A benchmark study on current GWAS models in admixed populations.

OBJECTIVE: The performances of popular genome-wide association study (GWAS) models have not been examined yet in a consistent manner under the scenario of genetic admixture, which introduces several challenging aspects: heterogeneity of minor allele frequency (MAF), wide spectrum of case-control ratio, varying effect sizes, etc. METHODS: We generated a cohort of synthetic individuals (N = 19 234) that simulates (i) a large sample size; (ii) two-way admixture (Native American and European ancestry) and (iii) a binary phenotype. We then benchmarked three popular GWAS tools [generalized linear mixed model associated test (GMMAT), scalable and accurate implementation of generalized mixed model (SAIGE) and Tractor] by computing inflation factors and power calculations under different MAFs, case-control ratios, sample sizes and varying ancestry proportions. We also employed a cohort of Peruvians (N = 249) to further examine the performances of the testing models on (i) real genetic and phenotype data and (ii) small sample sizes. RESULTS: In the synthetic cohort, SAIGE performed better than GMMAT and Tractor in terms of type-I error rate, especially under severe unbalanced case-control ratio. On the contrary, power analysis identified Tractor as the best method to pinpoint ancestry-specific causal variants but showed decreased power when the effect size displayed limited heterogeneity between ancestries. In the Peruvian cohort, only Tractor identified two suggestive loci (P-value $\le 1\ast{10}^{-5}$) associated with Native American ancestry. DISCUSSION: The current study illustrates best practice and limitations for available GWAS tools under the scenario of genetic admixture. Incorporating local ancestry in GWAS analyses boosts power, although careful consideration of complex scenarios (small sample sizes, imbalance case-control ratio, MAF heterogeneity) is needed.

The BrainLat project, a multimodal neuroimaging dataset of neurodegeneration from underrepresented backgrounds.

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.

Epidemiology of neurocognitive disorders in adults from urban-marginalized areas: a door-to-door population-based study in Puente Piedra, Lima, Peru.

Background: In Latin America (LA), the prevalence of dementia is expected to triple to 150 million people by 2050. The 2020 Lancet Commission report identified several modifiable dementia risk factors, yet few social and environmental factors, most relevant to vulnerable regions of LA, were highlighted in this report. We sought to assess the epidemiology of neurocognitive disorders (NCD) in Puente Piedra, one of the most socially and economically vulnerable districts of Lima, the capital of Peru. Methodology: This was a cross-sectional door-to-door observational study that used two-stage household sampling. One young adult (30-59 years) and one older adult (>60 years) per household were enrolled. We collected demographic, clinical, and neurocognitive data. Addenbrooke's Cognitive Examination (young adults) and the RUDAS-PE (older adults) were used, classifying participants as cognitively normal, possible mild NCD, or possible major NCD. Results: We enrolled 247 participants (median age 46 years; 67% female). One-fourth had not completed secondary school and more than 50% completed only secondary school. Most participants were housewives (46%) and 21% did not have health insurance. The overall prevalence of possible NCD was 30% (25.6 and 41.8% among younger adults and older adults, respectively). Among younger adults, those ages 55-59 years more frequently had NCD (70%) compared to younger age ranges. Among older adults, only 3 subjects (4.5%) had major NCD. Conclusion: We found a high frequency of possible NCDs in a socially and economically vulnerable community in Lima, Peru, with younger adults showing levels of NCD higher than expected. Our findings support the need for health systems to incorporate cognitive screenings programs for NCD in younger ages. Future research on NCD would include younger populations, particularly in vulnerable communities.

The Memory Alteration Test Is Correlated with Clinical, Cerebrospinal Fluid, and Brain Imaging Markers of Alzheimer Disease in Lima, Peru.

