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Basic Science and Pathogenesis
Sonal Agrawal1, Sue E Leurgans1, Scott Ayton2
1Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Insights
Cerebral amyloid angiopathy (CAA) is linked to higher brain iron levels, which worsen cognitive decline in older adults. Elevated iron exacerbates the impact of CAA on cognitive function, particularly perceptual speed.
Area of Science:
- Neuroscience
- Neuropathology
- Gerontology
Background:
- Cerebral amyloid angiopathy (CAA) is a common brain pathology linked to Alzheimer's Disease (AD) and cognitive decline.
- Elevated brain iron levels are associated with cognitive decline, and this study investigates its role in CAA.
Purpose of the Study:
- To explore the association between cerebral amyloid angiopathy (CAA) and brain iron levels.
- To examine if elevated iron modifies the association between CAA and cognitive decline.
- To investigate the independent contribution of high iron levels to cognitive decline, beyond AD neuropathologic changes (ADNC).
Main Methods:
- Utilized data from the Rush Memory and Aging Project (N=680) with longitudinal cognitive assessments and neuropathologic evaluation.
- Assessed CAA severity using immunohistochemistry and brain iron levels via Inductively Coupled Plasma Mass Spectrometry.
- Employed linear regression and mixed-effects models, adjusting for age, sex, education, and ADNC.
Main Results:
- Moderate-to-severe CAA was present in over one-third of participants (N=243).
- CAA was significantly associated with higher brain iron levels (p < 0.001).
- Both CAA and elevated iron independently predicted faster decline in global cognition, episodic memory, semantic memory, and perceptual speed. High iron also impacted working memory, while CAA affected visuospatial orientation. Notably, high iron levels amplified CAA's effect on perceptual speed decline (p=0.008).
Conclusions:
- Brain iron levels are associated with the clinical impact of cerebral amyloid angiopathy (CAA) in older individuals.
- Elevated iron exacerbates cognitive decline in the presence of CAA, highlighting iron's role in neurodegeneration.
Background:
Cerebral amyloid angiopathy (CAA) is a common brain pathology associated with Alzheimer's Disease (AD) and cognitive decline. Iron is an essential micronutrient for brain health; elevated brain iron is associated with cognitive decline in our prior studies. This study aims to explore the association between CAA and brain iron and to examine whether the association between CAA and cognitive decline is modified by elevated iron levels. We hypothesized that persons with CAA would exhibit higher brain iron levels, and that higher iron levels would contribute to accelerated cognitive decline independently of AD neuropathologic changes (ADNC).
Method:
Data came from the Rush Memory and Aging Project (N = 680, mean age at death 90 ± 6.1 years, 70% women). Participants completed baseline and longitudinal cognitive assessments and underwent detailed neuropathologic evaluation for CAA, ADNC, and other brain pathologies. Severity of CAA (none, mild, moderate and severe) was assessed from the four neocortical regions using immunohistochemistry against Aβ antibody. Brain iron level in the inferior temporal cortex was assessed using Inductively Coupled Plasma Mass Spectrophotometry and a composite mean z-score was generated. Linear regression and mixed-effects models, adjusted for age-at-death, sex, education, ADNC, and other pathologies, were used for analysis.
Result:
The mean follow-up before death was 6.7 ± 3.8 years. Over one-third of participants (N = 243) had moderate-to-severe CAA, and mean brain iron was 52 (SD=14) μg/g. CAA was associated with higher iron levels (Est=0.018, SE=0.004, p = <0.001). When examining associations with cognitive change, both CAA and elevated iron level were independently associated with faster decline in global cognition and three cognitive domains (episodic, semantic, and perceptual speed) (all p <0.024). High iron was also associated with steeper decline in working memory (p = 0.001); CAA was associated with steeper decline in visuospatial orientation (p = 0.018). Furthermore, in participants with high iron levels, CAA was associated with steeper perceptual speed decline (Est=-0.125, SE=0.048, P=0.008). No other interactions were found between CAA and iron for cognitive decline.
Conclusion:
Together, these findings demonstrate that the level of brain iron is associated with the clinical impact of CAA in older age.
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