A polymorphism in the cystatin C gene is a novel risk factor for late-onset Alzheimer’s disease

Crawford, Fiona; Freeman, Melissa J.; Schinka, John A.; Abdullah, Laila; Gold, Michael; Hartman, Richard D.; Krivian, K.; Morris, Mark; Richards, Dan R.; Duara, Ranjan; Anand, Ravi; Mullan, Michael

doi:10.1212/wnl.55.6.763

Cited by 105 publications

(75 citation statements)

References 36 publications

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“…4 Cystatin C is also believed to inhibit A␤ production and aggregation by the inhibition of cathepsins, a group of lysosomal proteases believed to promote A␤-amyloidogenesis. 26 Finally, there is genetic data that support a causal role for cystatin C in the development of AD, [8][9][10]27 although there are conflicting findings. 28 Interestingly, the Icelandic form of hereditary cerebral hemorrhage with amyloidosis is caused by a mutation in the cystatin C gene, and these patients are characterized by low levels of cystatin C in CSF as well as in the systemic circulation, increased deposition of A␤ in cerebral blood vessels, dementia and death before age 40 years.…”

Section: Resultsmentioning

confidence: 99%

“…Cystatin C is an endogenous cysteine inhibitor, produced by nearly all human cells and available in all body fluids. 1 During the past decade, experimental, 2-7 genetic, [8][9][10] and clinical data 6,11,12 have suggested that cystatin C activity in the brain may protect against the development of Alzheimer disease (AD) by inhibition of A␤ aggregation, one of the pathologic hallmarks of AD. 13 Recently, it was shown that in a transgenic mouse model, cystatin C binds to soluble A␤, preventing its deposition in the brain.…”

Section: Conclusion: Low Levels Of Serum Cystatin C Precede Clinicalmentioning

confidence: 99%

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Serum cystatin C and the risk of Alzheimer disease in elderly men

Sundelöf

Ärnlöv²,

Ingelsson³

et al. 2008

Neurology

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Section: Resultsmentioning

confidence: 99%

Section: Conclusion: Low Levels Of Serum Cystatin C Precede Clinicalmentioning

confidence: 99%

Serum cystatin C and the risk of Alzheimer disease in elderly men

Sundelöf

Ärnlöv²,

Ingelsson³

et al. 2008

Neurology

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“…The initial report identified the GG genotype with AD risk for survivors to ages 80 years and older (p ϭ 0.04). 6 Subsequently, a two-loci haplotype labeled B for promoter region and exon 1 G/A polymorphisms (n ϭ 907) 1 demonstrated a fourfold elevated risk, higher at age 75 years and older. A Japanese sample did not indicate a statistically significant association for CST 3 AA/AG or for APOE4 (low frequency among Japanese).…”

Section: Methodsmentioning

confidence: 99%

“…3 A polymorphism associated with AD is located in exon 1: A G/A transition results in Ala/Thr as the penultimate amino acid of the signal peptide, thought to reduce secretion and constitutive extracellular levels. 1,[4][5][6] The GG genotype doubles the risk in patients at ages 80 and older. 6 Subsequent studies did not replicate this finding or the associated risk with the A allele and at younger ages.…”

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confidence: 99%

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Ventromedial frontal lobe trauma

Ellenbogen¹,

Hurford²,

Liebeskind³

et al. 2005

Neurology

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Abstract-Cystatin C, a protease inhibitor with widespread distribution, is upregulated in response to injury. Levels are elevated in the brains of patients with Alzheimer disease (AD). We compared frequencies for the CST 3 exon 1 polymorphism in patients with AD and controls. A proportional odds model indicated that the CST 3 A and APOE4 combination carried a high risk: a 14-fold elevation for men and 16-fold for women. These risks apply to risk at ages older than 64 years and to a shift in onset to ages younger than 65 years. NEUROLOGY 2005;64:755-757 H.M. Cathcart, MS; R. Huang, MD; I.S. Lanham, BS; E.H. Corder, PhD; and S.E. Poduslo, PhD Cystatin C is a proteinase inhibitor of the cathepsins. It has wide distribution and is localized to both neurons and glia. Expression increases in response to injury.1 The protein colocalizes with the A␤ peptide in brain amyloid deposits in patients with Alzheimer disease (AD), in senile plaque, and in vessel walls.2 At least four polymorphisms have been described: two in the 5'-untranslated region and in exons 1 and 2. 1The gene for cystatin C is situated on chromosome 20, 20p11.2. It is 7.3 kb long and consists of three exons.3 A polymorphism associated with AD is located in exon 1: A G/A transition results in Ala/Thr as the penultimate amino acid of the signal peptide, thought to reduce secretion and constitutive extracellular levels.1,4-6 The GG genotype doubles the risk in patients at ages 80 and older.6 Subsequent studies did not replicate this finding or the associated risk with the A allele and at younger ages. 7-9We compared the frequencies of CST 3 A and G alleles found for 179 AD cases and 141 spouse control subjects. The combination of one or two A alleles, i.e., the AG or AA genotypes, and APOE4 carried a high risk, shifting the onset to younger ages.Methods. Subjects. There were 179 patients with AD (white; 126 female, 53 male; average age at onset 71 Ϯ 8 years, 142 older than 65 years) and 141 spouse control subjects (white; 83 female, 58 male; average age at onset 72 Ϯ 8 years, 120 older than 65 years). The clinical diagnosis of probable AD was made according to National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria (see reference E-1 on the Neurology Web site at www. neurology.org). We also included a CT scan or MRI or both that showed cortical atrophy. Each participant or authorized representative gave written informed consent for the study in accordance with institutional review board guidelines. Enrollment occurred in Texas and Georgia; additional cases were obtained from the National Cell Repository. Mean ages and sex frequencies for each case group were similar. The three groups were analyzed separately for population stratification by allele frequencies (see reference E-2), and no significant differences were found; thus, they were combined for the analysis.Genotyping. APOE was genotyped as before (see reference E-3). The primers for the CST 3 exon 1 polymorphism and pr...

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Current Awareness

2001

Int. J. Geriat. Psychiatry

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In order to keep subscribers up‐to‐date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of geriatric psychiatry. Each bibliography is divided into 9 sections: 1 Books, Reviews & Symposia; 2 General; 3 Assessment; 4 Epidemiology; 5 Therapy; 6 Care; 7 Dementia; 8 Depression; 9 Psychology. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted

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A polymorphism in the cystatin C gene is a novel risk factor for late-onset Alzheimer’s disease

Cited by 105 publications

References 36 publications

Serum cystatin C and the risk of Alzheimer disease in elderly men

Serum cystatin C and the risk of Alzheimer disease in elderly men

Ventromedial frontal lobe trauma

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