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Objective Automated machine learning (autoML) platforms allow health care professionals to play an active role in the development of machine learning (ML) algorithms according to scientific or clinical needs. The aim of this study was to develop and evaluate such a model for automated detection and grading of distal hand osteoarthritis (OA). Methods A total of 13,690 hand radiographs from 2,863 patients within the Swiss Cohort of Quality Management (SCQM) and an external control data set of 346 non‐SCQM patients were collected and scored for distal interphalangeal OA (DIP‐OA) using the modified Kellgren/Lawrence (K/L) score. Giotto (Learn to Forecast [L2F]) was used as an autoML platform for training two convolutional neural networks for DIP joint extraction and subsequent classification according to the K/L scores. A total of 48,892 DIP joints were extracted and then used to train the classification model. Heatmaps were generated independently of the platform. User experience of a web application as a provisional user interface was investigated by rheumatologists and radiologists. Results The sensitivity and specificity of this model for detecting DIP‐OA were 79% and 86%, respectively. The accuracy for grading the correct K/L score was 75%, with a κ score of 0.76. The accuracy per DIP‐OA class differed, with 86% for no OA (defined as K/L scores 0 and 1), 71% for a K/L score of 2, 46% for a K/L score of 3, and 67% for a K/L score of 4. Similar values were obtained in an independent external test set. Qualitative and quantitative user experience testing of the web application revealed a moderate to high demand for automated DIP‐OA scoring among rheumatologists. Conversely, radiologists expressed a low demand, except for the use of heatmaps. Conclusion AutoML platforms are an opportunity to develop clinical end‐to‐end ML algorithms. Here, automated radiographic DIP‐OA detection is both feasible and usable, whereas grading among individual K/L scores (eg, for clinical trials) remains challenging.

Objective: Neuroimaging investigations are critical to provide a more direct assessment of brain disturbances associated with osteoarthritis (OA)-related pain, and to better understand its pathophysiology to develop new treatment strategies. This viewpoint aims to summarize the importance of the brain in OA pain. Method: A European working group on pain in osteoarthritis GO-PAIN (Going Inside Osteoarthritis-related Pain Phenotyping) has been created to work on a global assessment of the OA-related pain. Relevant scientific literature was evaluated, summarized and discussed to expose advances in functional brain alterations related-to OA pain. Results: Findings of neuroimaging studies are highly heterogenous and based on small sample size, but some key brain alterations associated with OA pain can be identified across experiments. A systematic literature review conducted by Hall and colleagues (2023) found lower activity, connectivity, and grey matter volume in the right anterior insula in patients with OA than in healthy controls. Other works also pointed out that activity of specific brain regions could serve as a potential surrogate biomarker, but several limitations and confounding factors needs to be addressed. Conclusions: Brain functional imaging provides opportunities to accurately address an OA-related pain endophenotype. To encompass limitations and fill the gaps from the previous studies, we propose a blueprint for the next 5 years and stimulate ideas for others working in the field.

Abstract Purpose The infralimbic (IL) subregion of the medial prefrontal cortex (mPFC) regulates the extinction of conditioned fear memory. Glucocorticoid and gamma‐aminobutyric acid (GABA) receptors are expressed in the mPFC and are also critical in fear extinction. This study investigated the possible interactive effects of the glucocorticoids and GABAergic system in the IL on the regulation of fear extinction. Method The rats were trained using an auditory fear conditioning task during which they received three conditioned stimuli (tones, 30 s, 4 kHz, 80 dB), co‐terminated with the three unconditioned stimuli (footshock, 0.8 mA, 1 s). Extinction testing was conducted over 3 days (Ext 1–3). Thirty minutes before the first extinction trial (Ext 1), the rats received bicuculline (BIC, 1 mg/kg/2 mL, intraperitoneal [i.p.]) as a GABAA receptor antagonist or CGP55845 (CGP, 0.1 mg/kg/2 ML, i.p.) as a GABAB receptor antagonist followed by systemic injection of corticosterone (CORT, 3 mg/kg/2 ML, i.p.). Furthermore, separate groups of rats received a bilateral intra‐IL injection of BIC (100 ng/0.3 µL/side) or CGP (10 ng/0.3 µL/side) followed by a systemic injection of CORT (3 mg/kg/2 ML, i.p.) before the first extinction trial (Ext 1). The extracellular signal‐regulated kinase (ERK1) and cAMP response element‐binding (CREB) activity in the IL was examined by Western blot analysis after Ext 1. Finding The results indicated that systemic CORT injection facilitated fear extinction and increased the expression of ERK1 but not CREB in the IL. Both systemic and intra‐IL co‐injection of BIC or CGP blocked the effects of CORT on fear extinction and ERK1 expression. Conclusion These findings suggest that glucocorticoids and the GABAergic system may modulate fear extinction through the ERK pathway in the IL.

