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Qualitative and quantitative educational disparities and brain signatures in healthy aging and dementia across global settings
(Elsevier BV, 2025-04)
Raul Gonzalez-Gomez
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Josephine Cruzat
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Hernán Hernández
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Joaquín Migeot
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Agustina Legaz
Scopus© Citations 4 3
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Polygenic score analysis identifies distinct genetic risk profiles in Alzheimer’s disease comorbidities
(Springer Science and Business Media LLC, 2025-04-03)
Carlos F. Hernández
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Camilo Villaman
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Costin Leu
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Dennis Lal
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Ignacio Mata
4
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Comprehensive Analysis of Genetic Contributions to Alzheimer’s Disease and Frontotemporal Dementia in Admixed Latin American Populations
(Wiley, 2024-12)
Juliana Acosta‐Uribe
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Stefanie Danielle Pina Escudero
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J. Nicholas Cochran
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Jared W Taylor
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Caroline Warly Solsberg
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Most research initiatives have emerged from high‐income countries (HIC), leaving a gap in understanding the disease’s genetic basis in diverse populations like those in Latin American countries (LAC). ReDLat tackles this gap, focusing on LAC’s unique genetics and socioeconomic factors to identify specific Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) risk factors in Mexico, Colombia, Peru, Chile, Argentina, and Brazil.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>We employed a comprehensive genetic analysis approach, integrating Whole Genome Sequencing (WGS), Exome Sequencing, and SNP arrays to understand the cohort’s unique genetic architecture. We conducted ancestry analysis and searched for disease‐causing variants with mendelian inheritance, genome‐wide association studies (GWAS), rare variant enrichment, and evaluation of Polygenic Risk Scores (PRS).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We recruited and genotyped an initial cohort of 1046 participants with AD, 423 with FTD, and 855 healthy controls (HC) between 2020 and 2023. Analysis is ongoing, and we expect to sequence ∼600 additional samples in the coming months. Ancestry analysis revealed tri‐continental admixture, except for Brazil, which showed an additional Asian component (Figure 1). Top candidate gene rare variant enrichment associations (SKAT p < 0.05) were <jats:italic>TREM2</jats:italic> for FTD and <jats:italic>ABCA7</jats:italic> and <jats:italic>ABCA1</jats:italic> for AD. GWAS identified a robust association with the <jats:italic>APOE</jats:italic> locus on chromosome 19 in AD vs. HC.. We tested an AD PRS developed in European populations by Bellenguez et al (2020). on our cohort using 83 single‐nucleotide polymorphisms.. The PRS modestly distinguishes between all patients and HC (p = 2.4 × 10^‐12), AD vs. HC (p = 2.2 × 10^‐12), and even FTD vs. HC (p = 4.3 × 10^‐5), albeit with modest separation between groups, as expected for its application in a genetically admixed population.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our findings represent a pivotal step in understanding the genetic landscape of AD and FTD in admixed populations. They underscore the importance of including diverse populations in genetic research, paving the way for future studies. These findings have the potential to inform more personalized approaches to the diagnosis and treatment of neurodegenerative diseases in diverse global populations, as well as identify novel targets for therapeutic development.</jats:p></jats:sec>
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Functional Capacity in Activities of Daily Living in the Alzheimer’s Disease Continuum
(Wiley, 2024-12)
Fernando Henriquez
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Carmen Dominguez
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Fabrissio Grandi
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Cecilia Gonzalez Campo
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Patricio Riquelme Contreras
The most common and prevalent dementia worldwide is Alzheimer’s disease (AD). AD is a continuum composed of Subjective Cognitive Impairment (SCD), Mild Cognitive Impairment (MCI), and Alzheimer’s Disease dementia (ADD) stage. One of the main clinical variables in patients with dementia is performance in functional capacity since its alterations are associated with poor prognosis and disease progression. Functional capacity is measured through activities of daily living (ADL), which are divided into three domains: i) Basic (BADL), ii) Instrumental (IADL), and iii) Advanced (AADL). The study aimed to characterize the performance of the different stages of the AD continuum in the ADL domains and their association with cognitive abilities.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>A cross‐sectional study of subjects at different stages of the AD continuum was conducted: Healthy Controls (CTR) (n = 17), SCD (n = 77), MCI (n = 30), and ADD (n = 23), who were matched for age, sex, and education. ADLs were estimated using The Technology‐Activities of Daily Living Questionnaire (T‐ADLQ), which assesses the three domains and a total score. T‐ADLQ performance was compared across groups and correlated with cognitive ability instruments (ACE‐III and IFS).</jats:p></jats:sec><jats:sec><jats:title>Result</jats:title><jats:p>The results showed that patients with ADD performed worse on the BADL, IADL, and total ADLs compared to the other three groups. There were no significant differences between the CTR, SCD, and MCI on the BADL, IADL, and total ADLs. However, the AADL, in addition to differentiating the ADD patients from the other three groups, also showed differences between CTR and MCI subjects and between SCD and MCI subjects (Table 1 and Figure 1). The correlation study showed that AADL correlated significantly with global cognitive and executive function assessment (Figure 2).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>AADL shows progressive functional impairment at different stages of the AD continuum, which is further associated with global cognitive and executive function performances. As one progresses to a more advanced stage of the disease continuum, the performance of ADLs, especially AADLs, worsens, which could indicate a marker of disease progression, allowing for better patient follow‐up.
