Neurología Cognitiva.artículos

Identification of genetic modifiers of autosomal dominant Alzheimer's disease: a genome-wide association study

2026-06-01T00:00:00Z

Identification of genetic modifiers of autosomal dominant Alzheimer's disease: a genome-wide association study Patel, Maulikkumar; Feng, Wei; McKay, Nicole S.; Millar, Peter R.; Liu, Menghan; Yang, Chengran; Cetin, Arda; Johnson, Matthew; Budde, John P.; Western, Daniel; Marsh, Thomas W.; Saliu, Ibrahim O.; Gordon, Brian A.; Llibre Guerra, Jorge J.; Morris, John C.; Bateman, Randall J.; Allegri, Ricardo Francisco; Chrem Méndez, Patricio Alexis; Surace, Ezequiel Ignacio; Vázquez, Silvia Background: Individuals with autosomal dominant Alzheimer's disease (ADAD) arising from mutations in PSEN1, PSEN2, or APP exhibit variability in clinical presentation. Genetic studies of ADAD have shaped our understanding of the disease, and the discovery of genetic modifiers can inform therapeutic interventions and improve patient outcomes. We aimed to discover new genetic modifiers in individuals with mutations in the three ADAD genes. Methods: In this genome-wide association study, we analysed data from participants in three study cohorts (the Knight Alzheimer Disease Research Center [Knight-ADRC], the Dominantly Inherited Alzheimer Network [DIAN] observational study, and the Alzheimer Disease Sequencing Project [ADSP] R4). We did whole-genome sequencing on 101 unrelated, non-Hispanic, White, symptomatic participants with ADAD mutations and 5050 asymptomatic, unrelated control participants. Sensitivity analyses included related participants (148 cases and 5813 controls). We assessed the molecular mechanisms associated with each risk variant, including cis-regulatory effects, plasma protein levels (Knight-ADRC, 2338 participants), CSF concentrations of Alzheimer's disease biomarkers (DIAN, 64 participants), and neuroimaging data (MRI and PET; DIAN, 64 participants). We evaluated the association of risk variants with age at onset in ADAD and in 6177 participants with sporadic Alzheimer's disease (ADSP R5). Findings: Three genome-wide loci with significant risk were associated with ADAD risk, irrespective of the specific ADAD gene mutation. The CNIH4 locus association was driven by a missense variant (is caused by Gly54Ser, p<0·0001, odds ratio [OR] 11·99 [5·39-26·64]). The CCNG1 locus risk allele increased the risk of Alzheimer's disease (p<0·0001, OR 9·56 [4·29-21·24]) and reduced the age at dementia onset (p=0·0068, β=-10·15 [95% CI -17·31 to -2·77]). This allele was also positively associated with Tar DNA binding protein 43 (TDP-43) plasma protein levels and a larger gap between chronological age and structural MRI predicted brain age. The RHOJ risk allele (p<0·0001, OR 5·96 [3·42-10·36]) was associated with increased the risk of Alzheimer's disease, higher CSF total tau (p=0·0056, β=358·37) and phosphorated tau 181 (pTau181; p=0·0006, β=81·28), and lower Aβ42/Aβ40 ratio (p=0·016, β=-0·11) in DIAN ADAD participants, comparing those carrying the risk allele with those not carrying it. Interpretation: Our findings provide potential insights into disease biology, emphasising the role of Aβ, tau, TDP-43, astrocytes, and angiogenesis in Alzheimer's disease aetiology. This study offers invaluable insight for family genetic counselling and future clinical trial designs. Funding: National Institute of Health, National Institute on Aging, Alzheimer's Association, Hope Center Pilot 2025 Award, NGI Pilot Grant 2025 Award, BrightFocus Foundation, UK Dementia Research Institute at University College London, UK National Institutes for Health and Care Research University College London Hospitals Biomedical Research Centre, Dominantly Inherited Alzheimer Network, Freedom Together Foundation.

Conmociones cerebrales en el fútbol: avances recientes y desafíos en la gestión clínica y preventiva

