Citations

The Concise Guide to Pharmacology 2025/26 marks the seventh edition in this series of biennial publications in the British Journal of Pharmacology. Presented in landscape format, the guide provides a comparative overview of the pharmacology of drug target families. The concise nature of the Concise Guide refers to the style of presentation, being clear, accessible, and well‐structured, rather than the scope of the content, which spans approximately 500 pages. The Concise Guide summarises the key pharmacological properties of around 1900 human drug targets, and nearly 7000 interactions, involving around 4400 ligands. While the content is a substantially condensed version of the more detailed information and links available at the www.guidetopharmacology.org website, the printed guide serves as a permanent, citable, point‐in‐time record, that remains stable despite ongoing updates to the online database. The full contents of this publication can be found at https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70233 . The Concise Guides provide expert‐curated recommendations of ‘Gold Standard’ selective pharmacological tools, available either commercially or as donations, which enable the identification of individual drug targets or families of drug targets. While the Concise Guide offers a more streamlined overview, more comprehensive information, including detailed pharmacological profiles and links to multiple online databases, is available through the Guide to Pharmacology website. The 2025/26 edition of the Concise Guide is based on material current as of mid‐2025, and supersedes all previous editions, including the 2023/24 Guide, and earlier Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), and as such provides official IUPHAR classification and nomenclature for human drug targets, where applicable. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. Each section includes nomenclature guidance, concise summaries, information of the best available pharmacological tools, key references, and suggestions for further reading.

Abstract Molecular profiling of human primary cell types is essential for understanding human biology. We present a transcriptome and proteome map of 28 primary human cell types. Three major clusters of epithelial, endothelial, and mesenchymal cell types were observed in both the transcriptome and proteome levels along with the discovery of cell type enriched molecules including GRAP and C1orf116. The epithelial cell specific protein C1orf116 was further validated using immunohistochemistry across various human tissues. An exhaustive protein database search considering 39 post-translational modifications (PTMs) revealed novel insights into the PTM landscape including identification of understudied PTMs such as serine O-acetylation and histidine methylation. This also enabled comprehensive characterization of proteins with diverse PTMs. Interestingly, an unexpectedly higher frequency of dioxidation on tryptophan compared to methionine led to the identification of oxidative mitochondria complex subunit proteins. Further, a search strategy accounting for alternative translational start sites, splice junctions and translational readthrough refined genome annotation using proteomic evidence. For example, peptides from translational readthrough including extended sequence of LDHB and MDH1 were detected representing the first peptide-level evidence of these protein readthrough isoforms. Our comprehensive transcriptome and proteome data revealed cell type-specific molecular cues and heterogeneity, offering new insights into disease mechanisms often overlooked by tissue proteomics.

Abstract Background Bedside cognitive screening tools intend to reliably and efficiently detect cognitive impairment in research, clinical, and community settings. Black American (BA) and Hispanic/Latino (H/L) adults obtain lower performance on widely used screeners, largely driven by demographics and structural and social determinants of health (SSDoH). This study characterized the performance of the Montreal Cognitive Assessment (MoCA) performance in a cohort of cognitively normal ethnoracially diverse adults while considering cohort‐specific factors that contributed to misclassification of impairment. Method Cognitively normal BA and H/L participants completed a comprehensive neurological assessment, neuropsychological testing, and MRI and amyloid‐ and tau‐PET imaging as part of a longitudinal study of memory and aging at Mayo Clinic in Florida. Demographically adjusted MoCA cutoffs were applied to BA (MoCA ≤ 22) and WH/L (MoCA ≤ 24) subgroups. Hierarchical binary logistic regression assessed whether amyloid burden (Centiloid value) improved prediction of scoring below demographically adjusted MoCA cutoffs beyond demographic/SSDoH factors, including age, education, and Area Deprivation Index (ADI). Result Participants included 105 (47 WH/L, 58 BA/AA) cognitively normal adults (mean age = 64.71 years, SD = 8.91; 62.9% female) with average of 16.07 years of education (SD=2.35) and mild‐to‐moderate neighborhood disadvantage (mean ADI=47.60, SD=23.77). 40% of H/L participants (MoCA (≤ 24) and 17% of BA participants (MoCa ≤22) scored below demographically adjusted MoCA cut‐offs. For the H/L subgroup, the best fitting model included age, education, ADI, and amyloid burden ( R 2 = 0 .43, χ 2 = 10.98, p = 0.03). Age (OR=1.21, 95% CI: 0.986 – 1.487) and amyloid burden (OR = 0.83, 95% CI: 0.67 – 1.03) approached statistical significance as individual predictors ( p = 0.06, p = 0.09). In the BA/AA subgroup, the best fitting model included age, education and ADI only ( R 2 = 0.47, χ 2 = 9.06, p = 0.02), with education approaching significance as an individual predictor (OR=0.46, 95% CI: 0.21 – 1.01, p = 0.05). Conclusion Sociodemographic factors continued to drive low MoCA performance in cognitively normal individuals despite applying demographically adjusted cut‐off scores by subgroup. These factors differentially impacted performance among BA/AA and WH/L participants. Careful consideration of these factors is warranted to mitigate risk of overdiagnosing impairment based on cognitive screening across clinical and research settings.

