Cortical Gray Matter Proteins Associated with Cerebral Amyloid Angiopathy in Community-Dwelling Older Adults: An Autopsy Study

Background and ObjectivesCerebral amyloid angiopathy (CAA) is the accumulation of β-amyloid (Aβ) in the walls of small vessels in the leptomeninges and cortex and is a risk factor of intracerebral hemorrhage and dementia, but its underlying mechanism is unknown. We examined cortical proteins in relation to CAA to elucidate the molecular mechanisms underlying CAA.MethodsData were collected from participants of 5 community-based cohorts of older adults. Participants were recruited from personal dwellings or retirement centers, were without known dementia at enrollment, and signed an Anatomic Gift Act for brain donation. At death, autopsy was performed and cortical proteins were quantified from the dorsolateral prefrontal cortex using mass spectrometry-based proteomic analysis, and pathologic indices of brain pathologies including CAA and Alzheimer disease (AD) were assessed during neuropathologic evaluations. Targeted mass spectrometry-based proteomic analysis was performed for the quantification of total Aβ protein and Aβ38 peptide. Ordinal logistic regression models were used to test the association between the proteins and CAA.ResultsA total of 887 participants were included, with a mean age at death of 89.0 (SD = 6.8) years, and 67.2% (n = 596) were women. Eighty proteins were related to CAA, of which 12 remained associated with CAA after controlling for AD pathology. However, only 4 proteins remained associated with CAA when all 12 proteins were examined in a single model: secreted modular calcium-binding protein 1 (SMOC1), secreted frizzled-related protein 1 (SFRP1), APOE, and APOE4. Examining the 4 proteins together with the 3 Aβ measures (Aβ load, total Aβ protein, and Aβ38 peptide) in a factor analysis and a structure equation model suggested 2 factors and paths: a factor including Aβ38, SFRP1, and APOE protein, which had the larger effect size in relation to CAA (standardized estimate = 0.459, SE = 0.050, p < 0.001), and a second factor including Aβ load, total Aβ protein, SMOC1, and APOE4 that had a smaller effect size in relation to CAA (standardized estimate = 0.253, SE = 0.083, p < 0.001).DiscussionThis study suggests 2 molecular pathways underlying CAA, with a larger effect size for the pathway including SFRP1 and APOE protein and C-terminally truncated Aβ before position 40. However, the study is an observational cross-sectional study that limits causal inference from the findings.