BACKGROUND:Mosaic loss of the Y chromosome (mLoY) is the most common age-related somatic mutation in male humans and has been associated with increased mortality and fibrotic cardiovascular phenotypes. OBJECTIVES:This study aimed to evaluate the associations among mLoY, atrial fibrillation (AF), and mortality in a large hospital-based biobank cohort. METHODS:We analyzed 17,916 male participants aged ≥20 years from the Mass General Brigham Biobank with available genomic and clinical data. mLoY was quantified using mean log R ratio of the Y chromosome values derived from genotyping array data. Two classification approaches were used: histogram-based cutoffs and a mean log R ratio of the Y chromosome-based threshold method. Associations among mLoY, AF, and mortality were evaluated using multivariable logistic regression, adjusting for cardiovascular comorbidities. RESULTS:Among 2,940 AF patients and 14,976 control participants, mLoY prevalence was higher in AF patients across both classification methods. After adjusting for age and comorbidities, individuals with Y chromosome value <-0.1 had a 25% increased odds of AF (adjusted OR: 1.25; 95% CI: 1.01-1.55). Among patients with AF, mLoY was independently associated with a 37% higher risk of all-cause mortality (adjusted OR: 1.37; 95% CI: 1.06-1.79). CONCLUSIONS:mLoY is independently associated with a higher prevalence of AF and higher mortality among AF patients. These findings support mLoY as a potential biomarker for cardiovascular risk stratification in aging men and highlight fibrosis as a key mechanistic pathway warranting further investigation.

Abstract Background Immune aging may contribute to Alzheimer’s disease. Bacillus Calmette–Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer’s risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We assessed whether BCG induces trained immunity–like responses in adults with and without Alzheimer’s-related changes. Methods We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n = 12 without Alzheimer’s-related pathology; n = 11 with Alzheimer’s-related pathology) recruited at a single center. Participants received two intradermal BCG vaccinations one month apart. Protocol-defined objectives included safety, neurocognitive outcomes, and longitudinal immune and Alzheimer’s biomarker changes in blood and cerebrospinal fluid. Immune responses were assessed using cytokine assays and single-cell profiling. All enrolled participants were included where data were available; longitudinal changes were analyzed using mixed-effects models. Results Here we show that BCG induces persistent, trained immunity–like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs. These responses differ from blood, suggesting compartment-specific immune imprinting. In participants without Alzheimer’s-related changes, these immune shifts are accompanied by decreased amyloid-β levels in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed. Conclusions These findings suggest trained immunity–like responses in the central nervous system that may influence Alzheimer’s-relevant pathways. This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations. Trial registration ClinicalTrials.gov NCT04507126 (June 23, 2020) and NCT05004688 (August 6, 2021).

Sex and apolipoprotein E ε4 (APOE4) interact to alter the risk for Alzheimer’s disease and other neurodegenerative disorders. Herein, we show sex-specific differences in immune activation and lymphatic function in the meningeal dura of humanized female and male mice expressing two alleles of APOE4 (E4/E4), when compared with their respective sex-matched E3/E3 controls. We also describe distinct effects of APOE4 on brain lipid composition and inflammation in females and males that were partially reverted upon colony-stimulating factor 1 receptor (CSF1R) inhibition. Suppressing innate immunity reduced neuroinflammation and restored cognitive function in E4/E4 females, while exacerbating neuroinflammation and accelerating cognitive decline in E4/E4 males. Finally, in line with the E4/E4 humanized mouse model data, we show that APOE4 expression is linked to sexually dimorphic leukocyte activation profiles in the human brain. This study highlights the need for personalized therapies when targeting APOE, brain immunity, and meningeal lymphatics to promote cognitive resilience in both females and males.

Protein misfolding in the brain is a key pathological hallmark of neurodegenerative diseases. Optical imaging of misfolded proteins in disease models is essential for elucidating etiology and early diagnosis. However, developing specific optical imaging probes for each misfolded protein is time-consuming and challenging, leaving many pathological targets without effective detection tools, especially for in vivo imaging. Here, we present a dual-mode chemiluminescence strategy that enables both generic and specific detection of misfolded proteins using a single probe platform. In the generic mode, we demonstrate that ADLumin-1, a chemiluminescent probe, enables highly sensitive detection of diverse misfolded proteins in vitro, achieving up to 128-fold higher signal enhancement than Thioflavin T, and allows noninvasive imaging in mice models of Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. In the specific mode, ADLumin-1 combined with protein misfolding cyclic amplification allows femtomolar-level detection of α-synuclein in cerebrospinal fluid, while integration with a bio-orthogonal chemiluminescence resonance energy transfer technique enables in vivo discrimination of α-synuclein from Aβ. This dual-mode, modular approach offers a practical solution to the current probe limitations, with potential preclinical and clinical applications in neurodegenerative disorders.

