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Vascular Pathology in Alzheimer Disease: Correlation of Cerebral Amyloid Angiopathy and Arteriosclerosis/Lipohyalinosis with Cognitive Decline
Abstract
Sporadic, late-onset Alzheimer disease (AD) constitutes the most frequent cause of dementia in the elderly population. AD-related pathology is often accompanied by vascular changes. The predominant vascular lesions in AD are cerebral amyloid angiopathy (CAA) and arteriosclerosis/lipohyalinosis (AS/LH). The present study was carried out to examine the coincidence of these small vessel pathologies during the development of cognitive deficits, amyloid beta-protein (A beta) deposition, and neurofibrillary tangle (NFT) formation in sporadic late-onset AD. We correlated the clinical dementia rating (CDR) score, the sequential extension of AD-related A beta deposition into different parts of the brain, and the extension of NFTs to involve more brain regions with the distribution of CAA and AS/LH in 52 human autopsy brains. The extension of CAA and AS/LH to involve different areas of the brain was associated with a rise of CDR scores and an increase in the extension of A beta deposition and NFT generation. AD cases showed a higher number of regions with CAA and AS/LH compared to nondemented patients with AD-related pathology and controls. Moreover, we demonstrated a hierarchical sequence in which the different regions of the brain exhibited CAA and AS/LH-affected vessels, allowing the distinction of 3 stages in the development of CAA and AS/LH. The first stage of CAA involved leptomeningeal and neocortical vessels. The second stage was characterized by additional A beta deposition in allocortical and midbrain vessels. Finally, in a third stage, CAA was observed in the basal ganglia, the thalamus, and in the lower brainstem. In contrast, AS/LH initially affected the basal ganglia in stage A. In stage B this pathology made inroads into the deep white matter, the leptomeningeal arteries of the cortex, the cerebellum, and into the thalamus. Stage C was characterized by AS/LH in brainstem vessels. Our results demonstrate widespread CAA and AS/LH to be associated with the development of cognitive deficits in AD. A combination of both CAA and AS/LH may, therefore, contribute to neurodegeneration in AD. These data also suggest that small vessel disease due to arteriosclerosis and fibrolipohyalinosis is a potential target for the treatment of AD.
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“Both CAA and CCA variants of VAβ pathology have been described in AD autopsies and their relative preponderance has been linked to various APOE genotypes [40–43].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [41]
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Metadata
- Authors
- Thal, D. R., Ghebremedhin, E., Orantes, M., & Wiestler, O. D.
- Affiliations
- University of Bonn (DE)
- Goethe University Frankfurt (DE)
- Corresponding author
- Thal, Dietmar Rudolf
- ORCID
- Thal, Dietmar Rudolf
- Venue
- Journal of Neuropathology & Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-12
- Volume
- 62
- Issue
- 12
- Pages
- 1287-1301
- ISSN
- 0022-3069 (ISSN-L)
- 1554-6578
- OpenAlex
- W1603244154
- Cited by
- 384
- References
- 51
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 14 · 2023: 14 · 2022: 29 · 2021: 23 · 2020: 26 · 2019: 22 · 2018: 15 · 2017: 10 · 2016: 15 · 2015: 22 · 2014: 23 · 2013: 21 · 2012: 11
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (TH624 4–1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Keywords
- Alzheimer's disease, cerebral amyloid angiopathy, arteriosclerosis, lipohyalinosis, cerebral small vessel disease, cognitive decline, amyloid-beta deposition, neurofibrillary tangles, disease staging, vascular pathology, dementia, neurodegeneration
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Analysis of Variance, Intracranial Arteriosclerosis, Cognition Disorders, Female, Humans, Male, Middle Aged, Cerebral Amyloid Angiopathy
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