Genetic associations between cathepsin D exon 2 C->T polymorphism and Alzheimer's disease, and pathological correlations with genotype
Open accessAbstract
Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C-->T (224Ala-->Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD. The objective of this study was to investigate whether possession of the CTSD exon 2 T allele increases the risk of developing AD, and to determine whether this modulates the amyloid pathology of the disease in conjunction with, or independent of, the APOE e4 allele. Blood samples were obtained from 412 patients with possible or probable AD and brain tissues from a further 148 patients with AD confirmed by postmortem examination. CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases. Pathological measures of amyloid beta protein (Abeta), as plaque Abeta40 and Abeta42(3) load and degree of cerebral amyloid angiopathy were made by image analysis or semiquantitative rating, respectively. CTSD genotype frequencies in AD were not significantly different from those in control subjects, nor did these differ between cases of early or late onset AD or between younger and older controls. There was no gene interaction between the CTSD T and APOE e4 alleles. The amount of plaque Abeta40 was greater in patients carrying the CTSD T allele than in non-carriers, and in patients bearing APOE e4 allele compared with non-carriers. Possession of both these alleles acted synergistically to increase levels of plaque Abeta40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Abeta42(3) load or degree of CAA. Possession of the CTSD T allele does not increase the risk of developing AD per se, but has a modulating effect on the pathogenesis of the disorder by increasing, in concert with the APOE e4 allele, the amount of Abeta deposited as senile plaques in the brain in the form of Abeta40.
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Post-differentiation, neurons must survive many decades without dividing or being replaced, so they rely more heavily on clearance pathways such as the lysosome-autophagy system.
“Post-differentiation, neurons must survive many decades without dividing or being replaced. Thus, they rely more heavily that cells that are turned over on clearance pathways such as the lysosome-autophagy system.44”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [44]
The Discussion (page unavailable) addresses amyloid-β clearance and cathepsin D activity, not how long neurons survive or whether they depend more heavily than other cells on lysosome-autophagy pathways. Searches for post-differentiation, neuronal turnover, and lysosomal-autophagy clearance found no passage addressing that comparison. (LLM, conf=0.75)
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Cites
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The Role of Cathepsin D in the Pathogenesis of Human Neurodegenerative Disorders
Vidoni, C., Follo, C., Savino, M., Melone, M. A. B., & Isidoro, C. (2016) · Medicinal Research Reviews · doi:10.1002/med.21394 · Cited by 164 · see citing works
Haure-Mirande, J.-V., Audrain, M., Fanutza, T., Kim, S. H., Klein, W. L., Glabe, C., Readhead, B., Dudley, J. T., Blitzer, R. D., Wang, M., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1737-3 · Cited by 127 · see citing works
Lane-Donovan, C., Paredes, M., & Kao, A. W. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102854 · Cited by 3 · see citing works
- Authors
- Davidson, Y.
- Affiliations
- University of Manchester (GB)
- Corresponding author
- Davidson, Y
- Venue
- Journal of Neurology, Neurosurgery & Psychiatry
- Publisher
- BMJ
- Published
- 2006-04-01
- Volume
- 77
- Issue
- 4
- Pages
- 515-517
- ISSN
- 0022-3050 (ISSN-L)
- PMC
- PMC2077521
- OpenAlex
- W2145683911
- Cited by
- 45
- References
- 1
- Citations by year
- 2025: 4 · 2024: 6 · 2022: 4 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 1 · 2014: 2 · 2013: 2 · 2012: 1
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cathepsin D, APOE ε4, genetic risk factors, amyloid plaques, Aβ40, cerebral amyloid angiopathy, gene-gene interaction, late-onset Alzheimer's disease, postmortem brain
- MeSH terms
- Aged, Alleles, Alzheimer Disease, Apolipoproteins E, Cathepsin D, Exons, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Polymorphism, Genetic, Prospective Studies, Risk Factors, Sensitivity and Specificity, Gene Expression, Polymerase Chain Reaction, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Point Mutation, Apolipoprotein E4, Plaque, Amyloid
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