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.
“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]
The CAA section (page unavailable) reports capillary amyloid-β deposits in autopsy cases and describes them as indicative of an APOE ε4-associated type of CAA. The APOE section (page unavailable) finds more extensive CAA in ε4 carriers. Neither passage establishes the relative preponderance of CAA and capillary variants across APOE genotypes. (LLM, conf=0.84)
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- 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
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › 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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