Abstract Background Alzheimer's disease (AD) exhibits significant genetic heterogeneity, with no single model fully explaining its inheritance pattern. Structural variants (SVs) may contribute to the missing heritability of AD, particularly in disease pathology and familial AD, which remain largely unexplored. Method Structural variants (SVs) were analyzed in unrelated 1,162 individuals from the ROSMAP study (687 cognitively normal (CN), 475 AD patients), as well as 197 Non‐Hispanic White (NHW) families (926 individuals, 58.5% with AD) and 214 Caribbean Hispanic (CH) families (1,340 individuals, 59.17% with AD). Large insertions and deletions were identified using Manta, Absinthe, and MELT from whole‐genome sequencing, supplemented by Sniffles2 and external SV call sets. This approach generated a unified VCF file containing 45,251 insertions and 76,566 deletions. After filtering for missingness rate and allele counts, a total of 9,290 insertions and 9,529 deletions were retained for analysis. Genome‐wide SV analyses were performed with AD‐related metrics in ROSMAP, adjusting for age, sex, and principal components, and validated in an independent ADSP replication cohort comprising 29,055 unrelated individuals (17,110 CN and 11,945 AD patients). Result We identified nine SVs (one insertion and eight deletions) segregating in AD families. An insertion near PDCD10 in NHW families reached genome‐wide significance ( p <5×10 ‐8 ) for AD risk in the replication cohort. Two deletions in KIF26B and SPHKAP were found in both CH and NHW families, while five appeared only in NHW and one in CH. All eight deletions showed genome‐wide significance for AD risk. SV GWAS on AD pathologies in ROSMAP revealed an insertion in INPP4B with the strongest association to global brain pathology (β=0.19; p = 2.32×10 ‐5 ), also linked to pathological AD, diffuse plaques, and Braak staging. A deletion near ADGRB1 (β=1.53; p = 5.05×10 ‐6 ) was associated with neuritic plaques, and another near ARMC2 (β=1.66; p = 2.17×10 ‐6 ) was linked to diffuse plaques. All three SVs associated with AD ( p <5×10 ‐6 ) in replication. Conclusion Our findings reveal numerous SVs segregating in familial AD across both CH and NHW families, as well as additional SVs linked to sporadic AD. Prioritizing these SVs based on their potential effects on gene function and expression will provide deeper insight into their contributions to both familial and sporadic AD.

Abstract Background Apolipoprotein E (APOE), the major genetic risk factor for Alzheimer's disease (AD), has three common alleles (2, 3 and 4), giving rise to genotypes that are associated with six levels of AD risk: (2/2<2/3<3/3<2/4<3/4<4/4). In our new Arizona APOE Cohort Study, we have begun to establish a longitudinal cohort of more than 300 cognitively unimpaired persons (50‐90 year‐old) stratified by APOE genotype and age decile, matched by age and sex, and have an extensive battery of cognitive, clinical, amyloid (NAV4694) and tau (MK6240) PET, MRI, cerebrospinal fluid (CSF), plasma, and DNA. The study is intended to clarify the impact of APOE4 and APOE2 allelic dose on the predisposition to and protection from AD and inform the design of secondary and primary prevention therapies. Here, we describe the study and the resource of data and samples that are now available to researchers. Methods Participants were recruited from across the United States using GeneMatch and other sources. Comprehensive clinical assessments, brain images, and lumbar punctures are performed every 2 years, 50mL blood samples are acquired annually, and whole genome sequencing is in progress. Results As of January 2025, baseline assessments were completed in 303 participants, 68±9 years of age, including 205 females and 98 males. Sixteen percent are from underrepresented groups. Baseline CSF samples were obtained in 89% of the participants. The complete cohort consists of 17, 63, 41, 65, 66, and 51 persons with the APOE 2/2, 2/3, 3/3, 2/4, 3/4, and 4/4 genotype, respectively. In the first 287 participants with available amyloid PET scans 6% of 2/2, 5% of 2/3, 14% of 3/3, 26% of 2/4, 29% of 3/4, and 52% of 4/4 participants had a positive amyloid PET (≥20 centiloids). Conclusions Building up on our decades of experience in APOE research, we launched the new Arizona APOE Cohort which promises to provide a valuable resource of data and samples to advance the study of APOE, its variants and interactions with other risk and protective factors, and the development, treatment, and prevention of AD. Baseline data are now available to interested and eligible research collaborators.

