Primary lateral sclerosis associated with PSEN1 Pro284Leu variant in a Colombian family: Clinical and neuropathological features.

INTRODUCTION: This study investigates primary lateral sclerosis (PLS) as a rare manifestation of the presenilin 1 (PSEN1) NM_000021 c.851C > T p.Pro284Leu variant in three siblings of a Colombian family, outlining its clinical and neuropathological features and their relationship to Alzheimer's disease (AD). METHODS: Data were gathered using clinical evaluations, next-generation genetic sequencing, magnetic resonance imaging, biomarker analysis, and neuropathological examination. RESULTS: Carriers of the PSEN1 Pro284Leu variant exhibited classic PLS symptoms, including unilateral onset and bulbar syndromes, along with cognitive decline. Neuropathology showed corticospinal tract degeneration without amyloid beta deposition in spinal white matter. DISCUSSION: Our findings suggest an overlap between PLS and AD pathology in PSEN1 variant carriers. Results support considering PLS when diagnosing AD-related motor syndromes and including PSEN1 evaluation when performing genetic testing for PLS. The study highlights the need for further research to clarify the PLS-AD relationship, informing future treatments and clinical trials. HIGHLIGHTS: Pathogenic variants in presenilin 1 (PSEN1) can manifest as hereditary primary lateral sclerosis PSEN1 Pro284Leu carriers present motor, cognitive, and behavioral alterations  Cases had corticospinal tract microgliosis and severe Aß pathology in motor cortex  There was no evidence of amyloid deposition in the spinal cord white matter  All the neuropathology images are available for online visualization  Myelin pallor in the spinal cord is confined to the lateral corticospinal tracts.

APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease.

BACKGROUND: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).

Viscous dynamics associated with hypoexcitation and structural disintegration in neurodegeneration via generative whole-brain modeling.

INTRODUCTION: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) lack mechanistic biophysical modeling in diverse, underrepresented populations. Electroencephalography (EEG) is a high temporal resolution, cost-effective technique for studying dementia globally, but lacks mechanistic models and produces non-replicable results. METHODS: We developed a generative whole-brain model that combines EEG source-level metaconnectivity, anatomical priors, and a perturbational approach. This model was applied to Global South participants (AD, bvFTD, and healthy controls). RESULTS: Metaconnectivity outperformed pairwise connectivity and revealed more viscous dynamics in patients, with altered metaconnectivity patterns associated with multimodal disease presentation. The biophysical model showed that connectome disintegration and hypoexcitability triggered altered metaconnectivity dynamics and identified critical regions for brain stimulation. We replicated the main results in a second subset of participants for validation with unharmonized, heterogeneous recording settings. DISCUSSION: The results provide a novel agenda for developing mechanistic model-inspired characterization and therapies in clinical, translational, and computational neuroscience settings.

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.

Psychological Status of the Participants in Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Colombia.

BACKGROUND: The SARS-CoV2 global pandemic impacted participants in the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) clinical trial, who faced three stressors: 1) fear of developing dementia; 2) concerns about missing treatment; and 3) risk of SARS-CoV2 infection. OBJECTIVE: To describe the frequency of psychological disorders among the participants of the API ADAD Colombia clinical study, treated by a holistic mental health team during the COVID-19 pandemic. The extent of use of mental health team services was explored considering different risk factors, and users and non-users of these services were compared. METHODS: Participants had free and optional access to psychology and psychiatry services, outside of the study protocol. Descriptive statistics was used to analyze the frequency of the mental health difficulties. A multivariable logistic regression model has been used to assess associations with using this program. RESULTS: 66 participants were treated by the Mental Health Team from March 1, 2020, to December 31, 2020. Before and after the start of the pandemic, the most common psychological problems were anxiety (36.4% before, 63.6% after) and depression (34.8% before, 37.9% after). 70% of users assisted by psychology and 81.6% of those assisted by psychiatry felt that the services were useful for them. Female sex, depression, and anxiety before the pandemic were positively associated with being assisted by either psychology or psychiatry, while the association with hyperlipidemia was negative. CONCLUSIONS: A holistic mental health program, carried out in the context of a study, could mitigate psychopathology during pandemics such as COVID-19.

Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man.

We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

Plasma p-tau217 predicts in vivo brain pathology and cognition in autosomal dominant Alzheimer's disease.

INTRODUCTION: Plasma-measured tau phosphorylated at threonine 217 (p-tau217) is a potential non-invasive biomarker of Alzheimer's disease (AD). We investigated whether plasma p-tau217 predicts subsequent cognition and positron emission tomography (PET) markers of pathology in autosomal dominant AD. METHODS: We analyzed baseline levels of plasma p-tau217 and its associations with amyloid PET, tau PET, and word list delayed recall measured 7.61 years later in non-demented age- and education-matched presenilin-1 E280A carriers (n = 24) and non-carrier (n = 20) family members. RESULTS: Carriers had higher plasma p-tau217 levels than non-carriers. Baseline plasma p-tau217 was associated with subsequent amyloid and tau PET pathology levels and cognitive function. DISCUSSION: Our findings suggest that plasma p-tau217 predicts subsequent brain pathological burden and memory performance in presenilin-1 E280A carriers. These results provide support for plasma p-tau217 as a minimally invasive diagnostic and prognostic biomarker for AD, with potential utility in clinical practice and trials. HIGHLIGHTS: Non-demented presenilin-1 E280A carriers have higher plasma tau phosphorylated at threonine 217 (p-tau217) than do age-matched non-carriers. Higher baseline p-tau217 is associated with greater future amyloid positron emission tomography (PET) pathology burden. Higher baseline p-tau217 is associated with greater future tau PET pathology burden. Higher baseline p-tau217 is associated with worse future memory performance.

Ataxia with Ocular Apraxia Type 1 (AOA1) (APTX, W279* Mutation): Neurological, Neuropsychological, and Molecular Outlining of a Heterogenous Phenotype in Four Colombian Siblings.

Hereditary ataxias are a group of devastating neurological disorders that affect coordination of gait and are often associated with poor coordination of hands, speech, and eye movements. Ataxia with ocular apraxia type 1 (AOA1) (OMIM: 606,350.0006) is characterized by slowly progressive symptoms of childhood-onset and pathogenic mutations in APTX; the only known cause underpinning AOA1. APTX encodes the protein aprataxin, composed of three domains sharing homology with proteins involved in DNA damage, signaling, and repair. We present four siblings from an endogamic family in a rural, isolated town of Colombia with ataxia and ocular apraxia of childhood-onset and confirmed molecular diagnosis of AOA1, homozygous for the W279* p.Trp279Ter mutation. We predicted the mutated APTX with AlphaFold to demonstrate the effects of this stop-gain mutation that deletes three beta helices encoded by amino acid 270 to 339 rescinding the C2H2-type zinc fingers (Znf) (C2H2 Znf) DNA-binding, the DNA-repair domain, and the whole 3D structure of APTX. All siblings exhibited different ages of onset (4, 6, 8, and 11 years old) and heterogeneous patterns of dysarthria (ranging from absence to mild-moderate dysarthria). Neuropsychological evaluation showed no neurocognitive impairment in three siblings, but one sibling showed temporospatial disorientation, semantic and phonologic fluency impairment, episodic memory affection, constructional apraxia, moderate anomia, low executive function, and symptoms of depression. To our knowledge, this report represents the most extensive series of siblings affected with AOA1 in Latin America, and the genetic analysis completed adds important knowledge to outline this family's disease and general complex phenotype of hereditary ataxias.

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects.

BACKGROUND: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. METHODS: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. RESULTS: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. CONCLUSIONS: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

Substance Use-Related Cognitive Decline in Families with Autosomal Dominant Alzheimer's Disease: A Cohort Study.

