Abstract
BackgroundAggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer’s disease (AD). The exact pathophysiology leading to dementia is still uncertain, but the apolipoprotein E (APOE) ε4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid β aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE ε4 genotype.MethodsWe tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE ε4 carriers, average age 75 ± 7 years) against 60 controls with normal CSF amyloid β, normal cognition, and no APOE ε4 allele (average age 75 ± 6 years).ResultsOne hundred twenty-nine proteins (53%) were associated with aggregated amyloid β. APOE ε4 carriers with AD showed altered concentrations of proteins involved in the complement pathway and glycolysis when cognition was normal and lower concentrations of proteins involved in synapse structure and function when cognitive impairment was moderately severe. APOE ε4 non-carriers with AD showed lower expression of proteins involved in synapse structure and function when cognition was normal and lower concentrations of proteins that were associated with complement and other inflammatory processes when cognitive impairment was mild. Repeating analyses for 114 proteins that were available in an independent EMIF-AD MBD dataset (n = 275) showed that 80% of the proteins showed group differences in a similar direction, but overall, 28% effects reached statistical significance (ranging between 6 and 87% depending on the disease stage and genotype), suggesting variable reproducibility.ConclusionsThese results imply that AD pathophysiology depends on APOE genotype and that treatment for AD may need to be tailored according to APOE genotype and severity of the cognitive impairment.
Highlights
Aggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer’s disease (AD)
Protein levels in cerebrospinal fluid (CSF) may depend on apolipoprotein E (APOE) ε4 genotype, which has been reported for beta secretase-1 [Beta secretase 1 (BACE1)] [14] and chitinase-3-like protein 1 [Chitinase-3-like protein 1 (YKL40)] [15], both proteins associated with AD-type dementia, and so, it is plausible that APOE ε4 genotype may influence other protein markers in the CSF as well
129 (53%) proteins and protein fragments were associated with aggregated amyloid, with 27 (21%) proteins showing higher levels and the majority of proteins (102, 79%) showing lower levels in AD compared to controls
Summary
Aggregation of amyloid β into plaques in the brain is one of the earliest pathological events in Alzheimer’s disease (AD). The presence of an apolipoprotein E (APOE) ε4 allele, the major genetic risk factor for AD [4], lowers the age of onset through an as of yet unknown mechanism It is largely unclear which biological processes eventually lead to cognitive decline once amyloid β has aggregated, as well as whether such processes are influenced by the presence of the APOE ε4 allele. Not all subjects with a clinical diagnosis of AD-type dementia have aggregated amyloid, and on average, 30% of cognitively normal subjects are already in the preclinical stage of AD [3, 12, 13] It remains uncertain which of the previously reported markers are specific for AD pathology, i.e., aggregated amyloid. Protein levels in CSF may depend on APOE ε4 genotype, which has been reported for beta secretase-1 [BACE1] [14] and chitinase-3-like protein 1 [YKL40] [15], both proteins associated with AD-type dementia, and so, it is plausible that APOE ε4 genotype may influence other protein markers in the CSF as well
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