INTRODUCTION:Despite the identification of familial Alzheimer's disease (FAD) genes and neuropathological alterations, AD displays complex genetic heterogeneity and molecular pathogenesis that warrant further investigation. GBF1 (Golgi brefeldin A resistant guanine nucleotide exchange factor 1) regulates protein trafficking, and genetic variants of GBF1 are associated with axonal neuropathy, intelligence, and cognitive function. METHODS:We sought to identify GBF1 neuropathological and molecular alterations using human post mortem brains, 5XFAD mouse brains, and FAD cells, as well as two family-based datasets (total sample size of 2522) to explore candidate GBF1 variants associated with AD. RESULTS:GBF1 revealed neuropathological alterations in association with amyloid plaques. Genetic analysis identified GBF1 suggestive variants associated with AD. Downregulation of GBF1 retarded amyloid beta (Aβ) protein precursor maturation and reduced levels of Aβ proteins. DISCUSSION:Collectively, GBF1 reveals neuropathological alterations in AD, and may lead to AD by a pathogenic mechanism altering Aβ levels and amyloid deposition in the brain.

Alzheimer's disease (AD) drug development has undergone cycles, driven initially by amyloid-β-based hypotheses and later setbacks by clinical failures. Recent advances in biotechnology, improved understanding of AD pathogenesis, and unmet medical needs have revitalized the field. This new wave is exemplified by lecanemab, the first fully FDA-approved disease-modifying therapy in two decades. We review approved and clinical-stage AD therapeutics using data from Cortellis and the FDA.

Angiotensin-converting enzyme (ACE) is a validated risk locus for developing late-onset Alzheimer's disease (AD). Although ACE1 expression and enzyme activity correlate with AD diagnosis, the mechanism by which this occurs is unclear. As a cell membrane-bound and shed peptidase, ACE1 is most commonly known to produce angiotensin II (Ang II), which has been linked to AD pathogenesis but also has been shown to cleave toxic Aβ42 to Aβ40, further complicating its role in AD. Previous work from our group characterized a rare ACE coding variant discovered through whole-genome and whole-exome sequencing of late-onset AD families: ACE rs4980 (R1279Q mutation) increases neuronal ACE1 and subsequent signaling through the central renin-angiotensin system (RAS), inducing age-associated hippocampal neurodegeneration. In this work, we report on two additional ACE variants associated with increased risk for developing AD: rs3730043 (T916M) and rs142947404 (N1036K). These variants were selected to investigate their effect on ACE1 protein processing and function in SH-SY5Y stable cell lines. In these cell lines, ACE1 protein trafficking to the cell surface was unaltered. Interestingly, however, both T916M and N1036K mutant cell lines resulted in increased ACE1 catalytic activity. Consequently, both mutant cell lines produced elevated levels of Ang II, a known mediator of neurodegeneration. This study provides further evidence for the role of ACE1 in AD and warrants continued research on this topic.

INTRODUCTION:Alzheimer's disease (AD) is the most common form of dementia. Studies have suggested prevalence is greater in individuals self-identifying as Hispanic. Population-specific results enable personalized and equitable interventions. Ethnicity as a stratifier co-occurs with genomic inflation due to heterogeneity. METHODS:We conducted genome-wide association studies (GWAS) and meta-analyses among subjects from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella whole genome sequencing (WGS) dataset who self-identified as Hispanic and All of Us (AoU) sub-cohorts matched to that cohort, using projected genetically-derived principal components. RESULTS:We identified a common variant in PIEZO2 on chromosome 18 protective for AD in ADSP subjects, with a p-value just beyond genome-wide significance (p =  5.4 × 10 - 8 $5.4\ \times {{10}^{ - 8}}$ ). Meta-analyses with genetically-matched AoU participants yielded three (two novel) genome-wide significant AD-associated loci based on rare lead variants: rs374043832 (RGS6/PSEN1), rs192423465 (ASPSCR1), and rs935208076 (GDAP2), which were nominally significant in AoU sub-cohorts. DISCUSSION:We demonstrate a way to match subjects between large biobanks and small disease-specific cohorts, enabling novel findings.