INTRODUCTION: As disease-modifying therapies become available for Alzheimer's disease (AD), detection of AD in early stages of illness (mild cognitive impairment [MCI], early dementia) becomes increasingly important. Biomarkers for AD in low- and middle-income countries (LMICs) are costly and not widely available; hence, it is important to identify cognitive tests that correlate well with AD biomarker status. In this study, we evaluated the memory alteration test (M@T) to detect biomarker-proven AD and quantify its correlation with neurodegeneration and cerebrospinal fluid (CSF) AD biomarkers in a cohort of participants from Lima, Peru. METHODS: This is a secondary analysis of a cohort of 185 participants: 63 controls, 53 with amnestic MCI (aMCI), and 69 with dementia due to AD. Participants underwent testing with M@T and a gold standard neuropsychological battery. We measured total tau (t-tau), phosphorylated tau (p-tau), and beta-amyloid (ß-amyloid) in CSF, and evaluated neurodegeneration via medial temporal atrophy score in MRI. We used receiver-operator curves to determine the discriminative capacity of the total M@T score and its subdomains. We used the Pearson coefficient to correlate M@T score and CSF biomarkers. RESULTS: The M@T had an area under the curve (AUC) of 0.994 to discriminate between controls and cognitively impaired (aMCI or AD) patients, and an AUC of 0.98 to differentiate between aMCI and AD patients. Free-recall and cued recall had the highest AUCs of all subdomains. Total score was strongly correlated with t-tau (-0.77) and p-tau (-0.72), and moderately correlated with ß-amyloid (0.66). The AUC for discrimination of neurodegeneration was 0.87. CONCLUSION: The M@T had excellent discrimination of aMCI and dementia due to AD. It was strongly correlated with CSF biomarkers and had good discrimination of neurodegeneration. In LMICs, the M@T may be a cost-effective screening tool for aMCI and dementia caused by AD.

Diagnóstico de la variante conductual de demencia frontotemporal basado en estadios clínicos adaptado para países con baja educación: el caso de Perú

Demencia frontotemporal (DFT) es una condición neurodegenerativa escasamente reconocida en personas menores a 65 años de edad. El diagnóstico de DFT variante conductual (DFTvc) se basa en una entrevista clínica comprehensiva, complementada por una evaluación multidimensional (neurológica, cognitiva, neuropsiquiátrica, de biomarcadores e imágenes cerebrales) adaptada y validada a la población a estudiar; sin embargo, a pesar del incremento de su prevalencia en Latinoamérica y el Caribe, existe necesidad de herramientas estandarizadas y un consenso para el diagnóstico de DFTvc. El artículo intenta realizar una aproximación del enfoque de diagnóstico de DFTvc en escenario de paises con bajos y medianos ingresos, como el Perú.

Frontotemporal dementia (FTD) is a widely recognized neurodegenerative condition in people under 65 years old. The diagnosis of behavioral variant FTD (bvFTD) is based on a comprehensive clinical assessment, complemented by a multidimensional assessment (neurological, cognitive, neuropsychiatric, biomarker and brain imaging) adapted and validated to the population to be studied; however, despite its increasing prevalence in Latin America and the Caribbean, there is a need for standardized tools and consensus for the bvFTD diagnosis. The manuscript attempts to approximate the approach for the diagnosis of bvFTD in the setting of low and middle-income countries, including Peru.

A task force for diagnosis and treatment of people with Alzheimer's disease in Latin America.

Alzheimer's disease (AD) represents a substantial burden to patients, their caregivers, health systems, and society in Latin America and the Caribbean (LAC). This impact is exacerbated by limited access to diagnosis, specialized care, and therapies for AD within and among nations. The region has varied geographic, ethnic, cultural, and economic conditions, which create unique challenges to AD diagnosis and management. To address these issues, the Americas Health Foundation convened a panel of eight neurologists, geriatricians, and psychiatrists from Argentina, Brazil, Colombia, Ecuador, Guatemala, Mexico, and Peru who are experts in AD for a three-day virtual meeting to discuss best practices for AD diagnosis and treatment in LAC and create a manuscript offering recommendations to address identified barriers. In LAC, several barriers hamper diagnosing and treating people with dementia. These barriers include access to healthcare, fragmented healthcare systems, limited research funding, unstandardized diagnosis and treatment, genetic heterogeneity, and varying social determinants of health. Additional training for physicians and other healthcare workers at the primary care level, region-specific or adequately adapted cognitive tests, increased public healthcare insurance coverage of testing and treatment, and dedicated search strategies to detect populations with gene variants associated with AD are among the recommendations to improve the landscape of AD.

Heterogeneous factors influence social cognition across diverse settings in brain health and age-related diseases.

Aging may diminish social cognition, which is crucial for interaction with others, and significant changes in this capacity can indicate pathological processes like dementia. However, the extent to which non-specific factors explain variability in social cognition performance, especially among older adults and in global settings, remains unknown. A computational approach assessed combined heterogeneous contributors to social cognition in a diverse sample of 1063 older adults from 9 countries. Support vector regressions predicted the performance in emotion recognition, mentalizing, and a total social cognition score from a combination of disparate factors, including clinical diagnosis (healthy controls, subjective cognitive complaints, mild cognitive impairment, Alzheimer's disease, behavioral variant frontotemporal dementia), demographics (sex, age, education, and country income as a proxy of socioeconomic status), cognition (cognitive and executive functions), structural brain reserve, and in-scanner motion artifacts. Cognitive and executive functions and educational level consistently emerged among the top predictors of social cognition across models. Such non-specific factors showed more substantial influence than diagnosis (dementia or cognitive decline) and brain reserve. Notably, age did not make a significant contribution when considering all predictors. While fMRI brain networks did not show predictive value, head movements significantly contributed to emotion recognition. Models explained between 28-44% of the variance in social cognition performance. Results challenge traditional interpretations of age-related decline, patient-control differences, and brain signatures of social cognition, emphasizing the role of heterogeneous factors. Findings advance our understanding of social cognition in brain health and disease, with implications for predictive models, assessments, and interventions.

