Further Evidence Linking Late-Onset Alzheimer Disease With Chromosome 12

Scott, William K.; Grubber, Janet M.; Abou-Donia, Suzanne M.; Church, Tony D.; Saunders, Ann M.; Roses, Allen D.; Pericak‐Vance, M. A.; Conneally, P. Michael; Small, Gary W.; Haines, Jonathan L.

doi:10.1001/jama.281.6.513

Cited by 37 publications

(27 citation statements)

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“…In EOAD, several families have been reported in which mutations in the known AD genes were excluded [63,165], but no new chromosomal loci have been identified to date. More progress is made in LOAD, where several genome scans have revealed candidate loci on chromosome 9, 10, and 12 [166,167,168,169,170,171,172,173,174]. Although a number of genes from these chromosomal loci are proposed as potential AD genes, i.e., insuline degrading enzyme (IDE), α2 macroglobuline (A2M), and more recently urokinase-type plasminogen activator (uPA), none of the candidate genes have shown indisputable results in mutation and association studies [175,176].…”

Section: Resultsmentioning

confidence: 99%

Genetics of Early-Onset Alzheimer Dementia

Rademakers

Cruts

Broeckhoven

2003

The Scientific World JOURNAL

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Alzheimer's dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD). To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the ε4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD. Many studies reported other susceptibility genes, but the APOE 4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological pathway resulting in abnormal APP processing by subtle different mechanisms. Now, transgenic mice are produced to study the influence of EOAD mutations in vivo, eventually leading to the development of novel therapeutic strategies. KEYWORDS:Alzheimer dementia, neurodegeneration, mutations, linkage analysis, association analysis, mouse models DOMAINS: genetics (man), aging, neuroscience INTRODUCTIONAlzheimer's disease (AD) is a degenerative disorder of the central nervous system that causes progressive memory loss and cognitive decline during mid to late adult life, leading to dementia and ultimately death. AD is the most common form of dementia in the elderly, and represents the fourth largest cause of death in the developed world. In the near future, the impact of AD on our society will dramatically increase since, as populations live longer, the number of elderly people continues to grow.The clinical symptoms of AD display a substantial overlap with clinical symptoms observed in other neurodegenerative disorders with dementia as accompanying feature, such as *Corresponding author. Address: Department of Molecular Genetics (VIB8), Neurogenetics Group, University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerpen, Belgium; Tel: +32 3 8202601/Fax: +32 3 8202541 ©2003 with author.497 Rademakers et al.: Genetics of Early-Onset Alzheimer Dementia TheScientificWorldJOURNAL (2003) 3, 497-519 frontotemporal dementia (FTD) and Creutzfeldt Jacob's disease (CJD). Therefore a definite diagnosis of AD can only be obtained at autopsy. Extensive neuronal loss, and two particular brain lesions in the cerebral cortex, hippocampus, and amygdala characterize AD: the senile plaques (SPs) and neurofibrillary tangles (NFTs). The SPs are compact extracellular deposits that consist of a large amyloid β (Aβ) core surrounded by dystrophic neurites. NFTs are intraneuronal inclusions of paired helical filaments (PHF) that are mainly composed of hyperphosphorylated microtubule associated protein tau (MAPT).Based on the age at which the first clinical symptoms become...

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Section: Resultsmentioning

confidence: 99%

Genetics of Early-Onset Alzheimer Dementia

Rademakers

Cruts

Broeckhoven

2003

The Scientific World JOURNAL

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“…Subsequent work by her group, ourselves, and others has suggested that there may be two separate loci on chromosome 12 depending on the presence of APOE-e4 and clinical heterogeneity related to the presence of Lewy bodies. 5,10,16,36,38,39,41 In the initial scan, Kehoe et al 3 observed a peak at 12p only for the APOE-e4 negative families, not for the APOE-e4-positive families. However, when Blacker et al 38 followed up the earlier genome scan using a larger sample, the support for linkage on 12p weakened.…”

Section: Discussionmentioning

confidence: 99%

Fine mapping of 10q and 18q for familial Alzheimer's disease in Caribbean Hispanics

et al. 2004

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Familial Alzheimer's disease (AD [MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the lateonset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly lateonset AD. We observed the strongest support for linkage on 18q (LOD ¼ 3.14). However, 17 additional markers (chromosomes 1-6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112 cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P ¼ 0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134-138 cM), the NPL score decreased from 3.15 (P ¼ 0.000486) to 2.1 (P ¼ 0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimer's disease, and strong evidence for a new locus on 18q.

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“…In addition, other methods such as population-based linkage disequilibrium have been employed (Daw et al 1999). These analyses have identified susceptible loci on chromosomes 1, 9, 10, 12, and 13 for late-onset AD (Kehoe et al 1999;Hiltunen et al 1999;Scott et al 1999;Ertekin-Taner et al 2000;Bertram et al 2000;Myers et al 2000). Additionally, late-onset AD is associated with genetic polymorphisms in genes for apolipoprotein E (APOE) Corder et al 1993); presenilin-1; butyrylcholine esterase K, an enzyme that can hydrolyze choline esters including acetylcho-line (Tilly et al 1999); very low-density lipoprotein receptor (McIlroy et al 1999); lipoprotein lipase, which hydrolyzes triglycerides (Baum et al 1999); choline acetyltransferase (Baskin et al 1999); deficiency in aldehyde dehydrogenase-2, which metabolizes acetaldehyde produced from ethanol to acetate (Kamino et al 2000); estrogen receptor α (Brandi et al 1999); low-density lipoprotein receptor-related protein, which is a receptor for APOE; α-2-microglobulin, which is a serum protease inhibitor (Wavrant-DeVrieze et al 1999;Alvarez et al 1999); α-1-chymotrypsin inhibitor; bleomysin hydrolase (see review by Shastry and Giblin 1999); myeloperoxidase; dihydrolipoylsuccinyl transferase; N-acetyl transferase; angiotensin-converting enzyme; cathepsin D; transferrin; human leukocyte antigen (HLA) (A2 allele); seretonin receptor; interleukin-6 (Tanzi 1999); cystatin C (Finckh et al 2000); and transcription factor LBP-1c/CP2/LSF (Lambert et al 2000).…”

Section: Late-onset Admentioning

confidence: 99%

Molecular and cell biological aspects of Alzheimer disease

Shastry

2001

J Hum Genet

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Alzheimer disease (AD) is one of several types of chronic and very common dementing disorders, affecting individuals aged 65 years or older. During the last five years, an enormous growth in the field has enriched our understanding of this complex condition. Molecular genetic studies have identified at least three genes that, when mutated, cause the autosomal dominant, early-onset familial form of the disease. The late-onset, most common forms of the disease are likely to be associated with various genetic susceptibility factors. The application of cell biological techniques has given insight into basic aspects of the functions of important proteins involved in disease progression, and transgenic animal studies have further enriched our knowledge of the pathophysiological aspects of the disease. More efficient therapeutic drugs to retard its progression have been developed, as well as techniques to identify the preclinical phase of the disorder. Although we are still lacking the molecular basis and order of events involved in the disease process, the future for AD research, as well as for AD patients, is more promising than ever before.

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Further Evidence Linking Late-Onset Alzheimer Disease With Chromosome 12

Cited by 37 publications

References 2 publications

Genetics of Early-Onset Alzheimer Dementia

Genetics of Early-Onset Alzheimer Dementia

Fine mapping of 10q and 18q for familial Alzheimer's disease in Caribbean Hispanics

Molecular and cell biological aspects of Alzheimer disease

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