The genetics of Alzheimer's disease in Brazil: 10 years of analysis in a unique population.

Alzheimer's Disease (AD) is the most common type of dementia among the elderly, with devastating consequences for the patient, their relatives, and caregivers. More than 300 genetic polymorphisms have been involved with AD, demonstrating that this condition is polygenic and with a complex pattern of inheritance. This paper aims to report and compare the results of AD genetics studies in case-control and familial analysis performed in Brazil since our first publication, 10 years ago. They include the following genes/markers: Apolipoprotein E (APOE), 5-hidroxytryptamine transporter length polymorphic region (5-HTTLPR), brain-derived neurotrophin factor (BDNF), monoamine oxidase A (MAO-A), and two simple-sequence tandem repeat polymorphisms (DXS1047 and D10S1423). Previously unpublished data of the interleukin-1alpha (IL-1alpha) and interleukin-1 beta (IL-1beta) genes are reported here briefly. Results from others Brazilian studies with AD patients are also reported at this short review. Four local families studied with various markers at the chromosome 21, 19, 14, and 1 are briefly reported for the first time. The importance of studying DNA samples from Brazil is highlighted because of the uniqueness of its population, which presents both intense ethnical miscegenation, mainly at the east coast, but also clusters with high inbreeding rates in rural areas at the countryside. We discuss the current stage of extending these studies using high-throughput methods of large-scale genotyping, such as single nucleotide polymorphism microarrays, associated with bioinformatics tools that allow the analysis of such extensive number of genetics variables, with different levels of penetrance. There is still a long way between the huge amount of data gathered so far and the actual application toward the full understanding of AD, but the final goal is to develop precise tools for diagnosis and prognosis, creating new strategies for better treatments based on genetic profile.

A mutation in human VAP-B--MSP domain, present in ALS patients, affects the interaction with other cellular proteins.

Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset Motor Neuron Disease (MND), characterized by motor neurons death in the cortex, brainstem and spinal cord. Ten loci linked to Familial ALS have been mapped. ALS8 is caused by a substitution of a proline by a serine in the Vesicle-Associated Membrane Protein-Associated protein-B/C (VAP-B/C). VAP-B belongs to a highly conserved family of proteins implicated in Endoplasmic Reticulum-Golgi and intra-Golgi transport and microtubules stabilization. Previous studies demonstrated that the P56S mutation disrupts the subcellular localization of VAP-B and that this position would be essential for Unfolded Protein Response (UPR) induced by VAP-B. In the present work we expressed and purified recombinant wild-type and P56S mutant VAP-B-MSP domain for the analysis of its interactions with other cellular proteins. Our findings suggest that the P56S mutation may lead to a less stable interaction of this endoplasmic reticulum protein with at least two other proteins: tubulin and GAPDH. These two proteins have been previously related to other forms of neurodegenerative diseases and are potential key points to understand ALS8 pathogenesis and other forms of MND. Understanding the role of these protein interactions may help the treatment of this devastating disease in the future.

No evidence of association between the D10S1423 locus and Alzheimer disease in Brazilian patients.

In a genome survey for Alzheimer's disease (AD), Zubenko et al. (1998) reported that the 234bp allele of the D10S1423 locus was more frequent among AD cases than in controls. We have analyzed this polymorphic locus in patients and healthy controls and observed that the 226bp allele is the most frequent allele in the D10S1423 locus in Brazilian AD patients. However, no statistically significant association between any D10S1423 allele was observed in AD patients as well as in controls.

Analysis of the disease risk locus DXS1047 polymorphism in Brazilian Alzheimer patients.

Alzheimer's disease (AD) is a disorder characterized by a progressive deterioration in memory and other cognitive functions. Four genes associated with early onset AD have been identified but familial AD is rare. The majority of late onset AD (LOAD) is caused by a complex inheritance with several genes interacting with environmental factors. The epsilon4 allele of the apolipoprotein E (APOE) gene has been reported worldwide as a risk factor associated with LOAD. The short variant of a polymorphism in the transcriptional region of the serotonin transporter gene (5-HTTLPR) was analyzed in several psychiatric conditions and found to be more frequently associated with European and Brazilian LOAD patients. Recently, allelic associations with LOAD were reported for five other loci, the most significant for one X-linked 202-bp allele, at the DXS1047 locus. We have analyzed this locus in Brazilian LOAD patients and observed that the 202-bp allele was not significantly more frequent among patients. In contrast, two other alleles (200 bp and 208 bp) were less frequent among AD male patients than in controls, confirming the importance of replicating association studies in different populations.