Loss of neuronal regenerative capacity is a common feature of neurodegenerative disease and axonal injury, yet the transcriptional programs governing this state remain poorly defined. Stathmin-2 (STMN2), a tubulin-binding protein essential for axon maintenance and repair, is profoundly depleted following loss of nuclear TDP-43 in neurodegenerative disease. Here, we identify statins as potent inducers of STMN2 expression. Pharmacological and genetic suppression of the mevalonate pathway, and subsequent prevention of protein geranylgeranylation, restored STMN2 levels in TDP-43 deficient cells and promoted neurite growth. STMN2 induction was abrogated when using a statin analogue unable to interact with HMG-CoA reductase, and through co-administration of mevalonate or geranylgeranyl diphosphate substrates. RNA-seq revealed that statins induce a coordinated pro-regenerative transcriptional response, including activation of the AP-1 transcription factor complex gene, ATF3. Loss of ATF3 attenuated STMN2 induction in vitro, and diminished injury-induced Stmn2 upregulation in spinal motor neurons in vivo. These results demonstrate statins as modulators of ATF3 and STMN2 expression and highlight their therapeutic potential in neurodegenerative disease.

Alzheimer's disease (AD) risk is strongly influenced by genetic variants that converge on pathways regulating endosomal homeostasis. Among these, BIN1 and RIN3 have emerged as susceptibility genes, yet their functional relationship in AD remains largely unknown. Here, we investigated how BIN1 and RIN3 interaction regulates RAB5 activity and endosomal pathology. RIN3 has been shown to bind BIN1, and we previously reported that this interaction modulates amyloid-β (Aβ) precursor protein (APP) trafficking and Aβ generation in vitro. To extend these findings, we used Rin3 constitutive knockout (Rin3-CKO) mice and CRISPR-Cas9-edited human induced pluripotent stem cell-derived neurons carrying either BIN1 knockout or rare familial AD RIN3 missense mutations within the BIN1-binding domain. We found that disruption of BIN1-RIN3 binding, through either genetic deletion or pathogenic RIN3 variants, resulted in RIN3-mediated RAB5 hyperactivation and enlargement of neuronal endosomes, a hallmark of early AD pathology. Transcriptomic profiling further revealed dysregulated expression of AD-related genes. Together, these findings establish BIN1 as a critical regulator of RIN3-driven RAB5 activation and neuronal endosomal homeostasis.

Abstract GWAS typically focus on SNPs, often excluding complex genetic variants, such as short tandem repeats. Here, we report the results of GWAS analyses systematically assessing the role of short tandem repeats, both imputed and directly genotyped by whole genome sequencing, on risk for Alzheimer’s disease in a large collection of ~330,000 individuals (3287 cases; 47,048 Alzheimer’s disease-by-proxy cases, 283,111 controls) from the UK biobank. Using short tandem repeat genotype data, we identify 15 independent loci showing evidence for genome-wide significant association with Alzheimer’s disease risk. While most identified loci had already been highlighted by SNP-based GWAS, we detect short tandem repeat-based signals near the genes SNX32 (chr. 11q13) and WSB1 (chr. 17q11). In addition, we delineate several other loci where short tandem repeats (and not SNPs) either represent the lead signal (ABCA7) or make substantial contributions to the SNP-driven associations (HLA-DRB1, MINDY/ADAM10, and APOE). Heritability analyses estimate that short tandem repeats account for at least 3% of the total phenotypic variance of Alzheimer’s disease in this dataset. Aligning our top short tandem repeats with DNA methylation and transcriptome profiles from human brain samples suggests that several short tandem repeats may unfold their effects by impacting gene expression.