1
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Alzheimer Disease as a Clinical-Biological Construct—An International Working Group Recommendation
(2024)
Bruno Dubois
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Nicolas Villain
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Lon Schneider
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Nick Fox
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Noll Campbell
<jats:sec id="ab-nsc240001-1"><jats:title>Importance</jats:title><jats:p>Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer’s Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations.</jats:p></jats:sec><jats:sec id="ab-nsc240001-2"><jats:title>Objective</jats:title><jats:p>To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states.</jats:p></jats:sec><jats:sec id="ab-nsc240001-3"><jats:title>Evidence Review</jats:title><jats:p>PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms “biomarker” OR “amyloid” OR “tau” OR “neurodegeneration” OR “preclinical” OR “CSF” OR “PET” OR “plasma” AND “Alzheimer’s disease.” The references of relevant articles were also searched.</jats:p></jats:sec><jats:sec id="ab-nsc240001-4"><jats:title>Findings</jats:title><jats:p>In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease.</jats:p></jats:sec><jats:sec id="ab-nsc240001-5"><jats:title>Conclusions and Relevance</jats:title><jats:p>The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.</jats:p></jats:sec>
Scopus© Citations 73 2
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The BrainLat project, a multimodal neuroimaging dataset of neurodegeneration from underrepresented backgrounds
(2023)
Pavel Prado
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Vicente Medel
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Raul Gonzalez-Gomez
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Agustín Sainz-Ballesteros
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Victor Vidal
The Latin American Brain Health Institute (BrainLat) has released a unique multimodal neuroimaging dataset of 780 participants from Latin American. The dataset includes 530 patients with neurodegenerative diseases such as Alzheimer’s disease (AD), behavioral variant frontotemporal dementia (bvFTD), multiple sclerosis (MS), Parkinson’s disease (PD), and 250 healthy controls (HCs). This dataset (62.7 ± 9.5 years, age range 21–89 years) was collected through a multicentric effort across five Latin American countries to address the need for affordable, scalable, and available biomarkers in regions with larger inequities. The BrainLat is the first regional collection of clinical and cognitive assessments, anatomical magnetic resonance imaging (MRI), resting-state functional MRI (fMRI), diffusion-weighted MRI (DWI), and high density resting-state electroencephalography (EEG) in dementia patients. In addition, it includes demographic information about harmonized recruitment and assessment protocols. The dataset is publicly available to encourage further research and development of tools and health applications for neurodegeneration based on multimodal neuroimaging, promoting the assessment of regional variability and inclusion of underrepresented participants in research.
30Scopus© Citations 22
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The “when” matters: Evidence from memory markers in the clinical continuum of Alzheimer’s disease.