Objective: To assess morphological and histological features of cartilage at the posterior medial condyle in advanced pre-prosthetic osteoarthritis (OA), which is notably thicker compared to non-OA knees. Design: Cartilage thickness was measured pre-operatively using MRI in 10 subjects with medial femorotibial OA (mean age: 70.2 years). Posterior condyles were obtained during arthroplasty and cartilage thickness, relative collagen content and subchondral bone volume fraction (BV/TV) were determined using phosphotungstic acid (PTA)-enhanced micro-CT. Regions of interest (ROI) around the maximum cartilage thickness were further analyzed through histomorphometry (Mankin score) and immunohistochemistry (cell density and apoptosis rates). Results: Maximum cartilage thickness was 2.63 ​± ​0.51 ​mm in vivo and 3.04 ​± ​0.55 ​mm ex vivo and both measurements were strongly correlated (r ​= ​0.84, p ​= ​0.003). Cartilaginous collagen content measured by PTA-enhanced micro-CT was negatively correlated with maximum cartilage thickness (r ​= ​–0.70, p ​= ​0.02). Average subchondral BV/TV was 31.6 ​± ​3.4% and did not correlate with cartilage thickness. Extensive loss of proteoglycan staining and tidemark multiplication were common histomorphological features around the maximum cartilage thickness. Chondrocyte densities were 315 ​± ​67 and 194 ​± ​36 ​cells/mm2 at the superficial and transitional cartilage zones, respectively. Chondrocyte apoptosis rates were approximately 70% in both zones. Maximum cartilage thickness correlated with superficial chondrocyte densities (r ​= ​0.79, p ​= ​0.01). Conclusions: Thicker cartilage at the posterior medial condyle in OA knees displayed degenerative changes both in cartilage tissue and at the osteochondral junction. Cartilage thickening may be influenced by alterations in the superficial zone, necessitating further investigation through molecular studies.

Abstract Objective To systematically review radiomic feature reproducibility and model validation strategies in recent studies dealing with CT and MRI radiomics of bone and soft-tissue sarcomas, thus updating a previous version of this review which included studies published up to 2020. Methods A literature search was conducted on EMBASE and PubMed databases for papers published between January 2021 and March 2023. Data regarding radiomic feature reproducibility and model validation strategies were extracted and analyzed. Results Out of 201 identified papers, 55 were included. They dealt with radiomics of bone (n = 23) or soft-tissue (n = 32) tumors. Thirty-two (out of 54 employing manual or semiautomatic segmentation, 59%) studies included a feature reproducibility analysis. Reproducibility was assessed based on intra/interobserver segmentation variability in 30 (55%) and geometrical transformations of the region of interest in 2 (4%) studies. At least one machine learning validation technique was used for model development in 34 (62%) papers, and K-fold cross-validation was employed most frequently. A clinical validation of the model was reported in 38 (69%) papers. It was performed using a separate dataset from the primary institution (internal test) in 22 (40%), an independent dataset from another institution (external test) in 14 (25%) and both in 2 (4%) studies. Conclusions Compared to papers published up to 2020, a clear improvement was noted with almost double publications reporting methodological aspects related to reproducibility and validation. Larger multicenter investigations including external clinical validation and the publication of databases in open-access repositories could further improve methodology and bring radiomics from a research area to the clinical stage. Critical relevance statement An improvement in feature reproducibility and model validation strategies has been shown in this updated systematic review on radiomics of bone and soft-tissue sarcomas, highlighting efforts to enhance methodology and bring radiomics from a research area to the clinical stage. Key points • 2021–2023 radiomic studies on CT and MRI of musculoskeletal sarcomas were reviewed. • Feature reproducibility was assessed in more than half (59%) of the studies. • Model clinical validation was performed in 69% of the studies. • Internal (44%) and/or external (29%) test datasets were employed for clinical validation. Graphical Abstract