Alzheimer's disease (AD) is the most common form of dementia in elderly, affecting 6.9 million individuals in the United States. Some studies have suggested the prevalence of AD is greater in individuals who self-identify as Hispanic. Focused results are relevant for personalized and equitable clinical interventions. Ethnicity as a stratifying tool in genetic studies is often accompanied by genomic inflation due to heterogeneity. In this study, we report GWAS and meta-analyses conducted among NIAGADS subjects who self-identified as Hispanic and All of Us (AoU) sub-cohorts matched to that cohort, using projected genetically-derived principal components, with and without age and sex. In Hispanic NIAGADS subjects, we identified a common variant in PIEZO2 that was protective for AD with a p-value just beyond genome-wide significance (p = 5.4*10-8). Meta-analyses with genetically-matched AoU participants yielded three (two novel) genome-wide significant AD-associated loci based on rare lead variants: rs374043832 (RGS6/PSEN1), rs192423465 (ASPSCR1), and rs935208076 (GDAP2), which were also nominally significant in AoU sub-cohorts. We thus demonstrate an efficient way to select subjects from large heterogeneous biobank cohorts who are genetically similar to a smaller disease-specific cohort, yielding novel disease-relevant findings.

A method to quantitate the stabilization of Mitochondria-Associated endoplasmic reticulum Membranes (MAMs) in a 3-dimensional (3D) neural model of Alzheimer's disease (AD) is presented here. To begin, fresh human neuro progenitor ReN cells expressing β-amyloid precursor protein (APP) containing familial Alzheimer's disease (FAD) or naïve ReN cells are grown in thin (1:100) Matrigel-coated tissue culture plates. After the cells reach confluency, these are electroporated with expression plasmids encoding red fluorescence protein (RFP)-conjugated mitochondria-binding sequence of AKAP1(34-63) (Mito-RFP) that detects mitochondria or constitutive MAM stabilizers MAM 1X or MAM 9X that stabilize tight (6 nm ± 1 nm gap width) or loose (24 nm ± 3 nm gap width) MAMs, respectively. After 16-24 h, the cells are harvested and enriched by a fluorescence-activated cell sorter (FACS). An equal number of FACS-enriched cells are seeded in the 3-dimensional matrix (1:1 Matrigel) and allowed to differentiate into mature neurons for 10 days. Live cell images of the 10-day differentiated cells expressing the RFP-conjugated MAM stabilizers are captured under a fluorescent microscope equipped with a live-cell imaging culture chamber maintaining the CO2 (5%), temperature (37 °C), and humidity (~90%). Toward this end, we performed live-cell imaging and kymographic analyses to measure the motility of free mitochondria labeled with Mito-RFP or ER-bound mitochondria of tight or loose gap widths stabilized by MAM 1X or MAM 9X, respectively, in the most extended neuronal process of each ReN GA neuron which is at least 500 nm long, considering these as axons.

INTRODUCTION:Emerging evidence has connected Alzheimer's disease (AD) to systemic inflammation, intestinal abnormalities, and altered gut microbiota, highlighting the significance of the gut-brain axis. Here, we investigated the impact of acute experimental colitis (acute colitis) on AD pathology. METHODS:Acute colitis was induced in 2-month-old 5xFAD mice using dextran sodium sulfate (DSS) to assess the effects of intestinal inflammation on the microbiome, systemic inflammation, neuroinflammation, and beta-amyloid deposition. RESULTS:Induction of acute colitis in 5xFAD mice led to microbial dysbiosis and systemic inflammation. As a result, monocyte infiltration was observed in the brain accompanied by reduced cerebral beta-amyloid deposition and increased beta-amyloid efflux into the bloodstream. DISCUSSION:Increased infiltration of monocytes and elevated beta-amyloid release into the bloodstream could both be responsible for the reduced beta-amyloid deposition in 5xFAD mice following acute colitis. These results further highlight an important connection between gut-induced peripheral inflammation and the progression of AD. HIGHLIGHTS:Microbial dysbiosis occurs as a result of acute colitis in 5xFAD mice. Acute colitis in 5xFAD mice affects beta-amyloid deposition. Increased IL-2 and IL-6 cytokine levels in the hippocampus of 5xFAD colitis mice. Colitis in 5xFAD mice increases serum proinflammatory cytokine levels and endotoxins. Acute colitis in 5xFAD mice increases monocyte infiltration and serum beta-amyloid.