A benchmark study on current GWAS models in admixed populations.

Objective: The performances of popular Genome-wide association study (GWAS) models haven't been examined yet in a consistent manner under the scenario of genetic admixture, which introduces several challenging aspects such as heterogeneity of minor allele frequency (MAF), a wide spectrum of case-control ratio, and varying effect sizes etc. Methods: We generated a cohort of synthetic individuals (N=19,234) that simulates 1) a large sample size; 2) two-way admixture [Native American-European ancestry] and 3) a binary phenotype. We then examined the inflation factors produced by three popular GWAS tools: GMMAT, SAIGE, and Tractor. We also computed power calculations under different MAFs, case-control ratios, and varying ancestry percentages. Then, we employed a cohort of Peruvians (N=249) to further examine the performances of the testing models on 1) real genetic data and 2) small sample sizes. Finally, we validated these findings using an independent Peruvian cohort (N=109) included in 1000 Genome project (1000G). Results: In the synthetic cohort, SAIGE performed better than GMMAT and Tractor in terms of type-I error rate, especially under severe unbalanced case-control ratio. On the contrary, power analysis identified Tractor as the best method to pinpoint ancestry-specific causal variants, but showed decreased power when no adequate heterogeneity of the true effect sizes was simulated between ancestries. The real Peruvian data showed that Tractor is severely affected by small sample sizes, and produced severely inflated statistics, which we replicated in the 1000G Peruvian cohort. Discussion: The current study illustrates the limitations of available GWAS tools under different scenarios of genetic admixture. We urge caution when interpreting results under complex population scenarios.

Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm-FINGERS): Study design and harmonization.

INTRODUCTION: Latin American Initiative for Lifestyle Intervention to Prevent Cognitive Decline (LatAm-FINGERS) is the first non-pharmacological multicenter randomized clinical trial (RCT) to prevent cognitive impairment in Latin America (LA). Our aim is to present the study design and discuss the strategies used for multicultural harmonization. METHODS: This 1-year RCT (working on a 1-year extension) investigates the feasibility of a multi-domain lifestyle intervention in LA and the efficacy of the intervention, primarily on cognitive function. An external harmonization process was carried out to follow the FINGER model, and an internal harmonization was performed to ensure this study was feasible and comparable across the 12 participating LA countries. RESULTS: Currently, 1549 participants have been screened, and 815 randomized. Participants are ethnically diverse (56% are Nestizo) and have high cardiovascular risk (39% have metabolic syndrome). DISCUSSION: LatAm-FINGERS overcame a significant challenge to combine the region's diversity into a multi-domain risk reduction intervention feasible across LA while preserving the original FINGER design.

Impact of COVID-19 Mandatory Lockdown Measures on Cognitive and Neuropsychiatric Symptoms in Persons with Alzheimer's Disease in Lima, Peru.

BACKGROUND: Neuropsychiatric symptoms (NPS) in patients with Alzheimer's disease (AD) worsened during the COVID-19 lockdowns, but their progression thereafter is unknown. We present the first longitudinal study tracking them before, during, and after restrictions. OBJECTIVES: To describe the effect of the COVID-19 mandatory lockdowns on Cognitive and Neuropsychiatric symptoms in patients with Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD). METHODS: Cohort of 48 patients with amnestic MCI and 38 with AD in Lima, Peru. They received three rounds of cognitive (RUDAS, CDR, M@T), behavioral (NPI), and functional (ADCS-ADL) assessments. We assessed the change in score means across the time points and for each domain of NPS and tracked the changes in individual patients. RESULTS: RUDAS declined 0.9 (SD 1.0) from baseline to lockdown and 0.7 (SD 1.0) after restrictions. M@T declined 1.0 (SD 1.5) from baseline to lockdown and 1.4 (SD 2.0) after restrictions. CDR worsened in 72 patients (83.72%) from baseline to post-lockdown. NPI worsened by 10 (SD 8.3) from baseline to lockdown but improved by 4.8 (SD 6.4) after restrictions. Proportionally, 81.3% of all patients had worsened NPS during the lockdowns, but only 10.7% saw an increase thereafter. Improvement was statistically significant for specific NPS domains except hallucinations, delusions, and appetite changes. Anxiety, irritability, apathy, and disinhibition returned to baseline levels. CONCLUSION: Following confinement, cognition continued to decline, but NPS demonstrated either stability or improvement. This highlights the role modifiable risk factors may have on the progression of NPS.

