Genetics of dementia: insights from Latin America

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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.

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Most cited references 55

Record: found
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Resistance to autosomal dominant Alzheimer’s in an APOE3 -Christchurch homozygote: a case report

Joseph Arboleda-Velasquez, Francisco Lopera, Michael N. O’Hare … (2019)

We identified a PSEN1 mutation carrier from the world’s largest autosomal dominant Alzheimer’s disease kindred who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. She had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid, and limited tau/tangle and neurodegenerative measurements. Our findings have implications for APOE’s role in the pathogenesis, treatment, and prevention of Alzheimer’s disease.

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Record: found
Abstract: found
Article: not found

MAPT mutations, tauopathy, and mechanisms of neurodegeneration

Kevin H. Strang, Todd E. Golde, Benoit Giasson (2019)

In multiple neurodegenerative diseases, including Alzheimer’s disease (AD), a prominent pathological feature is the aberrant aggregation and inclusion formation of the microtubule associated protein tau. Because of the pathological association, these disorders are often referred to as tauopathies. Mutations in the MAPT gene that encodes tau can cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), providing the clearest evidence that the tauopathy plays a causal role in neurodegeneration. However, large gaps in our knowledge remain regarding how various FTDP-17 linked tau mutations promote tau aggregation and neurodegeneration, and more generally how the tauopathy is linked to neurodegeneration. Herein, we review what is known about how FTDP-17-linked pathogenic MAPT mutations cause disease with a major focus on the prion-like properties of wild-type and mutant tau proteins. The hypothesized mechanisms by which mutations in the MAPT gene promote tauopathy are quite varied, and may not provide definitive insights into how tauopathy arises in the absence of mutation. Further, differences in the ability of tau and mutant tau proteins to support prion-like propagation in various model systems raises questions about the generalizability of this mechanism in various tauopathies. Notably, understanding the mechanisms of tauopathy induction and spread and tau-induced neurodegeneration have important implications for tau-targeting therapeutics.

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Record: found
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Article: not found

Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes.

B. Rall, R Mahley, Alex Y C Huang (1999)

Type III hyperlipoproteinemia (HLP) is a genetic disorder characterized by accumulation of remnant lipoproteins in the plasma and development of premature atherosclerosis. Although receptor binding-defective forms of apolipoprotein (apo) E are the common denominator in this disorder, a number of apparent paradoxes concerning its pathogenesis still exist. However, studies in transgenic animals are resolving the mechanisms underlying this disorder. PARADOX I: Defective apoE (commonly apoE2) is essential but not sufficient to cause overt type III HLP. In fact, most apoE2 homozygotes are hypolipidemic. Studies in apoE2 transgenic models have demonstrated the impact of other genes or hormones in converting the hypolipidemia to hyperlipidemia. PARADOX II: Among apoE2 homozygotes, men are more susceptible than women to type III HLP. Transgenic studies have shown that estrogen affects both LDL receptor expression and lipolytic processing, explaining the resistance of women to this disorder until after menopause. PARADOX III: ApoE deficiency is associated with hypercholesterolemia, whereas the type III HLP phenotype is characterized by both hypercholesterolemia and hypertriglyceridemia. The hypercholesterolemia is caused by impaired receptor-mediated clearance, whereas the hypertriglyceridemia is caused primarily by impaired lipolytic processing of remnants and increased VLDL production associated with increased levels of apoE. PARADOX IV: ApoE2 is associated with recessive inheritance of this disorder, whereas other defective apoE variants are associated with dominant inheritance. Determinants of the mode of inheritance are the differential binding of apoE variants to the LDL receptor versus the HSPG/LRP complex and the preference of certain apoE variants for specific lipoproteins. Thus, the pathogenesis of this sometimes mysterious disorder has been clarified.

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Author and article information

Journal

Journal ID (nlm-ta): Dement Neuropsychol

Journal ID (iso-abbrev): Dement Neuropsychol

Journal ID (publisher-id): dn

Title: Dementia & Neuropsychologia

Publisher: Associação de Neurologia Cognitiva e do Comportamento

ISSN (Print): 1980-5764

ISSN (Electronic): 1980-5764

Publication date (Print and electronic): Jul-Sep 2020

Publication date (Print): Jul-Sep 2020

Volume: 14

Issue: 3

Pages: 223-236

Affiliations

[1 ]Neurosciences Group of Antioquia, School of Medicine, Universidad de Antioquia - Medellín, Colombia.

[2 ]UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco - San Francisco, CA, United States.

Author notes

Claudia Ramos. Calle 62, 52-59 - Sede de Investigación Universitaria - 050010 Medellín - Colombia. E-mail: claudia.ramos@ 123456gna.org.co

Disclosure: C. Cordano reports no conflicts of interest. C. Ramos reports the following (pertinent to the last five years): grant and contract support from the National Institute on Aging (NIA), Genentech/Roche, and an anonymous foundation to develop the Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease (API ADAD) Registry and helped conduct the API ADAD Trial in Colombia. D. Aguillón reports the following (pertinent to the last five years): grant and contract support from NIA, Genentech/Roche, and an anonymous foundation to develop the API ADAD Registry. F. Lopera reports the following (pertinent to the last five years): grant and contract support from NIA, Genentech/Roche, and an anonymous foundation to develop the API ADAD Registry and helped conduct the API ADAD Trial in Colombia. The authors have no financial interests related to the material in the manuscript.

Authors’ contributions. All authors contributed significantly to and approved the content of this manuscript.