INTRODUCTION:Lipid regulation is crucial role in Alzheimer's disease (AD) pathogenesis. In AD, microglia show elevated sterol O-acyltransferase 1/Acyl-coenzymeA: Choleseterol Acyltransferase 1 (SOAT1) expression, encoding Acyl-coenzymeA: Cholesterol Acyltransferase 1  (ACAT1), which produces cholesteryl esters (CEs) in lipid droplets. Inhibiting ACAT1 has been shown to reduce amyloid beta (Aβ) pathology, though the mechanism is unclear. METHODS:We inhibited ACAT1 using avasimibe (AV) in wild-type, triggering receptor expressed on myeloid cells 2 (TREM2) knockout (KO), and low-density lipoprotein receptor related protein 1 (LRP1) KO mouse BV2 and human induced pluripotent stem cell-derived microglia and measured the impact on Aβ uptake to determine the mechanism through which the inhibition of ACAT1 enhances Aβ uptake. RESULTS:ACAT1 inhibition increased LRP1 levels and soluble TREM2 (sTREM2) release via enhanced TREM2 cleavage by ADAM metallopeptidase domain 10/17 (ADAM10/17). KO of TREM2 or blockade of sTREM2 release prevented AV-enhanced Aβ uptake. This effect was rescued by recombinant sTREM2, but only when LRP1 was present. DISCUSSION:ACAT1 inhibition promotes microglial Aβ uptake in a sTREM2- and LRP1-dependent manner, offering insights into novel therapeutic strategies for AD. HIGHLIGHTS:Inhibition of ACAT1, the major enzyme that catalyzes cholesterol storage via esterification enhances microglia-mediated Aβ uptake. Increased Aβ uptake is dependent on the presence of both TREM2 and LRP1. Inhibition of ACAT1 increases cleavage of TREM2 via ADAM10/17 to release sTREM2. Treatment of microglial cells with sTREM2 rescues Aβ uptake in TREM2 KO BV2 cells. Inhibition of ACAT1 promotes Aβ uptake through increased shedding of TREM2, which enhances Aβ uptake through a LRP1-dependent mechanism.

Long-term preservation of fully differentiated human neurons poses a longstanding challenge in neuroscience research. Numerous cellular disease models have been established using cultured human neuronal cells, including our three-dimensional (3D) human neural cell culture model of Alzheimer’s disease (AD). However, the absence of a reliable method for preserving fully differentiated human neural cell cultures for a long time has hindered the sharing and standardization of these models. To address this critical limitation, we focused on cryopreservation, which is the gold standard for long-term preservation, and combined this with three key technological advancements. First, we employed parallelized microfluidic devices for the efficient generation of 3D cell cultures within uniform hydrogel microbeads (~ 220 μm), which facilitate the rapid exchange of media ingredients and cryoprotectants. Second, we implemented a cytophobic microwell system to safeguard neuron-encapsulated microbeads from fusion and aggregation. Third, we developed a novel inducible AD cell model optimized for cryopreservation and AD drug testing. We have successfully maintained encapsulated control and AD neural progenitor cells in microwells during differentiation for 12 days. Notably, fully differentiated human neural cells can be cryopreserved within Matrigel microbeads while retaining intact and mature neuronal processes, exhibiting no signs of damage to neurites following freeze/thaw cycles. Furthermore, we have demonstrated the successful cryopreservation, thawing, and induction of pathogenic Amyloid-β 42 (Aβ42) generation in fully differentiated AD neural progenitor cells. Our study offers a solution for one of the major challenges in neuroscience research, utilizing porous hydrogel microbead structures to facilitate rapid delivery of cryoprotectants and protect complex neuronal structures without undergoing damaging cell dissociation steps. The inducible "3D human microbead model of AD" enhances the speed, efficacy, and reproducibility of AD drug screening.