Biomarkers for dementia in Latin American countries: Gaps and opportunities.

Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we reported a survey to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The results show that neuroimaging is the most used biomarker (73%), followed by genetic studies (40%), peripheral fluids biomarkers (31%), and cerebrospinal fluid biomarkers (29%). Regarding barriers in LAC, lack of funding appears to undermine the implementation of biomarkers in clinical or research settings, followed by insufficient infrastructure and training. The survey revealed that despite the above barriers, the region holds a great potential to advance dementia biomarkers research. Considering the unique contributions that LAC could make to this growing field, we highlight the urgent need to expand biomarker research. These insights allowed us to propose an action plan that addresses the recommendations for a biomarker framework recently proposed by regional experts.

Classification of Alzheimer's disease and frontotemporal dementia using routine clinical and cognitive measures across multicentric underrepresented samples: A cross sectional observational study.

Background: Global brain health initiatives call for improving methods for the diagnosis of Alzheimer's disease (AD) and frontotemporal dementia (FTD) in underrepresented populations. However, diagnostic procedures in upper-middle-income countries (UMICs) and lower-middle income countries (LMICs), such as Latin American countries (LAC), face multiple challenges. These include the heterogeneity in diagnostic methods, lack of clinical harmonisation, and limited access to biomarkers. Methods: This cross-sectional observational study aimed to identify the best combination of predictors to discriminate between AD and FTD using demographic, clinical and cognitive data among 1794 participants [904 diagnosed with AD, 282 diagnosed with FTD, and 606 healthy controls (HCs)] collected in 11 clinical centres across five LAC (ReDLat cohort). Findings: A fully automated computational approach included classical statistical methods, support vector machine procedures, and machine learning techniques (random forest and sequential feature selection procedures). Results demonstrated an accurate classification of patients with AD and FTD and HCs. A machine learning model produced the best values to differentiate AD from FTD patients with an accuracy = 0.91. The top features included social cognition, neuropsychiatric symptoms, executive functioning performance, and cognitive screening; with secondary contributions from age, educational attainment, and sex. Interpretation: Results demonstrate that data-driven techniques applied in archival clinical datasets could enhance diagnostic procedures in regions with limited resources. These results also suggest specific fine-grained cognitive and behavioural measures may aid in the diagnosis of AD and FTD in LAC. Moreover, our results highlight an opportunity for harmonisation of clinical tools for dementia diagnosis in the region. Funding: This work was supported by the Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat), funded by NIA/NIH (R01AG057234), Alzheimer's Association (SG-20-725707-ReDLat), Rainwater Foundation, Takeda (CW2680521), Global Brain Health Institute; as well as CONICET; FONCYT-PICT (2017-1818, 2017-1820); PIIECC, Facultad de Humanidades, Usach; Sistema General de Regalías de Colombia (BPIN2018000100059), Universidad del Valle (CI 5316); ANID/FONDECYT Regular (1210195, 1210176, 1210176); ANID/FONDAP (15150012); ANID/PIA/ANILLOS ACT210096; and Alzheimer's Association GBHI ALZ UK-22-865742.

Impact of Sociodemographic Features and Lifestyle on Cognitive Performance of Peruvian Adults.

BACKGROUND: Cognitive impairment and dementia may result from a combination of modifiable and nonmodifiable risk and protective factors, such as the environment, educational attainment, time devoted to cognitively stimulating activities, and physical activity. OBJECTIVE: This study aimed to investigate the mediating role of sociodemographic characteristics and lifestyle factors in the years of education and cognitive performance in Peruvian adults. METHODS: This cross-sectional study included 1,478 subjects assessed by Addenbrooke's Cognitive Examination Revised (ACE-R). Using mediation models, we evaluated the mediation role of parents' educational level, reading time (RT), and physical activity time (PAT) in the years of education (IYE) and cognitive performance. RESULTS: People who reported having lived in an urban area during their childhood are estimated to have, on average, 2.085 years more formal education than those who lived in rural areas. In addition, 49% of cognitive performance scores are explained by the mediation effect of reading and physical activity time in the IYE. This implies that higher levels of education, mediated by RT and PAT per week, are 1.596 units associated with higher scores on the ACE-R. CONCLUSION: Despite the fact that nonmodifiable factors (i.e., childhood residence area, parents' educational level) seem to exert an effect on older adults' cognition, their influence is mediated by other factors that are indeed modifiable (i.e., reading time, physical activity engagement). In this sense, lifestyle changes could help prevent or decrease the risk of cognitive impairment and reduce the disease's impact on vulnerable environments in Latin American and Caribbean countries.

