Citations

Abstract Background Gastrointestinal (GI) cancer remains a major global health challenge. This study provides updated 2022 estimates of GI cancer incidence and mortality worldwide, along with projections of incident cases and deaths through 2050 to inform cancer control strategies. Methods In this population‐based study, data from the GLOBOCAN 2022 database were used to examine incidence and deaths associated with GI cancer. By using global demographic projections, this study estimated the projected number of incident cases and deaths until the year 2050. Results By 2050, the global burden of GI cancer is projected to reach 9.06 million incident cases (+85%) and 6.42 million deaths (+93%) from 2022. Increases in incidence are projected for both females (+87%) and males (+83%), as are increases in mortality for both females (+97%) and males (+91%). Whereas the Western Pacific region will have the highest absolute burden, with 3.88 million new cases and 2.79 million deaths, the greatest relative increase is expected in Africa, with incidence and deaths rising by 157% and 160%, respectively. As measured by the Human Development Index (HDI), the steepest increases are projected in low (+151% incidence; +152% deaths) and medium (+112% incidence; +114% deaths) HDI countries. Overall, all GI cancer types are projected to increase, led by pancreatic cancer in incidence (+95%) and colorectal cancer in deaths (+103%). Conclusions GI cancer incidence and deaths are expected to nearly double by 2050, with increases across sexes, cancer types, and regions, especially in lower HDI countries.

ABSTRACT Objective To determine the test performance of cutaneous phosphorylated alpha‐synuclein (P‐SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. Methods This is the first subgroup analysis of the Synuclein‐One study, a prospective, blinded study evaluating P‐SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control ( N = 151) and DLB ( N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P‐SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40–99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. Results After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P‐SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. Interpretation In this prospective, blinded, cross‐sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P‐SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P‐SYN detected. These results support a role for skin biopsy detection of P‐SYN in patients with DLB. Trial Registration NCT04700722

ABSTRACT Aims To investigate whether the association between the nitrite‐generating capacity of the subgingival microbiome and early cardiometabolic risk biomarkers varies by dietary nitrate intake. Materials and Methods Cross‐sectional data from 668 participants (mean age 31 ± 9 years, 73% women) were analysed. Dietary nitrate intake was calculated from food frequency questionnaires. Subgingival 16S rRNA sequencing (Illumina, MiSeq) and PICRUSt2 estimated microbial genes. The Microbiome‐Induced Nitric Oxide Enrichment Score (MINES) was calculated as a ratio of microbial gene abundances representing enhanced net capacity for NO generation. Adjusted multivariable linear models regressed cardiometabolic risk biomarkers (HbA1c, glucose, insulin, insulin resistance (HOMA‐IR), blood pressure) on nitrate intake and MINES together with a MINES × nitrate intake interaction term. Results Mean nitrate intake was 190 ± 171 mg/day. Significant interactions of MINES and nitrate intake were observed for insulin and HOMA‐IR ( p < 0.05). Among participants with a low MINES, higher nitrate intake was associated with lower HOMA‐IR (1.2 [1.1–1.4] vs. 1.5 [1.3–1.6]; p = 0.002), but levels were similar in those with high MINES ( p = 0.84). Conclusions A biomarker of higher microbial NO‐generating capacity in subgingival plaque is associated with lower insulin and insulin resistance among individuals with lower dietary nitrate intake. Future trials evaluating the cardiometabolic benefits of nitrate‐rich diets should incorporate measures of the entire oral microbiome.

Abstract Background Even among cognitively unimpaired (CU) older adults, specific patterns of neuropsychological performance impart differential risk for progression to Alzheimer's disease and related dementias (ADRD). Early identification in the prodromal phase may inform early intervention efforts. We used a data‐driven approach to classify neuropsychological phenotypes within CU older adults from the Atherosclerosis Risk in Communities (ARIC) study and tested for differences in ADRD and cerebrovascular outcomes. Method Participants included 4737 CU (via a previously published algorithm plus consensus diagnosis protocol) older adults (mean age=75.1 years, 60.8% female, 23.1% Black) with neuropsychological data from Visit 5 (2011‐2013) of the ARIC study. Latent profile analysis was leveraged to identify unique cognitive phenotypes using 10 demographically adjusted (age, sex/gender, education, race‐center, WRAT Reading) neuropsychological z‐scores. Cognitive phenotypes were then compared on demographics, depressive symptoms, and vascular risk factors (VRFs). In a subset with available neuroimaging and biofluid data ( n range=1102‐1678), white matter hyperintensity (WMH) and bilateral hippocampal (HV) volumes normalized for intracranial volume and plasma biomarkers (i.e., Aβ42/40, ptau181, NfL, and GFAP) were examined by phenotype. Phenotype comparisons adjusted for demographic variables, VRFs, and an indicator of kidney function (i.e., eGFR‐creatinine) for plasma biomarkers. We applied Tukey adjustment for pairwise comparisons. Result A 6‐class solution of cognitive phenotypes emerged as the best fitting model: Average Overall (28%), Low Overall/Very Low Memory (7%), Average Overall/Super Memory (11%), Subtle Low Overall/Low Executive (22%), Subtle Low Executive/High Memory (13%), and Average Overall/Low Memory (19%; Figure 1). Phenotypes differed on education, race, and word reading, despite prior adjustments for these variables when creating the neuropsychological z‐scores (Table 1). Additionally, phenotypes differed on depressive symptoms, VRFs, WMH, HV, Aβ42/40, and ptau181 (all p s < .05). The Subtle Low Overall/Low Executive group had the highest WMH volumes, the Subtle Low Executive/High Memory group had the lowest Aβ42/40, and the Low Overall/Very Low Memory group had the lowest HV and highest levels of plasma ptau181 (Table 2). Conclusion Cognitive heterogeneity is observed even among CU older adults, with lower executive performance associated with cerebrovascular changes and lower memory associated with certain AD‐related changes, possibly indicating risk for cognitive progression through distinct pathways.