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 Disparities in structural and social determinants of health in Latino and Black communities may increase the burden of Alzheimer disease and related dementias (ADRD). Identifying dementia risk factors, which may account for up to 45% of ADRD risk, is crucial to implement effective risk‐reduction strategies. This study aimed to assess ADRD risk factors in community‐dwelling, cognitively normal, Latino and Black Americans by measuring the frequency of modifiable dementia risk factors through subjective and objective measures. Method Community‐dwelling, cognitively normal, Latino and Black adults (≥45‐years‐old) were enrolled in a longitudinal study of memory and aging at Mayo Clinic in Jacksonville, Florida. Baseline assessments conducted between Mach 2022 and November 2024 included demographics, self‐reported race/ethnicity, and history of dementia risk factors. Socioeconomic deprivation [Area Deprivation Index (ADI) State scores] and modifiable dementia risk factors were reported by participants and directly measured, including hypertension (BP >130/80 mmHg), obesity (BMI≥30), hyperlipidemia (LDL>100 mg/dL), hyperglycemia (HbA1C >5.6%), low vitamin B12 (B12<350 pg/mL), hearing loss (bedside assessment), vision loss (bedside assessment), and depression (Geriatric Depression Scale ≥5). Result 105 participants (47 Latino, 55 Black), 64.7 (±8.8) years‐old, female 66 (63%), with 16 (±2.3) years of education were assessed. Black participants experienced higher socioeconomic deprivation than Latino participants (median ADI 7 vs 3; p <0.001). Dementia risk factors were common in Latino and Black participants. These included, hypertension (55.3%, 70.3%; p = 0.291), hyperlipidemia (58.7%, 55.8%; p = 0.908), obesity (29.8%, 45.5%; p = 0.263), hyperglycemia (51.1%, 49.1%; p = 0.834), low vitamin B12 (23.9%, 28.0%; p = 0.270), hearing loss (19.1%, 7.3%; p = 0.111), vision loss (85.1%, 85.2%; p = 0.771), and depression (6.4%, 5.5%; p = 0.168). Objective measures revealed a higher frequency of risk factors compared with participant‐provided history, highlighting a substantial proportion of unrecognized or inadequately treated risk factors: hypertension (62.3%, 45.1%; p = 0.067), hyperlipidemia (57.6%, 47.5%; p = 0.004), hyperglycemia (49%, 20%; p = <0.001), vitamin B12 deficiency (27.8%, 9.3%; p = 0.170), and depression (6.9%, 11.9%; p = 0.009). Conclusion Modifiable dementia risk factors were detected in most cognitively normal Latino and Black adults engaged in a longitudinal study of memory and aging. Objective measures highlighted unrecognized and undertreated risk factors. Active surveillance programs are needed to detect and treat modifiable ADRD risk factors in underrepresented populations.

