Ekaterina Rogaeva, PhD, Associate Professor, Centre for Research in Neurodegenerative Diseases, University of Toronto, Department of Medicine, Toronto, ON.

There are at least four well-confirmed genes responsible for Alzheimer’s disease (AD), the most common form of dementia. In addition, many reports indicate an association between the disease and genetic variations in different gene candidates. The complexity and interpretation of these studies are discussed using, as an example, the recent discovery of the association between AD and the SORL1 gene. The knowledge obtained from AD genetics is applicable to many other forms of dementia, which are also genetically complex disorders and are almost all associated with the deposition of different aberrant proteins in the brain.
Key words: Alzheimer’s disease, gene, APP, APOE, SORL1.

Yosuke Wakutani, MD, Centre for Research in Neurodegenerative Diseases, Departments of Medicine, University of Toronto, and Toronto Western Hospital Research Institute, Toronto, ON.
Peter St. George-Hyslop, MD, Centre for Research in Neurodegenerative Diseases, Departments of Medicine, University of Toronto, and Toronto Western Hospital Research Institute, Toronto, ON.
Ekaterina Rogaeva, PhD, Centre for Research in Neurodegenerative Diseases, Departments of Medicine, University of Toronto, and Toronto Western Hospital Research Institute, Toronto, ON.

There are ~200 human diagnostic categories presenting as or accompanying dementia (interested readers may investigate the database Online Mendelian Inheritance in Man, a catalog of human genes and genetic disorders, at www.ncbi.nlm.nih.gov/ genome/guide/human/). Many forms of dementia are associated with deposition of different aberrant proteins in the brain. Familial aggregation in Alzheimer’s disease (AD), frontotemporal dementia (FTD), and other forms of dementia implies the presence of inherited susceptibility factors. Many forms of dementia remain genetically unexplained; however, linkage analyses suggest that most of them are complex disorders with several underlying genetic factors. Here we provide an update on known genes responsible for dementia with the strongest focus on AD and FTD, which are the most common forms of dementia.
Key words: dementia, Alzheimer’s disease, gene, APP, APOE, frontotemporal dementia.

Ekaterina Rogaeva, PhD, Assistant Professor, Department of Medicine, University of Toronto, Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON.

To date, four genes responsible for Alzheimer disease (AD) have been identified. However, in about 50% of the familial AD cases, there is no known cause of the disease. The majority of AD cases are sporadic with onset after 65 years of age. The apolipoprotein E gene is the only well-replicated risk factor for late-onset AD. Up to 5% of AD cases are early-onset AD, for which genetic analyses have found three causal genes: b-amyloid precursor protein, presenilin-1 and presenilin-2. Treatment and diagnostic strategies based on genetic knowledge are now about to reach the clinic.
Key words: Alzheimer disease, presenilin, gene, bAPP, apolipoprotein E.

Introduction
Alzheimer disease (AD) is a progressive dementia and is the fourth leading cause of death in industrialized countries. AD brain pathology is characterized by neuronal loss, intra-neuronal tau-accumulation and extracellular amyloid plaques. The plaques consist mainly of Ab40/42 peptides generated by cleavage of the b-amyloid precursor protein (bAPP) (Figure 1). The longer and more neurotoxic isoforms, Ab42, appear to be elevated in the brains of individuals affected with either sporadic or familial AD, implying that they have a shared pathogenetic mechanism.

A team of researchers studying highly inbred families in Kuwait, Tunisia and Saudi Arabia has identified a new gene for an inherited form of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. Although only 5-10% of cases of ALS are hereditary, the findings may explain the mechanisms that underlie the disease.

ALS2 is an autosomal recessive form of juvenile ALS and has been mapped to chromosome 2q33. The researchers reported two independent deletion mutations linked to ALS2 in the coding region of a new gene, ALS2. The deletion mutations lead to frameshifts that generate premature stop codons. The gene is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein that is suggested to be a putative GTPase regulator. Deletion mutations that are predicted to cause a loss of protein function provide strong evidence that ALS2 is the causative gene underlying this form of the disease.

It is hoped that if the gene controls a protein that is necessary for cell survival, this could help in the development of drugs to protect these neurons in ALS, and possibly in other forms of neurodegenerative diseases.

Source

1. Hadano S, Hand CK, Osuga H, et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nature Genetics 2001;29:166-173.

After twenty years of searching, Toronto researchers have located a gene in mice called opgl, that can activate mature osteoclasts and mediate osteoclastogenesis. The tumour-necrosis-factor family molecule osteoprotegerin ligand (OPGL), is an important factor for osteoclast maturation in vivo. Mice who lack the opgl gene exhibited severe osteopetrosis, stunted growth, defective tooth eruption and a complete lack of lymph nodes. Scientists also discovered that the gene was necessary for T- and B-cell maturation. Interestingly researchers found that OPGL secreted from activated T cells may "directly modulate osteoclastogenesis and the activity of mature osteoclasts." Although the implications of this discovery for humans are as yet undetermined, this may bring scientists one step closer to finding a cure for osteoporosis and T-cell-mediated arthritis.

For the full article see Nature 1999;397:315-23.

Shari Al, BSc, MSc

Alzheimer's Disease (AD) is defined as a disorder characterized by the progressive deterioration of mental function. Specific research into the genetics of this disease has recently uncovered several important details as to the pathology and progression of the disorder. These discoveries, in turn, may lead to improved diagnosis and/or treatment of AD, with obvious repercussions for clinicians. In the case of AD genetic heterogeneity and the discovery that variations at any one of several loci cause the same disease, initially made it difficult for researchers to progress. The table below summarizes the results of current genetic research showing which genes are linked to each specific type of AD, and the percentage of patients affected by each type.