Cognitive resilience, the ability to maintain cognitive function despite extensive Alzheimer's disease (AD) pathology, offers a unique window into natural protective mechanisms. Understanding its molecular and cellular basis can reveal powerful therapeutic approaches for AD. This study investigates the molecular hallmarks of cognitive resilience and protection against AD by integrating genetic, transcriptomic, and cellular data. We interrogated bulk RNA sequencing ( n  = 631) and single-nucleus RNA sequencing ( n  = 48) data from multiple brain regions from the Religious Orders Study and the Memory and Aging Project (ROSMAP). Subjects were classified into AD, resilient, and control groups based on cognitive status and β-amyloid and tau pathology. Genetic analyses were paired with transcriptomic profiling and cell population mapping to identify resilience-associated pathways and protected neuronal subtypes. Cognitive resilience was associated with an intermediate AD polygenic risk profile and subtle tissue-level transcriptomic changes, including upregulation of GFAP and downregulation of KLF4 . Investigations of cellular resilience revealed a reorganization of protein folding and degradation pathways in excitatory neurons. Critical resilient excitatory neuronal subpopulations mapped in the entorhinal cortex exhibited distinctive protective signaling through neurotrophin and angiopoietin pathways. Novel candidate markers of resistance and protection-associated inhibitory neurons included RBFOX1 and KIF26B. This study reveals cellular and molecular features of cognitive resilience, highlighting the roles of excitatory and inhibitory neurons, protein folding pathways, and protective signaling networks. Our observations expose that the excitatory-inhibitory balance, which is disrupted in AD, is maintained in resilience. Our findings provide a foundation for leveraging resilience mechanisms to develop targeted therapies for AD.

Successful Alzheimer’s disease (AD) interventions in preclinical models often fail in human trials. While preclinical models offer insights into AD mechanisms, there is no systematic approach to verify whether preclinical target mechanisms retain therapeutic relevance in humans. Bridging this preclinical-to-clinical translational gap accelerates therapeutic development by precisely addressing whether failures are due to testing ineffective drugs, targeting the wrong mechanism, or relying on unrepresentative models. We have developed a novel bioinformatics platform, named Integrative Pathway Activity Analysis (IPAA), that maps pathway activity from omics data. IPAA precisely captures the degree to which disease functions in models match those in human brains and prioritizes targetable pathways in the most representative models. We assessed the mechanistic similarities between the transcriptomes of three AD brain regions and multiple 2D/3D human AD cellular models to define targetable functions. We performed phosphoproteomics analysis and compared pathway activity changes with transcriptomic findings. Top pathways were pharmacologically evaluated for their impact on AD pathology in 3D models. IPAA found high correlation of pathway dysregulation between brain regions (r=0.84, temporal cortex and parahippocampal gyrus), suggesting IPAA’s ability to detect conserved AD functions. IPAA found 83 dysregulated transcriptomic pathways shared between AD brains and a 3D model with a high Amyloid-beta (Aβ) 42/40 ratio. Shared dysregulated pathways included p38 MAPK, YAP1/TAZ, E-cadherin, CDC20, and APC/C, which were confirmed at the protein level. Elevated active p38 MAPK was observed in the 3D models, human AD brains, and 5XFAD mice, localized to presynaptic dystrophic neurites. Phosphoproteomic analysis confirmed an increase in p38 MAPK substrate phosphorylation driven by Aβ42 accumulation. Targeting p38 MAPK with a clinical p38α/β MAPK inhibitor (Losmapimod)– which has not been tested for AD– significantly reduced Aβ-induced tau, Aβ accumulation, neuronal loss, and microglial activation in 3D models and human microglia. We further found that MAPK-activated protein kinase 2 (MK2) plays crucial roles in mediating Aβ-induced tau pathology. IPAA enables rapid preclinical assessment of target pathways with confidence for impact on AD pathology prior to clinical trials. Our findings highlight the critical role of protein kinase networks, particularly the p38 MAPK-MK2 axis, in driving AD pathology in humans.

Protein misfolding is a crucial pathological phenomenon driving neurodegenerative diseases that affect millions of people. Visualizing misfolded proteins would greatly facilitate early diagnosis, etiology elucidation, and therapy monitoring of neurodegeneration. Although several probes have been reported, versatile and sensitive detection in vivo is still challenging. We demonstrated that both generic and precise detection of misfolded proteins could be achieved with a chemiluminescence probe, ADLumin-1. For generic aspect, ADLumin-1 was highly sensitive to various misfolded proteins, showing up to 127.73-fold higher signal-to-noise ratio than gold standard dye of Thioflavin T. ADLumin-1 could also non-invasively visualize misfolded proteins in mouse models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. For precise aspects, ADLumin-1 can selectively detect α-synuclein in CSF at the femtomolar level by combining with protein misfolding cyclic amplification technology in vitro. In addition, ADLumin-1 enables selective in vivo imaging of misfolded α-synuclein in transgenic mice models by employing bioorthogonal chemiluminescence resonance energy transfer strategy. Combining generality and precision, our findings could be widely applied in preclinical and clinical studies of neurodegenerative diseases.