Background: Hip osteoarthritis (OA) involves structural degeneration of different joint compartments, including femoral head cartilage, periarticular ligaments and the acetabular labrum. However, the molecular mechanisms underlying labrum degeneration in hip OA remain poorly understood. Aim: To assess secretion of putative biomarkers for OA from explanted human labrum tissues under basal and inflammatory conditions and to determine whether these could differentiate between OA and calcification status compared to fracture controls. Methods: Intact labrum specimens were collected from patients undergoing joint arthroplasty for primary hip OA (n ​= ​15, mean age 70) or non-OA femoral neck fracture (n ​= ​5, mean age 64). Tissues were dissected in equal-sized samples and explanted for one week. To mimic activation of inflammatory signaling by endogenous damage-associated molecular patterns (DAMP) tissue were stimulated with a toll-like receptor 4 (TLR4) agonist (1 ​μg/mL LPS). The involvement of transforming growth factor-beta (TGF-beta) signaling was evaluated by treatment with a TGF-beta type 1 receptor inhibitor (10 ​μM SB-505124). Secretion of aggrecan (ACAN), pro-collagen-I alpha (Pro-Col-Iα), cartilage oligomeric matrix protein (COMP), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) was assessed by enzyme-linked immunosorbent assay (ELISA). Labrum calcification was evaluated by 3D whole mount fluorescent microscopy of ethyl cinnamate-based optically cleared tissues stained with Alcian blue/Alizarin red. Results: Whole mount microscopy revealed non-OA fracture controls were non-calcified, whereas six OA labra (40%) were partially calcified or ossified. Basal secretion of Pro-Col-Iα and VEGF was increased four-fold in OA versus non-OA labra. Pro-Col-Iα levels were correlated with those of VEGF (r ​= ​0.65) and COMP (r ​= ​0.54). Stimulation of DAMP signaling through TLR4 affected secretion of IL-6, VEGF, COMP and Pro-Col-Iα, with distinct responses between non-OA and OA tissues. Inhibition of TGF-beta signaling specifically reduced elevated secretion of Pro-Col- Iα and VEGF in calcified OA labrum. Conclusions: Secretion of the putative OA biomarkers Pro-Col-Iα and VEGF is elevated in degenerated human acetabular labrum and may serve as indicators of OA and calcification status. Secretion of both factors was partially regulated by TGF-beta signaling in calcified OA labrum tissues.The Translational potential of this article:Our findings suggest that a biomarker panel consisting of Pro-Col-Iα/VEGF/COMP may be valuable for assessing subradiographic labrum degeneration and calcification in hip OA. Targeting TGF-beta signaling may offer a means to reduce vascular invasion and fibrosis in acetabular labrum tissue.

Tenosynovial giant cell tumor (TGCT) is a rare and locally aggressive benign tumor arising from the synovium of joints, bursae, and tendon sheaths. It is classified into localized (L-TGCT) and diffuse (D-TGCT) forms based on the extent of involvement. Surgical resection is the primary treatment, though achieving a definitive cure remains challenging due to the high recurrence rates, especially in D-TGCT. Systemic therapies targeting the CSF1-CSF1R axis have emerged as promising treatment options. CSF1R tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, pexidartinib, and vimseltinib, alongside anti-CSF1R antibodies like emactuzumab, cabiralizumab, and lacnotuzumab, have shown encouraging results in managing TGCT, particularly when surgery is not feasible or poses significant morbidity. Other potential therapies, including local treatments and anti-inflammatory drugs, are being explored for TGCT management. This review provides an overview of systemic treatment options for D-TGCT, highlighting emerging therapeutic modalities and their potential implications. Effective management is crucial due to TGCT’s significant morbidity despite its non-life-threatening nature, necessitating novel approaches to improve patient prognosis and quality of life.

