) mild cognitive impairment (MCI, n = 10), or d) dementia due to AD (n = 9). Illumina-based sequencing of total RNA was performed and trimmed reads with a size of 15-31 bases were analyzed. Differential expression analysis (FDR ≤ 0.04) revealed 42 miRNAs significantly dysregulated among the NCI (independent of Braak stage), MCI, and AD groups. Two miRNAs, miR-99a (FDR-adjusted p = 0.01) and miR-664b (p = 0.005), were downregulated in AD vs NCI and MCI, while miR-30a (p = 0.006), miR-374a (p = 0.004), and miR-501 (p = 0.005) were significantly upregulated in MCI vs. NCI and AD. Three miRNAs were significantly downregulated in NCI-HP vs. NCI-LP: miR-103a (p = 0.04), miR-211 (p = 0.03), and miR-4443 (p = 0.03). These miRNAs may operate in resilience-related pathways. Correlation analysis revealed that decreasing PCC levels of miR-664b levels were associated with poorer performance on antemortem tests of episodic memory (r = 0.41, p = 0.009), semantic memory (r = 0.44, p = 0.004), and visuospatial ability (r = 0.45, p = 0.004). Taken together, these data may identify potential pathogenic or protective miRNA-related mechanisms contributing to PCC and DMN function during the progression of AD, which may inform biomarker and intervention strategies. Ongoing analysis will identify functional pathway enrichment and miRNA targets.

Small non-coding microRNA (miRNA) play a vital role in regulating various biological and pathological processes, including Alzheimer’s disease (AD), brain injury, and head trauma. AD hallmarks include brain amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques are the abnormal aggregation of amyloid-β peptides (Aβ) derived from Aβ precursor protein (APP), and NFTs consist mostly of hyper-phosphorylated tau proteins. We have recently shown that miRNAs, such as miR-20b, miR-153, and miR-298, can independently regulate AD-related protein expression (Wang et al-Mol Psychiatry-2022). APOE ε4 increases the risk of AD; however, the role of brain miR101 levels in APOE’s influence is presently unknown. Here, we studied the role of miR-101-3p (miR-101) in AD risk and in regulating levels of critical proteins such as APP, GSK3β, and ECE1 implicated in AD. Temporal lobes (TL), cerebellum (CB), and posterior cingulate cortices (PCC) were obtained from non-cognitively impaired (NCI) and AD subjects, and quantitative RT-PCR measured miR-101 levels. The target specificity of miR-101 was tested using dual reporter clones expressing the 3'-UTRs of either APP, ECE1, or GSK3β mRNAs. Human microglia and differentiated neuroblastoma (SKNSH) cells were transfected with miR-101 for 72 hours, and cellular RNA, total proteins, and secreted proteins were analyzed by ELISA and Westerns to understand miR-101-mediated regulation. TL and CB regions showed that increased miR-101 levels were associated with reduced AD risk in the absence of the APOEε4 allele. Interestingly, miR-101 may increase AD risk in the presence of two APOEε4 alleles. Transfection of miR-101 altered the translation of several AD-related proteins, including aggregation-prone proteins, processing enzymes, and cytokines. Mechanistically, miR-101 treatment reduced ECE1 and GSK3β mRNA 3’-UTR activities in reporter clones and protein levels. We have shown that miR-101 levels modify AD risk in an APOE allele-dependent manner. Notably, miR-101 targets the 3’-UTRs of ECE1 and GSK3β and reduces their expression, making it a key regulator of AD-related proteins across species and cell types. Our combined results suggest that miR-101 is critical in regulating essential proteins relevant to AD pathogenesis and could potentially be a novel “multi-hit” drug target for AD and other neurodegenerative diseases. NIH grants to DKL and SEC.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Aging, familial gene mutations, and genetic, environmental, and modifiable lifestyle risk factors predispose individuals to cognitive impairment or dementia by influencing the efficacy of multiple, often interdependent cellular and molecular homeostatic pathways mediating neuronal, glial, and vascular integrity and, ultimately, cognitive status. This review summarizes data from foundational and recent breakthrough studies to highlight common and differential vascular and nonvascular pathogenic mechanisms underlying the progression of Alzheimer disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies.