APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid1

Abstract

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.

Don’t forget about tau: the effects of ApoE4 genotype on Alzheimer’s disease cerebrospinal fluid biomarkers in subjects with mild cognitive impairment—data from the Dementia Competence Network

“…We consider this possible evidence for the apparent genetic effect on CSF biomarkers, which can become outweighed as the disease progresses. Consistent with the paradigm, in which the influence of ApoE4 leads to changes in CSF in the initial stages (before and during the phase in which patients are developing brain Aβ pathology), subsequently as frank neurodegeneration begins, there is no longer a significant increase in CSF ApoE levels as a function of increasing ApoE4 count (Berger et al 2021 ). Diagnostically, this implies that the information on ApoE4 carriership in AD is already “contained” in the pathological levels of Aβ42, t-Tau and p-Tau and thus, is not diagnostically relevant at the stage of MCI (Frölich et al 2017 ).…”

Impact of APOE ε3 and ε4 genotypes on plasma proteome signatures in Alzheimer’s disease

“…Unbiased proteomics analysis permits the simultaneous evaluation of many molecular processes in patients. To explore this, several research studies have used a CSF proteomics technique and described protein signatures linked with AD across the cognitive range 14,15 . Proteomics investigations on readily available fluids such as serum/plasma, on the other hand, are underutilized.…”

Associations of cerebrospinal fluid complement proteins with Alzheimer’s pathology, cognition, and brain structure in non-dementia elderly

“…However, preliminary clinical studies illustrated inconsistent findings. An increase in APOE-ε4 copy number has been reported to be inversely related to the level of complement proteins in cerebrospinal fluid [ 51 ]. The interaction between complement C3 and APOE-ε4 leads to increased Alzheimer’s disease-related pathology [ 40 ].…”