ObjectivesThe purpose of this agreement was to establish evidence-based consensus statements on imaging of scapholunate joint (SLJ) instability by an expert group using the Delphi technique.MethodsNineteen hand surgeons developed a preliminary list of questions on SLJ instability. Radiologists created statements based on the literature and the authors' clinical experience. Questions and statements were revised during three iterative Delphi rounds. Delphi panellists consisted of twenty-seven musculoskeletal radiologists. The panellists scored their degree of agreement to each statement on an eleven-item numeric scale. Scores of '0', '5' and '10' reflected complete disagreement, indeterminate agreement and complete agreement, respectively. Group consensus was defined as a score of '8' or higher for 80% or more of the panellists.ResultsTen of fifteen statements achieved group consensus in the second Delphi round. The remaining five statements achieved group consensus in the third Delphi round. It was agreed that dorsopalmar and lateral radiographs should be acquired as routine imaging work-up in patients with suspected SLJ instability. Radiographic stress views and dynamic fluoroscopy allow accurate diagnosis of dynamic SLJ instability. MR arthrography and CT arthrography are accurate for detecting scapholunate interosseous ligament tears and articular cartilage defects. Ultrasonography and MRI can delineate most extrinsic carpal ligaments, although validated scientific evidence on accurate differentiation between partially or completely torn or incompetent ligaments is not available.ConclusionsDelphi-based agreements suggest that standardized radiographs, radiographic stress views, dynamic fluoroscopy, MR arthrography and CT arthrography are the most useful and accurate imaging techniques for the work-up of SLJ instability.Key points• Dorsopalmar and lateral wrist radiographs remain the basic imaging modality for routine imaging work-up in patients with suspected scapholunate joint instability. • Radiographic stress views and dynamic fluoroscopy of the wrist allow accurate diagnosis of dynamic scapholunate joint instability. • Wrist MR arthrography and CT arthrography are accurate for determination of scapholunate interosseous ligament tears and cartilage defects.

Abstract Subchondral insufficiency fractures (SIFs) and SIFs with osteonecrosis (SIF-ONs) of the knee (previously misnamed spontaneous osteonecrosis of the knee (SONK)) are bone lesions that appear without prior traumatic, tumoral, or inflammatory event. Both conditions are characterized in the early stages by epiphyseal bone marrow edema (BME)-like signal at MRI. However, while SIFs usually heal spontaneously, they can also evolve to osteonecrosis (i.e., SIF-ON), which may progress to an irreversible collapse of the articular surface. Careful analysis of other MRI signs may help differentiate the two conditions in the early phase. In SIFs, the BME edema-like signal extends to the area immediately adjacent to the subchondral plate, while in SIF-ONs, this subchondral area shows low signal intensity on fluid-sensitive MR images due to altered bone marrow. The thickness and length of subchondral areas with low fluid-sensitive signal intensity are important factors that determine the prognosis of SIF-ONs. If they are thicker than 4 mm or longer than 14 mm, the prognosis is poor. The differential diagnosis of SIFs and SIF-ONs include bone lesions associated with the “complex regional pain syndrome” (CRPS), epiphyseal osteonecrosis of systemic origin, and those related to cartilage pathology. Clinical relevance statement Imaging plays an essential role in diagnosing subchondral insufficiency fractures (SIFs) from subchondral insufficiency fractures with osteonecrosis (SIF-ONs) and collapse, as well as in distinguishing them from other spontaneous knee subchondral bone lesions presenting with bone marrow edema-like signal. Key points • Subchondral insufficiency fractures may affect the knee, especially in older adults. • Subchondral insufficiency fractures usually heal spontaneously. • Sometimes, subchondral osteonecrosis and collapse may complicate subchondral insufficiency fractures. • Bone marrow-like edema is an aspecific sign seen in all these lesions. • Degraded marrow in osteonecrosis complicating fractures is hypointense on fluid-sensitive sequences. Graphical Abstract

Background: Recent reports suggested that dual-energy CT (DECT) may help discriminate between different types of calcium phosphate crystals in vivo, which would have important implications for the characterization of crystal deposition occurring in osteoarthritis. Purpose: Our aim was to test the hypothesis that DECT can effectively differentiate basic calcium phosphate (BCP) from calcium pyrophosphate (CPP) deposition diseases. Methods: Discarded tissue after total knee replacement specimens in a 71 year-old patient with knee osteoarthritis and chondrocalcinosis was scanned using DECT at standard clinical parameters. Specimens were then examined on light microscopy which revealed CPP deposition in 4 specimens (medial femoral condyle, lateral tibial plateau and both menisci) without BCP deposition. Regions of interest were placed on post-processed CT images using Rho/Z maps (Syngo.via, Siemens Healthineers, VB10B) in different areas of CPP deposition, trabecular bone BCP (T-BCP) and subchondral bone plate BCP (C-BCP). Results: Dual Energy Index (DEI) of CPP was 0.12 (SD ​= ​0.02) for reader 1 and 0.09 (SD ​= ​0.03) for reader 2, The effective atomic number (Zeff) of CPP was 10.83 (SD ​= ​0.44) for reader 1 and 10.11 (SD ​= ​0.66) for reader 2. Nearly all DECT parameters of CPP were higher than those of T-BCP, lower than those of C-BCP, and largely overlapping with Aggregate-BCP (aggregate of T-BCP and C-BCP). Conclusion: Differentiation of different types of calcium crystals using DECT is not feasible in a clinical setting.

Abstract Purpose To develop an isotropic three-dimensional (3D) T2 mapping technique for the quantitative assessment of the composition of knee cartilage with high accuracy and precision. Methods A T2-prepared water-selective isotropic 3D gradient-echo pulse sequence was used to generate four images at 3 T. These were used for three T2 map reconstructions: standard images with an analytical T2 fit (AnT2Fit); standard images with a dictionary-based T2 fit (DictT2Fit); and patch-based-denoised images with a dictionary-based T2 fit (DenDictT2Fit). The accuracy of the three techniques was first optimized in a phantom study against spin-echo imaging, after which knee cartilage T2 values and coefficients of variation (CoV) were assessed in ten subjects in order to establish accuracy and precision in vivo. Data given as mean ± standard deviation. Results After optimization in the phantom, whole-knee cartilage T2 values of the healthy volunteers were 26.6 ± 1.6 ms (AnT2Fit), 42.8 ± 1.8 ms (DictT2Fit, p

Objective: To characterize ambulatory knee moments with respect to medial knee osteoarthritis (OA) severity comprehensively and to assess the possibility of developing a severity index combining knee moment parameters.Methods: Nine parameters (peak amplitudes) commonly used to quantify three-dimensional knee moments during walking were analyzed for 98 individuals (58.7 ± 9.2 years old, 1.69 ± 0.09 m, 76.9 ± 14.5 kg, 56% female), corresponding to three medial knee osteoarthritis severity groups: non-osteoarthritis (n = 22), mild osteoarthritis (n = 38) and severe osteoarthritis (n = 38). Multinomial logistic regression was used to create a severity index. Comparison and regression analyses were performed with respect to disease severity.Results: Six of the nine moment parameters differed statistically significantly among severity groups (p ≤ 0.039) and five reported statistically significant correlation with disease severity (0.23 ≤ |r| ≤ 0.59). The proposed severity index was highly reliable (ICC = 0.96) and statistically significantly different between the three groups (p < 0.001) as well as correlated with disease severity (r = 0.70).Conclusion: While medial knee osteoarthritis research has mostly focused on a few knee moment parameters, this study showed that other parameters differ with disease severity. In particular, it shed light on three parameters frequently disregarded in prior works. Another important finding is the possibility of combining the parameters into a severity index, which opens promising perspectives based on a single figure assessing the knee moments in their entirety. Although the proposed index was shown to be reliable and associated with disease severity, further research will be necessary particularly to assess its validity.

Introduction: The basolateral amygdala (BLA) and infralimbic area (IL) of the medial prefrontal cortex (mPFC) are two interconnected brain structures that mediate both fear memory expression and extinction. Besides the well-known role of the BLA in the acquisition and expression of fear memory, projections from IL to BLA inhibit fear expression and have a critical role in fear extinction. However, the details of IL-BLA interaction have remained unclear. Here, we investigated the role of functional reciprocal interactions between BLA and IL in mediating fear memory extinction. Methods: Using lidocaine (LID), male rats underwent unilateral or bilateral inactivation of the BLA and then unilateral intra-IL infusion of corticosterone (CORT) prior to extinction training of the auditory fear conditioning paradigm. Freezing behavior was reported as an index for conditioned fear. Infusions were performed before the extinction training, allowing us to examine the effects on fear expression and further extinction memory. Experiments 1-3 investigated the effects of left or right infusion of CORT into IL and LID unilaterally into BLA on fear memory extinction. Results: Intra-IL infusion of CORT in the right hemisphere reduced freezing behavior when administrated before the extinction training. Auditory fear memory extinction was impaired by asymmetric inactivation of BLA and CORT infusion in the right IL; however, the same effect was not observed with symmetric inactivation of BLA. Conclusion: IL-BLA neural circuit may provide additional evidence for the contribution of this circuit to auditory fear extinction. This study demonstrates dissociable roles for right or left BLA in subserving the auditory fear extinction. Our finding also raises the possibility that left BLA-IL circuitry may mediate auditory fear memory extinction via underlying mechanisms. However, further research is required in this area.