(2023)
Gonzalo Forno
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Mario A. Parra
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Daniela Thumala
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Roque Villagra
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Mauricio Cerda
6Scopus© Citations 5
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The first genome‐wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease
(2023)
Maria Carolina Dalmasso
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Itziar de Rojas
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Natividad Olivar
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Carolina Muchnik
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Bárbara Angel
<jats:title>Abstract</jats:title><jats:sec><jats:title>INTRODUCTION</jats:title><jats:p>Genome‐wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta‐analysis and tested their genetic risk score (GRS) performance in this admixed population.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>We detected apolipoprotein E ε4 as the single genome‐wide significant signal (odds ratio = 2.93 [2.37–3.63], <jats:italic>P</jats:italic> = 2.6 × 10<jats:sup>−23</jats:sup>). The meta‐analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD‐GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose.</jats:p></jats:sec><jats:sec><jats:title>DISCUSSION</jats:title><jats:p>We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations.</jats:p></jats:sec><jats:sec><jats:title>Highlights</jats:title><jats:p><jats:list list-type="bullet"> <jats:list-item><jats:p>This is the first genome‐wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile.</jats:p></jats:list-item> <jats:list-item><jats:p>Trans‐ethnic meta‐analysis reveals four new loci involving lysosomal function in AD.</jats:p></jats:list-item> <jats:list-item><jats:p>This is the first independent replication for <jats:italic>TREM2L</jats:italic>, <jats:italic>IGH‐gene‐cluster</jats:italic>, and <jats:italic>ADAM17</jats:italic> loci.</jats:p></jats:list-item> <jats:list-item><jats:p>A genetic risk score (GRS) developed in Europeans performed well in this population.</jats:p></jats:list-item> <jats:list-item><jats:p>The higher the Native American ancestry the lower the GRS values.</jats:p></jats:list-item> </jats:list></jats:p></jats:sec>
Scopus© Citations 3 1
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Network anatomy in logopenic variant of primary progressive aphasia
(2023)
Maria Luisa Mandelli
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Diego L. Lorca‐Puls
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Sladjana Lukic
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Maxime Montembeault
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GAJARDO VIDAL, ANDREA ELIZABETH
<jats:title>Abstract</jats:title><jats:p>The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross‐sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface‐based approach paired with an anatomically fine‐grained parcellation of the cortical surface (i.e., HCP‐MMP1.0 atlas). Second, we combined cross‐sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter‐seeded resting‐state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically‐intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis.</jats:p>
Scopus© Citations 10 2
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Multivariate word properties in fluency tasks reveal markers of Alzheimer's dementia
(2023)
Franco J. Ferrante
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Joaquín Migeot
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Agustina Birba
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Lucía Amoruso
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Gonzalo Pérez
<jats:title>Abstract</jats:title><jats:sec><jats:title>INTRODUCTION</jats:title><jats:p>Verbal fluency tasks are common in Alzheimer's disease (AD) assessments. Yet, standard valid response counts fail to reveal disease‐specific semantic memory patterns. Here, we leveraged automated word‐property analysis to capture neurocognitive markers of AD vis‐à‐vis behavioral variant frontotemporal dementia (bvFTD).</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>Patients and healthy controls completed two fluency tasks. We counted valid responses and computed each word's frequency, granularity, neighborhood, length, familiarity, and imageability. These features were used for group‐level discrimination, patient‐level identification, and correlations with executive and neural (magnetic resonanance imaging [MRI], functional MRI [fMRI], electroencephalography [EEG]) patterns.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Valid responses revealed deficits in both disorders. Conversely, frequency, granularity, and neighborhood yielded robust group‐ and subject‐level discrimination only in AD, also predicting executive outcomes. Disease‐specific cortical thickness patterns were predicted by frequency in both disorders. Default‐mode and salience network hypoconnectivity, and EEG beta hypoconnectivity, were predicted by frequency and granularity only in AD.</jats:p></jats:sec><jats:sec><jats:title>DISCUSSION</jats:title><jats:p>Word‐property analysis of fluency can boost AD characterization and diagnosis.</jats:p></jats:sec><jats:sec><jats:title>Highlights</jats:title><jats:p><jats:list list-type="bullet"> <jats:list-item><jats:p>We report novel word‐property analyses of verbal fluency in AD and bvFTD.</jats:p></jats:list-item> <jats:list-item><jats:p>Standard valid response counts captured deficits and brain patterns in both groups.</jats:p></jats:list-item> <jats:list-item><jats:p>Specific word properties (e.g., frequency, granularity) were altered only in AD.</jats:p></jats:list-item> <jats:list-item><jats:p>Such properties predicted cognitive and neural (MRI, fMRI, EEG) patterns in AD.</jats:p></jats:list-item> <jats:list-item><jats:p>Word‐property analysis of fluency can boost AD characterization and diagnosis.</jats:p></jats:list-item> </jats:list></jats:p></jats:sec>
3Scopus© Citations 10

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