Abstract Background Amyloid related imaging abnormality edema (ARIA‐E) occurs in about 19% of individuals with autosomal dominant Alzheimer disease (ADAD) treated with an anti‐amyloid‐b monoclonal antibody (Salloway et al., 2021). In a previously reported case, ARIA‐E appeared to colocalize with decreases in PiB‐PET uptake (Joseph‐Mathurin, Llibre‐Guerra, et al, 2022), suggesting an association between amyloid‐b (Aβ) removal and ARIA‐E. Here, we compare longitudinal neuroimaging and corresponding neuropathology in an ADAD individual treated with gantenerumab, who experienced multiple ARIA‐E episodes as sulcal effusions that resolved by the end of the four‐year trial. Methods PiB‐PET and MRI were collected pre‐ and post‐randomization (2 and 4 years). The participant consented to brain donation, which was received a year after trial completion. Four tissue samples were taken from the location of the ARIA‐E in the parieto‐occipital left hemibrain as identified by MRI (one block contained the sulcus affected by ARIA‐E; the rest of the coronal section was captured in the remaining three blocks). Area fractions (AFs) of Aβ (10D5 immunohistochemistry (IHC)), tauopathy (PHF1), microglia (Iba1), and astrocytes (GFAP) in one sulcal region of interest (ROI) from each block and PiB‐PET SUVRs of corresponding ROIs were extracted ( n = 4, Figure 1). Additionally, we included PiB‐PET SUVRs corresponding to ARIA‐E findings observed in the right hemisphere at baseline, two‐year, and four‐year visits ( n = 6). Results Overall PiB‐PET uptake increased during the first two years (before ARIA‐E) and decreased during the last two years (including ARIA‐E episodes) (0.03±0.05 vs. ‐0.04±0.04 SUVR/year, p ‐value=0.01, Figure 2). The decrease seemed more pronounced in ARIA‐E ROIs versus normal‐appearing sulcus ROIs (‐0.05±0.04 vs. ‐0.02±0.03 SUVR/year). Lower PiB uptake at last visit appeared associated with lower Aβ AF (estimates=0.03±0.01, p ‐value=0.07). The ARIA‐E ROI had an Aβ AF of 0.009 while normal‐appearing sulcus ROIs had a mean of 0.02+0.003 (Figure 3). AFs for tauopathy, microglia, and astrocytes were within the range of those of normal‐appearing sulcus ROIs, suggesting an Aβ‐specific effect, although unexamined markers may play a role. Conclusions Our preliminary findings indicated that ARIA‐E is associated with longitudinal PiB‐PET decrease and Aβ AF, supporting the link between ARIA‐E, changes in PiB‐PET, and local Aβ removal observed at autopsy. Funding : K01AG080123; U01AG042791; R01AG046179; R01AG053267

Abstract Objective To compare the pathology outcomes of image-guided breast biopsies across a multistate health care enterprise by the method of detection (MOD), including the positive predictive value (PPV3) and histological types. Methods Biopsies from October 31, 2017, to July 6, 2023, across 18 imaging sites in 4 states were extracted. Radiologists prospectively assigned MODs, including symptomatic presentations (self-examination, clinical examination) and imaging modalities (mammogram, tomosynthesis, US, MRI, contrast-enhanced mammogram, molecular breast imaging, other imaging). For each MOD, the rates of malignancy and cancer subtypes were calculated. Univariate and multivariate logistic regression analyses were performed. Results In 26 932 biopsies on 22 582 patients (mean age 57.6 years ± 14.2 [SD]; 22 416 women), 6068 (81.1%) cancers were detected by screening, and 1144 (15.3%) were detected by symptoms. Symptomatic presentation MODs had a higher PPV3 (43.0% vs 25.6%; P &lt; .001), larger cancer lesion sizes (x̄ = 27.5 mm vs x̄ = 17.8 mm; P &lt; 001), and a higher association with invasive carcinoma (96.7% vs 76.8%; P &lt;.001) compared with screening imaging-based MODs. Methods of detection with higher PPV3s also tended to have higher rates of invasive carcinoma (Spearman’s ρ = 0.83). Conclusion Compared with breast cancers detected after symptomatic presentations, those identified via image-based screening were smaller and less often invasive, confirming the value of screening in early detection. Positive predictive value and the rate of invasive carcinoma varied in parallel across MODs.

Abstract Geroscience research benefits from interdisciplinary approaches, team science, and collaborations, which collectively facilitate the discovery of aging mechanisms and their translation into tangible, clinical interventions. Since its inception in 2019, the Midwest Aging Consortium (MAC) has provided an engaging platform for aging researchers in the United States’ Midwest to connect, collaborate, and exchange ideas. The Sixth Annual Research Symposium of the MAC held at the Mayo Clinic in Rochester, Minnesota, in April 2025 highlighted the continued impact of the MAC in bringing together aging researchers, including many trainees and early career investigators, into a collaborative environment. This record-setting event featured interdisciplinary research on key aging mechanisms, including lipid metabolism, mitochondrial dysfunction, stress response, cellular senescence, and immune adaptations across organ systems. New therapeutic concepts and clinical trial approaches were presented. Cutting-edge methodologies including single-cell and spatial transcriptomics, metabolomics, and organoid cultures, to dissect aging process in tissue-specific and systemic contexts also were presented. Overall, the MAC symposium underscored the translational potential of geroscience and reinforced the MAC’s mission to accelerate aging research through regional collaborations and innovation.