Abstract Background Agitation is a clinically significant symptom contributing to behavioral and psychological symptoms of dementia (BPSD) but is poorly understood across the different syndromes related to Frontotemporal Lobar Degeneration (FTLD). This study investigates sex differences in agitation across FTLD‐related syndromes and its relationship to various neuropsychiatric symptoms (NPS). Method We analyzed data from 1,654 participants (916 males, 738 females; average ages 65.8 and 65.9, respectively) from the National Alzheimer's Coordinating Center (NACC) and ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study with a FTLD‐related syndrome: behavioral variant FTD (bvFTD), Primary Progressive Aphasia (non‐fluent variant (nfvPPA), semantic variant (svPPA)), Corticobasal syndrome (CBS) and Progressive Supranuclear Palsy (PSP). Participants’ symptoms were assessed using the Neuropsychiatric Inventory (NPI). Prevalence ratios and odds ratios were computed to assess the likelihood of NPS comorbidities when agitation was present in males and females. Principal Component Analysis (PCA) was performed to identify NPS associated with agitation and how they varied by sex. Result Males were more likely to experience anxiety (bvFTD: p <0.001, CBS: p <0.01, PSP: p <0.0001), apathy (nfvPPA: p <0.01, PSP: p <0.01), depression (bvFTD: p <0.0001, PSP<0.01), disinhibition (nfvPPA: p <0.0001), PSP: p <0.001), and motor symptoms (bvFTD: p <0.01, CBS: p <0.01) when agitation was present. In contrast, females had a higher likelihood of experiencing disinhibition in svPPA ( p <0.001). These findings suggest that agitation is associated with a wider range of NPS in males than in females. Agitation and NPS are especially prominent in males with PSP. Conclusion This study reveals significant sex differences in NPS in FTLD‐related syndromes when agitation is present. Males and especially PSP, are more likely to experience a broader range of NPS in association with agitation. These findings underscore the need for further investigation into the underlying mechanisms driving these sex differences, particularly focusing on the neurobiological impact of agitation, the recognition of symptoms in the presence of greater behavioral disturbances, and potential variations from informant reports. Understanding these factors will provide valuable insights into the role of agitation in the presentation of NPS across FTLD‐related syndromes. Ultimately, addressing these gaps will enhance our ability to effectively treat and manage agitation in both male and female patients with FTLD‐related syndromes.

Abstract Background Staging disease severity in dementia research requires input from an informant. The Clinical Dementia Rating Sum of Boxes (CDR) is the most used instrument for staging in Alzheimer's Disease (AD); but has been expanded to stage patients with frontotemporal lobar degeneration (FTLD) with the CDR PLUS NACC‐FTLD. An informant effect on the CDR has been reported in AD. The aim of this study is to evaluate whether informant characteristics influence the CDR PLUS NACC‐FTLD in a large cohort of participants with frontotemporal dementia (FTD). Method We included participants with a FTLD‐related syndrome from the ALLFTD study. We included participants with a CDR PLUS NACC‐FTLD higher than 0, information on the Montreal Cognitive Assessment (MoCA) scores, and the Neuropsychiatric Inventory Questionnaire (NPI‐Q). We performed a conditional growth model using multilevel linear regression analysis. We performed an exploratory stratified analysis by patient sex. Result We included 1411 participants, totalling 2063 visits. The patient's age at the initial visit was 64.7±9.4 years and 44.0% were females. Females were 69.2% of the informants, and the relationship was 79.1% spouse or partner, 10.6% children, 4.1% were siblings and 6.2% other. The CDR PLUS NACC‐FTLD scores were affected by informant characteristics. The CDR PLUS NACC‐FTLD scores were 0.41 (CI 95%:0.08 to 0.75) higher with female informants. The frequency of visits was associated with a CDR PLUS NACC‐FTLD score 0.86 higher (CI 95%:0.17 to 0.56) when visiting at least once a week, 1.46 higher (CI 95%:0.46 to 2.47) when visiting daily, and 0.83 higher (CI 95%:0.06 to 1.60) when living with the patient compared with visiting less than once a week. As expected, CDR‐FLTD scores increased with lower MoCA and higher NPI‐Q scores. In the stratified analysis by sex, we found that female informant was associated with higher CDR PLUS NACC‐FTLD scores only when patients were male. Conclusion We found that the CDR PLUS NACC‐FTLD is influenced by informant sex and frequency of visits in patients with FTLD‐related syndromes. These results are similar to those observed in AD patients and underscore the need to recognize that informant characteristics may impact dementia severity scales.