Combining visual rating scales to identify prodromal Alzheimer's disease and Alzheimer's disease dementia in a population from a low and middle-income country.

Background: Many low- and middle-income countries, including Latin America, lack access to biomarkers for the diagnosis of prodromal Alzheimer's Disease (AD; mild cognitive impairment due to AD) and AD dementia. MRI visual rating scales may serve as an ancillary diagnostic tool for identifying prodromal AD or AD in Latin America. We investigated the ability of brain MRI visual rating scales to distinguish between cognitively healthy controls, prodromal AD and AD. Methods: A cross-sectional study was conducted from a multidisciplinary neurology clinic in Lima, Peru using neuropsychological assessments, brain MRI and cerebrospinal fluid amyloid and tau levels. Medial temporal lobe atrophy (MTA), posterior atrophy (PA), white matter hyperintensity (WMH), and MTA+PA composite MRI scores were compared. Sensitivity, specificity, and area under the curve (AUC) were determined. Results: Fifty-three patients with prodromal AD, 69 with AD, and 63 cognitively healthy elderly individuals were enrolled. The median age was 75 (8) and 42.7% were men. Neither sex, mean age, nor years of education were significantly different between groups. The MTA was higher in patients with AD (p < 0.0001) compared with prodromal AD and controls, and MTA scores adjusted by age range (p < 0.0001) and PA scores (p < 0.0001) were each significantly associated with AD diagnosis (p < 0.0001) but not the WMH score (p=0.426). The MTA had better performance among ages <75 years (AUC 0.90 [0.85-0.95]), while adjusted MTA+PA scores performed better among ages>75 years (AUC 0.85 [0.79-0.92]). For AD diagnosis, MTA+PA had the best performance (AUC 1.00) for all age groups. Conclusions: Combining MTA and PA scores demonstrates greater discriminative ability to differentiate controls from prodromal AD and AD, highlighting the diagnostic value of visual rating scales in daily clinical practice, particularly in Latin America where access to advanced neuroimaging and CSF biomarkers is limited in the clinical setting.

A Functional Assessment Tool to Distinguish Controls From Alzheimer's Disease in Lima, Peru.

BACKGROUND: The Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale is a versatile functional assessment tool for patients with Alzheimer's disease (ad). We evaluated its performance in controls, Peruvians with MCI or AD. METHODS: A cross-sectional study of older adults attending a neurology institute in Lima (Peru) with mild cognitive impairment (MCI), ad or cognitively healthy. Test-retest reliability (intraclass correlation coefficient, ICC; internal consistency, Cronbach's alpha) and validity were assessed. RESULTS: We enrolled 276 individuals (ad: 113, MCI: 68, controls: 95) with no age, sex, educational level, and depressive symptom differences. Reliability was ideal (ICC: .996), and Cronbach's alpha was adequate (.937). The ADCS-ADL could not differentiate MCI from controls but did differentiate ad severity. The ADCS-ADL correlated highly with nearly all tools. CONCLUSIONS: The ADCS-ADL scale is reliable in a population with ad in Lima, Peru. Future work may validate a tool for Peruvians with lower educational levels.

Validation of Picture Free and Cued Selective Reminding Test for Illiteracy in Lima, Peru.

Dementia in Latin America is a crucial public health problem. Identifying brief cognitive screening (BCS) tools for the primary care setting is crucial, particularly for illiterate individuals. We evaluated tool performance characteristics and validated the free and total recall sections of the Free and Cued Selective Reminding Test-Picture version (FCSRT-Picture) to discriminate between 63 patients with early Alzheimer's disease dementia (ADD), 60 amnestic mild cognitive impairment (aMCI) and 64 cognitively healthy Peruvian individuals with illiteracy from an urban area. Clinical, functional, and cognitive assessments were performed. FCSRT-Picture performance was assessed using receiver operating characteristic curve analyses. The mean ± standard deviation scores were 7.7 ± 1.0 in ADD, 11.8 ± 1.6 in aMCI, and 29.5 ± 1.8 in controls. The FCSRT-Picture had better performance characteristics for distinguishing controls from aMCI compared with several other BCS tools, but similar characteristics between controls and early ADD. The FCSRT-Picture is a reliable BCS tool for illiteracy in Peru.