2026-08-01T00:00:00Z

Conmociones cerebrales en el fútbol: avances recientes y desafíos en la gestión clínica y preventiva Russo, María Julieta; Salvat, Fernando; Ameriso, Sebastián Francisco; Villani, Donato; Vega, Jorge; Allegri, Ricardo Francisco; Sevlever, Gustavo Emilio Concussions in soccer are a key challenge for neurological health due to their high incidence, diagnostic complexity, and risk of long-term sequelae. This article provides a narrative review of their definition, epidemiology, pathophysiology, diagnosis, management, and prevention, integrating the most recent international guidelines. A search was conducted in Medline and Scopus (2013-2025) using terms related to "sports concussion", "traumatic brain injury," and "soccer"; 48 studies were selected. The 6th International Conference on Concussion in Sport and the criteria of the American Congress of Rehabilitation Medicine provide complementary frameworks for defining mild traumatic brain injury, based mainly on observational evidence and expert consensus. In soccer, concussions are mainly caused by head-to-head, head-to-ball, or head-to-ground impacts, with an approximate incidence of 0.5 per 1,000 hours of play and differences in recovery depending on gender. Diagnosis remains clinical and is supported by tools such as the Sport Concussion Assessment Tool 6 (SCAT6), its pediatric version (Child SCAT6), and the Concussion Recognition Tool 6 (CRT6). Current management emphasizes immediate removal from play, an initial period of relative rest, early subthreshold physical activity, and individualized rehabilitation. Biomarkers such as ubiquitin C-terminal hydrolase-L1 (UCHL1), glial fibrillary acidic protein (GFAP), and new tools such as SCOAT6 show potential but are not yet routinely recommended. The review identifies gaps in evidence for female players, youth populations, and the effects of repetitive heading, which guide future research priorities.

Peak width of skeletonized mean diffusivity reveals early and multifactorial white matter injury across sporadic and Down syndrome–associated Alzheimer's disease

2026-05-29T00:00:00Z

Peak width of skeletonized mean diffusivity reveals early and multifactorial white matter injury across sporadic and Down syndrome–associated Alzheimer's disease Morcillo Nieto, Alejandra O.; Franquesa Mullerat, Maria; Zsadanyi, Sara E.; Arriola‐Infante, José Enrique; Vaqué‐Alcázar, Lídia; Rozalem Aranha, Mateus; Allende Parra, José; Zhao, Zili; Arranz, Javier; Rodríguez‐Baz, Íñigo; Maure Blesa, Lucia; Videla, Laura; Barroeta, Isabel; Del Hoyo Soriano, Laura; Benejam, Bessy; Fernández, Susana; Sanjuan Hernandez, Aida; Pertierra, Lucía; Giménez, Sandra; Santos Santos, Miguel Ángel INTRODUCTION: This study investigates the evolution with disease progression and pathological correlates of peak width of skeletonized mean diffusivity (PSMD), a sensitive diffusion magnetic resonance imaging (MRI) marker of microvascular white matter (WM) injury, in sporadic Alzheimer's disease (sAD) and Down syndrome (DS)–associated AD (DSAD). METHOD: This cross-sectional study included 150 euploid controls, 118 subjects with sAD, and 228 DS adults (34.65% with symptomatic AD). PSMD was derived from 3T-MRI diffusion tensor imaging. Associations with sociodemographic, clinical stage, cerebrospinal fluid (CSF), and small vessel disease markers were examined. RESULTS: PSMD correlated with age in all groups, showing a stronger association in DS, with alterations apparent 15 years before the population's dementia age at onset. In euploid and DS, higher PSMD correlated with AD severity, CSF-neurofilament light chain (NfL), microbleeds, and WM hyperintensities (WMH). PSMD abnormalities were more frequent than WMH, especially in DS. DISCUSSION: PSMD is a sensitive early biomarker of WM injury across sAD and DSAD, preceding symptom onset and capturing multifactorial disease processes.

Recommendations for genetic counseling for individuals at risk of autosomal dominant Alzheimer's disease in Latin America

2026-05-27T00:00:00Z

Recommendations for genetic counseling for individuals at risk of autosomal dominant Alzheimer's disease in Latin America Jiménez, Daniel A.; Bagnati, Pablo M.; Flores Montes, Rosa Elena; Fernández, María Laura; Zuno Reyes, Angélica; Aguillón, David; Aláez Versón, Carmen; Becerra Solano, Luis Eduardo; Behrens, María Isabel; Branda, Kelly; Chrem Méndez, Patricio Alexis; Custodio, Nilton; Ducaine, Whitney; Dumois Petersen, Sofía; Figuera, Luis; Londoño Castaño, Marisol; Longoria, Erika Mariana; Matute, Esmeralda; Surace, Ezequiel Ignacio; Programa de asesoramiento genético en América Latina (PRAGA) Autosomal dominant Alzheimer's disease (ADAD) represents a small but impactful subset of Alzheimer's cases. Asymptomatic individuals at genetic risk face substantial personal and family implications when considering predictive testing for known familial variants. Genetic counseling and testing (GCT) frameworks remain limited in Latin America (LatAm). Recommendations for GCT in LatAm were developed through an iterative, multidisciplinary consensus process. Evidence inputs included a structured literature review, site‐level recommendations from participating LatAm centers, and a qualitative synthesis of focus groups with experienced investigators. The resulting model includes pre‐test evaluation, sample collection, result disclosure, and structured follow‐up. Core elements comprise mental health assessment, psychoeducation, exploration of expectations and decision‐making needs, guided disclosure with emotional support, and a suggested 3‐month post‐disclosure reassessment using validated psychological measures. Our framework provides structured guidance for the safe and ethical delivery of GCT for ADAD through a multidisciplinary, culturally informed, and patient‐centered approach in LatAm.