BACKGROUND: Cigarette smoking is a known risk factor for Alzheimer's disease (AD). However, the association between neurodegeneration and other substances has not been fully determined. It is of vital importance to evaluate this relationship in populations at high risk of dementia. Since substance use possibly modifies the progression rate of cognitive decline, we studied this association in a unique and well-phenotyped cohort from the University of Antioquia: carriers of the PSEN1-E280A genetic variant. OBJECTIVE: To determine the association between substance use and cognitive decline in carriers of the PSEN1-E280A genetic variant. METHODS: A retrospective cohort study was conducted with 94 carriers and 69 noncarriers recruited between January 2019 and April 2020. A psychiatrist interviewed the participants using the Consumption of Alcohol, Cigarettes and other Substances questionnaire. The participants were also submitted to cognitive evaluation. The relationship between cognitive decline and substance use was explored through a mixed effects regression model. RESULTS: There was an association between cigarettes and better performance on tasks related to perceptual organization, verbal fluency, and memory in carriers. Alcohol had a positive or negative effect on memory according to the type of alcoholic beverage. Results on marijuana use were no conclusive. Coffee was associated with progressive improvements in executive function and verbal fluency. CONCLUSION: Cigarette and alcohol were associated with an improvement of some cognitive assessments, possibly by a survival bias. In addition, coffee was related to improvements in executive function and language; therefore, its short-term neuroprotective potential should be studied.

Quality of life in early-onset Alzheimer's disease due to a PSEN1-E280A mutation.

PURPOSE: The present study aims to explore the association between the quality of life (QoL) score and the clinical and sociodemographic variables in patients with the PSEN1-E280A mutation. We also seek to evaluate the differences between the QoL reported by the patients (P-QoL) and the scores reported by the caregivers (C-QoL). METHODS: An analysis of 75 patients with the PSEN1-E280A mutation with mild cognitive impairment and dementia was performed. We used the Quality of Life in Alzheimer Disease (QoL-AD) survey to evaluate QoL as an outcome and evaluated its association with sociodemographic, lifestyle, clinical, and past medical history variables. RESULTS: The largest difference in the median of the QoL-AD score was in those who needed help to eat, those with moderate or severe dementia, those classified as frail or pre-frail, those with moderate social risk, and those with depression. Also, C-QoL was lower than the P-QoL, and the QoL-AD of individuals with severe dementia was lower than for milder forms of the disease. Not needing help to eat, not having a stressful situation in the past 3 months, and the years of education were positively correlated with QoL-AD in the linear model. CONCLUSION: As studies in similar populations with AD, factors with more impact on QoL are those related to loss of functionality and independence. These factors are also associated with variables related to the current literature with the burden of the disease for the caregivers.

Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer's disease: findings from the Colombia-Boston (COLBOS) biomarker study.

BACKGROUND: Neuroimaging studies of autosomal dominant Alzheimer's disease (ADAD) enable characterization of the trajectories of cerebral amyloid-ß (Aß) and tau accumulation in the decades prior to clinical symptom onset. Longitudinal rates of regional tau accumulation measured with positron emission tomography (PET) and their relationship with other biomarker and cognitive changes remain to be fully characterized in ADAD. METHODS: Fourteen ADAD mutation carriers (Presenilin-1 E280A) and 15 age-matched non-carriers from the Colombian kindred underwent 2-3 sessions of Aß (11C-Pittsburgh compound B) and tau (18F-flortaucipir) PET, structural magnetic resonance imaging, and neuropsychological evaluation over a 2-4-year follow-up period. Annualized rates of change for imaging and cognitive variables were compared between carriers and non-carriers, and relationships among baseline measurements and rates of change were assessed within carriers. RESULTS: Longitudinal measurements were consistent with a sequence of ADAD-related changes beginning with Aß accumulation (16 years prior to expected symptom onset, EYO), followed by entorhinal cortex (EC) tau (9 EYO), neocortical tau (6 EYO), hippocampal atrophy (6 EYO), and cognitive decline (4 EYO). Rates of tau accumulation among carriers were most rapid in parietal neocortex (~ 9%/year). EC tau PET signal at baseline was a significant predictor of subsequent neocortical tau accumulation and cognitive decline within carriers. CONCLUSIONS: Our results are consistent with the sequence of biological changes in ADAD implied by cross-sectional studies and highlight the importance of EC tau as an early biomarker and a potential link between Aß burden and neocortical tau accumulation in ADAD.

