Effects of age, amyloid, sex, and APOE ε4 on the CSF proteome in normal cognition

Abstract

Introduction It is important to understand which biological processes change with aging, and how such changes are associated with increased Alzheimer's disease (AD) risk. We studied how cerebrospinal fluid (CSF) proteomics changed with age and tested if associations depended on amyloid status, sex, and apolipoprotein E Ɛ4 genotype. Methods We included 277 cognitively intact individuals aged 46 to 89 years from Alzheimer's Disease Neuroimaging Initiative, European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery, and Metabolic Syndrome in Men. In total, 1149 proteins were measured with liquid chromatography mass spectrometry with multiple reaction monitoring/Rules‐Based Medicine, tandem mass tag mass spectrometry, and SOMAscan. We tested associations between age and protein levels in linear models and tested enrichment for Reactome pathways. Results Levels of 252 proteins increased with age independently of amyloid status. These proteins were associated with immune and signaling processes. Levels of 21 proteins decreased with older age exclusively in amyloid abnormal participants and these were enriched for extracellular matrix organization. Discussion We found amyloid‐independent and ‐dependent CSF proteome changes with older age, perhaps representing physiological aging and early AD pathology.

Quantitative proteomics of cerebrospinal fluid from African Americans and Caucasians reveals shared and divergent changes in Alzheimer’s disease

“…Finally, in this study we adjusted for co-factors such as age and sex to pinpoint changes that are most likely to be associated with race and AD. Sex and age have an impact on the abundance of CSF Tau and other protein levels (61). Therefore, future studies that assess the interactions between, age, sex and race will be informative.…”

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

“…What might these factors be? A comprehensive study of CSF proteomics in CU participants ranging in age from 46 to 89 years from three cohorts including ADNI sheds some light on this question 143 . Of 1149 proteins tested, 911 differed with age; among these 194 were altered in participants older than 60 years; 172, 22, and 352 proteins differed by Aβ status, APOE ε4 status, and sex, respectively.…”

Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures

“…Whilst significant progress has been made in characterising Aβ and tau progression in patients with AD 15 , direct real-time analysis of endogenous Aβ and tau levels, within the healthy human brain presents many challenges. Lumbar cerebrospinal fluid (CSF) displays lowered Aβ1-42 and increased phosphorylated tau during normal ageing, which is more pronounced in APOE ε4 carriers or AD patients [16][17][18][19] . However, CSF measures are an aggregate output from the brain influenced by many factors including: breakdown in the blood-brain barrier [20][21][22] , circadian rhythms [23][24][25] , and rates of protein production, degradation or clearance [26][27][28] .…”