Abstract Background Our group recently performed the largest‐to‐date X‐chromosome wide association study (XWAS) of Alzheimer's disease (AD). Here, we expand on this with additional samples, novel sex‐ and APOE *4‐stratified analyses, and evaluate escape from random X chromosome inactivation (eXCI) to better capture female‐biased risk genes. We then integrate these results with XWASs of various AD‐relevant traits to elucidate shared genetic signals and ultimately uncover novel AD risk genes and mechanisms. Method The AD XWAS design is shown in Figure 1A and includes random X chromosome inactivation (rXCI) and eXCI models. We further assessed suggestive AD signals ( p <1x10 ‐3 ) for pleiotropy using genetic colocalization with 2852 AD‐relevant traits (Figure 2A). Loci exhibiting X chromosome‐wide significance ( p <1x10 ‐5 ) or apparent trait colocalization underwent quantitative trait locus (QTL) colocalization analyses across 62 tissues and cell types to functionally prioritize AD risk genes. Result Full sample analyses reproduced Belloy et al. 2024 findings and identified 3 additional loci, including a male‐specific signal near GLUD2 that impacts glutamate/glutamine metabolism (Figure 1B). APOE *4‐stratified analyses revealed 9 additional loci, including 3 eXCI hits in APOE *4 carriers (Figure 1C‐D). Pleiotropy colocalization identified 38 loci, most being novel and many driven by eXCI and/or female‐specific AD XWAS, including MOSPD2, PNMA3 and GABRE loci that showed extensive colocalization with brain imaging traits (Figure 2B). The most significant XWAS locus, SLC9A7 , colocalized with total testosterone, HDL‐C, and various brain imaging traits. Only the NLGN4X locus colocalized with amyloid positivity, linking its proposed role in synaptic dysfunction to amyloid pathology. The locus at KDM6A , previously implicated as an AD resilience gene, colocalized with a functional MRI (fMRI) phenotype. QTL colocalization analyses confirmed gene prioritizations in Belloy et al. 2024, and additionally provided support for PNMA3 , an antigen highly expressed in the brain, and 3 APOE ‐stratified loci, including ACLS4 , which impacts lipid metabolism. Conclusion This study provides novel insights into biological mechanisms that contribute to X‐linked genetic risk for AD in an APOE *4 and sex‐specific manner, identifying various novel risk loci. Notably, 29 female‐biased risk loci were uncovered, which may shed light on sex disparities in AD. Overall, our findings will aid in elucidating AD pathways and drug targets relevant to personalized medicine.

Abstract Background In recent years, blood‐based biomarkers (BBMs) have transformed the diagnostic landscape of Alzheimer’s disease (AD), with some now approaching readiness for clinical implementation. This progress aligns with the growing importance of accurate early diagnostics and availability of anti‐Aβ therapies for the treatment of early symptomatic AD, reinforcing the need for more rapid and early diagnostic capabilities. To address this need, the Alzheimer’s Association convened a multidisciplinary panel of clinical experts, subject‐matter specialists, and guideline methodologists to conduct a systematic review and develop evidence‐based recommendations for the use of BBMs in the diagnostic evaluation of AD. The scope of this guideline is focused on individuals with cognitive impairment ‐ either MCI or dementia ‐ who are undergoing diagnostic assessment in secondary or tertiary care settings. Method The panel conducted a systematic review to assess BBMs' diagnostic test accuracy in detecting amyloid pathology for triaging (≥90% sensitivity, ≥75% specificity) and confirmatory (≥90% sensitivity and specificity) diagnostic workup. The BBMs of interest included plasma p ‐tau and Aβ tests measuring the following analytes: p ‐tau217, % p ‐tau217, p ‐tau181, p ‐tau231, and Aβ42/Aβ40 ratio. The reference standard tests included CSF, amyloid PET, or neuropathology examination. The panel applied the GRADE approach to assess the certainty of the evidence and the GRADE Evidence‐to‐Decision Framework to develop its recommendations. Result Across 49 observational studies meeting eligibility criteria, 31 different BBM tests were evaluated. Using predefined decision thresholds, the panel determined whether each test has 1) sufficient diagnostic test accuracy to be used as a triaging test where a positive test is to be confirmed by PET or CSF, 2) sufficient diagnostic test accuracy as a confirmatory test to replace PET or CSF, or 3) insufficient diagnostic test accuracy to recommend current use in clinical practice. Recommendations will be provided in case any BBMs met a priori DTA thresholds. Conclusion BBMs can improve early AD diagnosis and expand access to disease‐modifying therapies. Evidence‐based guidelines are key to standardizing their use and will be updated as new evidence and applications emerge.