Differential Profile of Systemic Extracellular Vesicles From Sporadic and Familial Alzheimer's Disease Leads to Neuroglial and Endothelial Cell Degeneration.

Evidence suggests that extracellular vesicles (EVs) act as mediators and biomarkers of neurodegenerative diseases. Two distinct forms of Alzheimer disease (AD) are known: a late-onset sporadic form (SAD) and an early-onset familial form (FAD). Recently, neurovascular dysfunction and altered systemic immunological components have been linked to AD neurodegeneration. Therefore, we characterized systemic-EVs from postmortem SAD and FAD patients and evaluated their effects on neuroglial and endothelial cells. We found increase CLN-5 spots with vesicular morphology in the abluminal portion of vessels from SAD patients. Both forms of AD were associated with larger and more numerous systemic EVs. Specifically, SAD patients showed an increase in endothelial- and leukocyte-derived EVs containing mitochondria; in contrast, FAD patients showed an increase in platelet-derived EVs. We detected a differential protein composition for SAD- and FAD-EVs associated with the coagulation cascade, inflammation, and lipid-carbohydrate metabolism. Using mono- and cocultures (endothelium-astrocytes-neurons) and human cortical organoids, we showed that AD-EVs induced cytotoxicity. Both forms of AD featured decreased neuronal branches area and astrocytic hyperreactivity, but SAD-EVs led to greater endothelial detrimental effects than FAD-EVs. In addition, FAD- and SAD-EVs affected calcium dynamics in a cortical organoid model. Our findings indicate that the phenotype of systemic AD-EVs is differentially defined by the etiopathology of the disease (SAD or FAD), which results in a differential alteration of the NVU cells implied in neurodegeneration.

The Role of Gait Speed in Dementia: A Secondary Analysis from the SABE Colombia Study.

INTRODUCTION: Gait speed (GS) is a predictor of negative outcomes in older adults and in those in risk to develop cognitive impairment; as such, it has been associated with dementia. Studies in Latin-American older adults showing this association are scarce. This study aimed to evaluate the relationship between GS and dementia in a representative sample of Colombian older adults. METHODS: This study is a secondary analysis from the Survey on Health, Well-Being, and Aging, SABE (from initials in Spanish: Salud, Bienestar & Envejecimiento) Colombia's survey conducted in 2015 with a sample of 23,694 elderly adults aged 60 years or older. RESULTS: A total of 19,470 participants from the SABE Colombia survey were available for analysis. The multivariate analysis shows that dementia was associated with slow GS (PR 2.39; CI 1.91-3.01) independently to the other variables (p < 0.001). Similarly, GS as a continuous variable shows a statistically significant association with dementia in the adjusted analysis (OR 0.06; CI 0.04-0.09; p < 0.001). CONCLUSION: Dementia was associated with slow GS. This finding provides evidence to include GS as a complementary parameter in the assessment of Colombian elderly adults.

Genetics of dementia: insights from Latin America.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are neurodegenerative disorders that result in a significant burden to both patients and caregivers. By 2050, the number of people with dementia in Latin America will increase 4-fold. A deep understanding of the relevant genetic factors of AD and FTD is fundamental to tackle this reality through prevention. A review of different genetic variants that cause AD or FTD in Latin America was conducted. We searched Medline and PubMed databases using the keywords "Alzheimer's disease," "frontotemporal dementia," "mutation," "America," and "Latin America," besides specific Latin American countries. Forty-five items were chosen and analyzed. PSEN1 mutations are the commonest cause of genetic early-onset Alzheimer's disease (EOAD), followed by PSEN2 and APP mutations. Genetic FTD can be mainly explained by GRN and MAPT mutations, as well as C9orf72 G4C2 repeat expansion. APOE ε4 can modify the prevalence and incidence of late-onset Alzheimer's disease (LOAD), in addition to the cognitive performance in affected carriers.

