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Cited by 265Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

REVIEWThe Gene Defects Responsible for Familial Alzheimer's Disease

Tanzi, Rudolph E., Kovacs, Dora M., Kim, Tae-Wan, Moir, Robert D., Guenette, Suzanne Y., Wasco, Wilma·1996·Neurobiology of Disease
DOI 10.1006/nbdi.1996.0016
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Abstract

Four different genes have now been found to contain AD-associated mutations or polymorphisms. While the pathogenic mutations in the early-onset FAD genes, APP, PS1, and PS2 directly cause AD with nearly 100% penetrance, in a larger subset of AD cases with onset over 60 years (maximally for onset at 61-65 years), inheritance of the APOE4 allele confers increased risk for AD but is not sufficient to cause the disease. Together, these four genes appear to account for approximately 50% of FAD cases. We are actively screening the genome for additional FAD loci by genotyping markers in over 400 FAD nuclear pedigrees and affected sib-pairs (83% late-onset and 17% early-onset). We have recently discovered genetic linkage to a novel FAD locus on chromosome 12 as well as another putative locus on chromosome 3 (unpublished findings). Positional cloning strategies are currently under way to identify these potentially novel FAD genes. A common event which is associated with all of the known FAD genes is the excessive accumulation of the A beta peptide and deposition of beta-amyloid in the brain. Thus, a common pathogenic pathway for AD neuropathogenesis appears to center around the cellular trafficking, maturation, and processing of APP, and the subsequent generation, aggregation, and deposition of A beta (or more specifically, A beta 1-42). APP and presenilin gene mutations most likely act as either gain-of-function or dominant negative gene defects which may ultimately lead to the transport of APP into intracellular compartments that promote the enhanced production of A beta or A beta 1-42. AD patients who carry an APOE4 allele experience increased amyloid burden in their brains compared to APOE4-negative AD cases. Thus, the presence of APOE4 would also appear to lead to abnormal generation, aggregation, or clearance of A beta in the brain A beta, perhaps by working in concert with its neuronal receptor, LRP. While the exact mechanisms by which the known FAD gene changes lead to the onset of AD remain unclear, the available data indicate that novel therapies aimed at curbing the generation, aggregation, and deposition of A beta would appear to carry the greatest potential for the effective treatment of this formidable disease.

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Crossref · 10.1006/nbdi.1996.0016

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  • More than 160 mutations are reported in three genes coding amyloid precursor, presenilin 1, and presenilin 2.

    “There are more than 160 mutations reported in three important genes which are responsible for coding amyloid precursor, presenilin 1, and presenilin 2 [67].”

    From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [67]

  • The association between ApoE ε4 allele carriers and occurrence of AD is well-accepted and lowers the overall age for onset of AD.

    “From now onwards, the association between the ApoE ε4 allele carriers and the occurrence of AD is well-accepted as it also lowers the overall age for onset for AD [66, 67], but does not hold any specific inference for the individual carrier.”

    From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [67]

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Authors
Tanzi, R. E., Kovacs, D. M., Kim, T.-W., Moir, R. D., Guenette, S. Y., & Wasco, W.
Affiliations
Harvard University (US)
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
1996-06
Volume
3
Issue
3
Pages
159-168
ISSN
0969-9961 (ISSN-L)
DOI
10.1006/nbdi.1996.0016
OpenAlex
W2035176443
Cited by
265
References
0
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 8 · 2015: 7 · 2014: 3 · 2013: 5 · 2012: 9
FWCI
15.99
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
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
familial Alzheimer's disease, APP gene, presenilin 1, presenilin 2, APOE ε4, late-onset Alzheimer's disease, genetic linkage, amyloid-beta, amyloid-beta deposition, APP processing, gain-of-function mutations, dominant negative mutation, Alzheimer's disease pathogenesis, positional cloning
MeSH terms
Alzheimer Disease, Animals, Humans, Membrane Proteins, Mutation, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Presenilin-1, Presenilin-2

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