APOE4 associated with lower levels of inflammatory markers in CNS fluid?

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APOE4 associated with lower levels of inflammatory markers in CNS fluid?

Postby BrianR » Sat Dec 19, 2020 8:50 am

The conclusion of this [paywalled] paper surprised me. I found an open access pre-print at https://www.medrxiv.org/content/10.1101/2020.06.30.20143578v1.full.pdf

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid
Miles Berger, et al.
J Alzheimers Dis. 2020 Dec 13.
doi: 10.3233/JAD-200747

(The lead author notes on twitter that he's willing to help provide a copy of the final paper.

Some clarifications, as I understand them:
  • APOE4 Copy Number - how many APOE4 alleles you have. E.g., APOE3/3 - 0, APOE3/4 - 1, APOE4/4 - 2
  • CRP - C-reactive protein
  • CNS - Central Nervous System
  • CSF - Cerebrospinal fluid
Background: APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear.

Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number.

Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction.

Results: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million.

Conclusion: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

From the pre-print (emphasis mine):
Here, we found that increasing APOE4 copy number is associated with increased CSF ALDOA, CH3L1 and FABH levels and decreased CSF CRP levels. Further, the CRP decrease remained significant even after controlling for AD clinical status. We also found significant associations between APOE4 copy number and several peptides from the APOE protein itself. As expected, we found a strong positive correlation between APOE4 copy number and CSF expression of the APOE4 allele specific peptide LGADMEDVR [37, 38]. Both of our statistical models (controlling for age and sex, or for age, sex and AD clinical status) showed that increased APOE4 copy number was associated with increased expression of peptides common to all APOE isoforms, such as LGPLVEQGR, which is often used as a measure of total APOE protein level.

There is conflicting evidence in the literature on whether the APOE4 carriers have altered CSF APOE protein levels. One study used ELISA assays and found that APOE4 carriers had higher CSF APOE levels vs non-carriers [39]. Two different studies using mass spectroscopy found no change in CSF APOE levels in APOE4 carriers [40, 41], though one of them found that APOE4 carriers had lower plasma APOE levels [40]. Similarly, another study using ELISA assays found reduced peripheral plasma APOE levels in APOE4 carriers versus non-carriers [42]. Yet, both models in this study showed that increasing APOE4 copy number was associated with increased CSF pan-APOE peptide levels. It is unclear whether these APOE4 copy number related increases in APOE protein levels are responsible for increased AD risk, versus whether the increased AD risk is due to functional changes in the APOE protein due to the two amino acid changes encoded by the APOE4 allele. Indeed, it remains debated in the field to what extent APOE4–related increased AD risk is due to a toxic gain of function(s) or a loss of protective function(s) (reviewed in [43]).

We also found that increasing APOE4 copy number was associated with reduced CSF levels of the CRP-derived peptide (ESDTSYVSLK). CRP is often thought of as a serum biomarker used to follow the acute progression of inflammation and infection [44]. CRP is also increasingly recognized as an active mediator of inflammatory and apoptotic processes, including the activation of the classical complement pathway [45] and the opsonization of atherosclerotic plaques [46] and infarcted myocardial tissues [47]. While elevated CRP levels are typically viewed as an acute marker of active inflammation, low and low-normal CRP levels have been found in chronic inflammatory diseases such as lupus [48], rheumatoid arthritis [49], and inflammatory bowel disease [50, 51]. Thus, the reduced CSF CRP levels observed here may similarly reflect chronically increased inflammation within the CNS of APOE4 carriers

Indeed, several studies have consistently found that reduced CRP levels in peripheral blood [52-55] and in CSF [56, 57] correlate with increased cognitive dysfunction and further AD progression in an APOE4-dependent manner. Notably, CRP has been implicated in the early development of amyloid plaque formation, neuronal damage, and AD risk [58-61]. The decreased CSF CRP levels observed here may reflect CRP deposition in beta-amyloid plaques and its consumption as a pro-inflammatory mediator in AD pathology, as has been suggested previously [62]. Future studies should examine the role of APOE4-dependent modulation of CRP expression and function in AD progression.

We also found that increasing APOE4 copy was also associated with increased expression of peptides derived from glycoprotein Chitinase 3-like protein 1 (CH3L1; also known as YKL-40) (q< 0.05), the cardiac injury biomarker heart-type fatty acid binding protein (FABPH) (q< 0.05) and the enzyme fructose-bisphosphate aldolase A (ALDOA; q< 0.05) as seen in a prior studies [63]. CH3L1 is a glycoprotein hypothesized to modulate tissue remodeling, and is highly expressed in reactive astrocytes after both acute and chronic neuroinflammation [64-66]. Another recent study using ELISA assays also found increased CSF CH3L1 (YKL-40) levels in APOE4 carriers [67], further corroborating the findings presented here. Taken together, these findings strongly suggest that APOE4 carriers have increased neuroinflammation and astroglial activation [68-70] independent of their AD clinical status. ...

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