A doença de Alzheimer (DA) e a demência frontotemporal (DFT) são distúrbios neurodegenerativos que causam uma sobrecarga significativa para pacientes e cuidadores. Em 2050, o número de pessoas com demência na América Latina aumentará 4 vezes. Uma compreensão profunda dos fatores genéticos relevantes da DA e da DFT é fundamental para enfrentar essa realidade por meio da prevenção. Foi realizada uma revisão de diferentes variantes genéticas que causam a DA ou a DFT na América Latina. Pesquisamos os bancos de dados Medline e PubMed usando as palavras-chave "doença de Alzheimer", "demência frontotemporal", "mutação", "América" e "América Latina", além de países latino-americanos específicos. Quarenta e cinco itens foram escolhidos e analisados. As mutações do PSEN1 são a causa mais comum da doença de Alzheimer genética de início precoce (DAIP), seguida pelas mutações do PSEN2 e da APP. A DFT genética pode ser explicada principalmente por mutações no GRN, MAPT e expansões repetidas da C9orf72 G4C2. O APOE ε4 pode modificar a prevalência e a incidência da doença de Alzheimer de início tardio (DAIT), mas também o desempenho cognitivo em portadores afetados.

Genetics of dementia: insights from Latin America / Genética das demências: percepção a partir da América Latina

ABSTRACT. Alzheimer's disease (AD) and frontotemporal dementia (FTD) are neurodegenerative disorders that result in a significant burden to both patients and caregivers. By 2050, the number of people with dementia in Latin America will increase 4-fold. A deep understanding of the relevant genetic factors of AD and FTD is fundamental to tackle this reality through prevention. A review of different genetic variants that cause AD or FTD in Latin America was conducted. We searched Medline and PubMed databases using the keywords "Alzheimer's disease," "frontotemporal dementia," "mutation," "America," and "Latin America," besides specific Latin American countries. Forty-five items were chosen and analyzed. PSEN1 mutations are the commonest cause of genetic early-onset Alzheimer's disease (EOAD), followed by PSEN2 and APP mutations. Genetic FTD can be mainly explained by GRN and MAPT mutations, as well as C9orf72 G4C2 repeat expansion. APOE ε4 can modify the prevalence and incidence of late-onset Alzheimer's disease (LOAD), in addition to the cognitive performance in affected carriers.

RESUMO. A doença de Alzheimer (DA) e a demência frontotemporal (DFT) são distúrbios neurodegenerativos que causam uma sobrecarga significativa para pacientes e cuidadores. Em 2050, o número de pessoas com demência na América Latina aumentará 4 vezes. Uma compreensão profunda dos fatores genéticos relevantes da DA e da DFT é fundamental para enfrentar essa realidade por meio da prevenção. Foi realizada uma revisão de diferentes variantes genéticas que causam a DA ou a DFT na América Latina. Pesquisamos os bancos de dados Medline e PubMed usando as palavras-chave "doença de Alzheimer", "demência frontotemporal", "mutação", "América" e "América Latina", além de países latino-americanos específicos. Quarenta e cinco itens foram escolhidos e analisados. As mutações do PSEN1 são a causa mais comum da doença de Alzheimer genética de início precoce (DAIP), seguida pelas mutações do PSEN2 e da APP. A DFT genética pode ser explicada principalmente por mutações no GRN, MAPT e expansões repetidas da C9orf72 G4C2. O APOE ε4 pode modificar a prevalência e a incidência da doença de Alzheimer de início tardio (DAIT), mas também o desempenho cognitivo em portadores afetados.