Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy
Abstract
Several mutations in the amyloid precursor protein (APP) gene have been found to associate with pathologic deposition of the beta-amyloid peptide (Abeta) in neuritic plaques or in the walls of cerebral vessels. We report a mutation at a novel site in APP in a three-generation Iowa family with autosomal dominant dementia beginning in the sixth or seventh decade of life. The proband and an affected brother had progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. Neuropathological examination of the proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and unusually extensive distribution of Abeta40 in plaques. The affected brothers shared a missense mutation in APP, resulting in substitution of asparagine for aspartic acid at position 694. This site corresponds to residue 23 of Abeta, thus differing from familial Alzheimer's disease mutations, which occur outside the Abeta sequence. Restriction enzyme analysis of DNA from 94 unrelated patients with sporadic cerebral amyloid angiopathy-related hemorrhage found no other instances of this mutation. These results suggest a novel site within Abeta that may promote its deposition and toxicity.
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APP mutations can lead to cerebrovascular pathology including BBB breakdown and cerebral amyloid angiopathy in humans and transgenic animal models expressing human APP mutations.
“APP mutations can lead to cerebrovascular pathology including BBB breakdown and cerebral amyloid angiopathy (CAA), as shown in humans (49, 211, 356, 674) and transgenic animal models expressing human APP mutations (56, 57, 137, 321, 322, 331, 336, 405, 420, 464, 467, 512, 513, 579, 606).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [211]
Individuals with vasculotropic APP mutations within Aβ 21-23 residues, including Dutch, Arctic, Flemish, Iowa, and Italian mutations, develop prominent CAA causing extensive cerebrovascular pathology.
“Individuals with 'vasculotropic' APP mutations within A 𝛃 21-23 residues including Dutch (E693Q), Arctic (E693G), Flemish (A692G), Iowa (D694N), and Italian (E693K) mutation (49, 211, 335, 356, 526, 674) develop prominent CAA (238, 640) causing extensive cerebrovascular pathology.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [211]
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- Authors
- Grabowski, T. J., Cho, H. S., Vonsattel, J. P. G., Rebeck, G. W., & Greenberg, S. M.
- Affiliations
- University of Iowa (US)
- Harvard University (US)
- Corresponding author
- Greenberg, Steven M.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2001
- Volume
- 49
- Issue
- 6
- Pages
- 697-705
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2076453964
- Cited by
- 523
- References
- 3
- Citations by year
- 2026: 8 · 2025: 19 · 2024: 17 · 2023: 13 · 2022: 16 · 2021: 19 · 2020: 26 · 2019: 28 · 2018: 21 · 2017: 26 · 2016: 10 · 2015: 25 · 2014: 24 · 2013: 27 · 2012: 24
- FWCI
- 12.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG00725)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid precursor protein, APP mutations, cerebral amyloid angiopathy, familial dementia, amyloid-beta, Aβ40, neurofibrillary tangles, leukoencephalopathy, aphasia, missense mutations, familial Alzheimer's disease
- MeSH terms
- Aged, Amino Acid Sequence, Autopsy, Base Sequence, Dementia, DNA Mutational Analysis, Female, Genes, Dominant, Germany, Humans, Iowa, Magnetic Resonance Imaging, Male, Middle Aged, Occipital Lobe, Pedigree, Tomography, X-Ray Computed, Amyloid beta-Protein Precursor, Cerebral Amyloid Angiopathy, Age of Onset, Mutation, Missense
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