The osteoarthritis (OA) research community has been advocating a shift from radiography-based screening criteria and outcome measures in OA clinical trials to a magnetic resonance imaging (MRI)-based definition of eligibility and endpoint. For conventional morphological MRI, various semiquantitative evaluation tools are available. We have lately witnessed a remarkable technological advance in MRI techniques, including compositional/physiologic imaging and automated quantitative analyses of articular and periarticular structures. More recently, additional technologies were introduced, including positron emission tomography (PET)-MRI, weight-bearing computed tomography (CT), photon-counting spectral CT, shear wave elastography, contrast-enhanced ultrasound, multiscale X-ray phase contrast imaging, and spectroscopic photoacoustic imaging of cartilage. On top of these, we now live in an era in which artificial intelligence is increasingly utilized in medicine. Osteoarthritis imaging is no exception. Successful implementation of artificial intelligence (AI) will hopefully improve the workflow of radiologists, as well as the level of precision and reproducibility in the interpretation of images.

Summary: Background: Cartilage damage in inflammatory arthritis is attributed to inflammatory cytokines and pannus infiltration. Activation of the coagulation system is a well known feature of arthritis, especially in rheumatoid arthritis (RA). Here we describe mechanisms by which fibrin directly mediates cartilage degeneration. Methods: Fibrin deposits were stained on cartilage and synovial tissue of RA and osteoarthritis (OA) patients and in murine adjuvant-induced arthritis (AIA) in wild-type or fibrinogen deficient mice. Fibrinogen expression and procoagulant activity in chondrocytes were evaluated using qRT-PCR analysis and turbidimetry. Chondro-synovial adhesion was studied in co-cultures of human RA cartilage and synoviocytes, and in the AIA model. Calcific deposits were stained in human RA and OA cartilage and in vitro in fibrinogen-stimulated chondrocytes. Findings: Fibrin deposits on cartilage correlated with the severity of cartilage damage in human RA explants and in AIA in wild-type mice, whilst fibrinogen deficient mice were protected. Fibrin upregulated Adamts5 and Mmp13 in chondrocytes. Chondro-synovial adhesion only occurred in fibrin-rich cartilage areas and correlated with cartilage damage. In vitro, autologous human synoviocytes, cultured on RA cartilage explants, adhered exclusively to fibrin-rich areas. Fibrin co-localized with calcification in human RA cartilage and triggered chondrocyte mineralization by inducing pro-calcification genes (Anx5, Pit1, Pc1) and the IL-6 cytokine. Similar fibrin-mediated mechanisms were observed in OA models, but to a lesser extent and without pseudo-membranes formation. Interpretation: In arthritis, fibrin plaques directly impair cartilage integrity via a triad of catabolism, adhesion, and calcification. Funding: None.

Tyrosine kinase inhibitors (TKIs) are nowadays a valuable treatment of desmoid tumors, a rare mesenchymal neoplasm. Although many side effects of imatinib and pazopanib, commonly or rarely occurring, have been described, reactional lymphadenopathy has not yet been reported. In this publication, we report two cases of patients with desmoid tumors, treated with pazopanib and imatinib, who developed reactional lymphadenopathy. As this side effect is presented as a newly formed mass, it can result in new diagnostic questions and added imaging tests and can even lead to discontinuation of the treatment. This report may help the clinicians facing similar problems adopt a “watch and wait” approach.

We performed case-control studies using 2 Canadian cohorts to examine the role of 10 promising Alzheimer's disease (AD) loci identified in recent genomewide association studies. Patients age 65 years and older diagnosed with AD at baseline (prevalent cases) or who developed AD during follow-up assessments (incident cases) were compared with control subjects with no cognitive impairment. Our prevalent case study comparing prevalent AD cases (n = 428) with participants with no cognitive impairment (n = 524) revealed a significant association of rs6656401 and rs3818361 (CR1), rs2075650 (TOMM40), rs7561528 (BIN1), and rs3865444 (CD33) with late-onset AD that were robust to adjustment with age and apolipoprotein E ε4 genotype. The incident case study comparing patients who developed AD during longitudinal observation (n = 152) with participants with no cognitive impairment found that rs2075650 (TOMM40) and rs3865444 (CD33) influence the risk of developing AD in this population. In addition, pooled analysis of our AD patients confirmed that CR1, TOMM40, BIN1, and CD33 contribute to late-onset AD susceptibility, in addition to apolipoprotein E.