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APOE ?4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease.

ABSTRACT: BACKGROUND:Aggregation of amyloid ? 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) ?4 genotype plays a major role. We aimed to identify the molecular pathways associated with amyloid ? aggregation using cerebrospinal fluid (CSF) proteomics and to study the potential modifying effects of APOE ?4 genotype. METHODS:We tested 243 proteins and protein fragments in CSF comparing 193 subjects with AD across the cognitive spectrum (65% APOE ?4 carriers, average age 75?±?7?years) against 60 controls with normal CSF amyloid ?, normal cognition, and no APOE ?4 allele (average age 75?±?6?years). RESULTS:One hundred twenty-nine proteins (53%) were associated with aggregated amyloid ?. APOE ?4 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 ?4 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. CONCLUSIONS:These 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.

SUBMITTER: Konijnenberg E

PROVIDER: S-EPMC7254647 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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APOE ε4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease.

Konijnenberg Elles E Tijms Betty M BM Gobom Johan J Dobricic Valerija V Bos Isabelle I Vos Stephanie S Tsolaki Magda M Verhey Frans F Popp Julius J Martinez-Lage Pablo P Vandenberghe Rik R Lleó Alberto A Frölich Lutz L Lovestone Simon S Streffer Johannes J Bertram Lars L Blennow Kaj K Teunissen Charlotte E CE Veerhuis Robert R Smit August B AB Scheltens Philip P Zetterberg Henrik H Visser Pieter Jelle PJ

Alzheimer's research & therapy 20200527 1

<h4>Background</h4>Aggregation 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.<h4>Methods</h4>We tested 243 proteins ...[more]

PMID: 32460813

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Project description:BackgroundApolipoprotein E (APOE) ɛ4 and low cerebrospinal fluid (CSF) amyloid-β42 (Aβ42) levels are predictors for developing Alzheimer's disease (AD). The results of several studies indicate an interaction between docosahexaenoic acid (DHA) consumption and cognitive outcomes by APOE genotype. Our objective in the present study was to examine whether APOE ɛ4 genotype and low CSF Aβ42 levels were associated with reduced delivery of DHA to CSF in the Alzheimer's Disease Cooperative Study-sponsored DHA clinical trial.MethodsPhospholipid DHA was assayed in the plasma of 384 participants and CSF of 70 participants at baseline. Forty-four of the 70 participants completed the 18-month follow-up visit after allocation to placebo (n = 15) or DHA (n = 29). Plasma and CSF DHA levels, CSF Aβ42, Tau, and phosphorylated Tau were measured at baseline and after the 18-month intervention. Participants were divided into tertiles based on baseline Aβ42 CSF levels. To assess DHA delivery across the blood-brain barrier, the ratio of CSF to plasma DHA levels was calculated.ResultsAt baseline, there were no significant differences between CSF or plasma phospholipid DHA levels by CSF Aβ42 tertiles or ɛ4 status. After 18 months of DHA supplementation, participants at the lowest Aβ42 tertile had significantly lower CSF DHA levels (p = 0.01) and lower CSF-to-plasma DHA ratios (p = 0.05) compared to the other tertiles. Baseline CSF Aβ42 levels were significantly lower in ɛ4 carriers than in ɛ4 noncarriers (p = 0.01). Participants carrying the ɛ4 allele (n = 25) demonstrated a less pronounced increase in CSF DHA level compared with noncarriers (n = 4), with a possible interaction effect between treatment and APOE genotype (p = 0.07).ConclusionsAPOE ɛ4 allele and lower CSF Aβ42 levels were associated with less transport of DHA to CSF. Brain amyloid pathology may limit the delivery of DHA to the brain in AD.Trial registrationClinicaltrials.gov identifier: NCT00440050 . Registered on 22 Feb 2007.

Project description:The ε4 allele of Apolipoprotein (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD), the most common form of dementia. Cognitively normal APOE4 carriers have developed amyloid beta (Aβ) plaques and cerebrovascular, metabolic and structural deficits decades before showing the cognitive impairment. Interventions that can inhibit Aβ retention and restore the brain functions to normal would be critical to prevent AD for the asymptomatic APOE4 carriers. A major goal of the study was to identify the potential usefulness of rapamycin (Rapa), a pharmacological intervention for extending longevity, for preventing AD in the mice that express human APOE4 gene and overexpress Aβ (the E4FAD mice). Another goal of the study was to identify the potential pharmacogenetic differences in response to rapamycin between the E4FAD and E3FAD mice, the mice with human APOE ε3 allele. We used multi-modal MRI to measure in vivo cerebral blood flow (CBF), neurotransmitter levels, white matter integrity, water content, cerebrovascular reactivity (CVR) and somatosensory response; used behavioral assessments to determine cognitive function; used biochemistry assays to determine Aβ retention and blood-brain barrier (BBB) functions; and used metabolomics to identify brain metabolic changes. We found that in the E4FAD mice, rapamycin normalized bodyweight, restored CBF (especially in female), BBB activity for Aβ transport, neurotransmitter levels, neuronal integrity and free fatty acid level, and reduced Aβ retention, which were not observe in the E3FAD-Rapa mice. In contrast, E3FAD-Rapa mice had lower CVR responses, lower anxiety and reduced glycolysis in the brain, which were not seen in the E4FAD-Rapa mice. Further, rapamycin appeared to normalize lipid-associated metabolism in the E4FAD mice, while slowed overall glucose-associated metabolism in the E3FAD mice. Finally, rapamycin enhanced overall water content, water diffusion in white matter, and spatial memory in both E3FAD and E4FAD mice, but did not impact the somatosensory responses under hindpaw stimulation. Our findings indicated that rapamycin was able to restore brain functions and reduce AD risk for young, asymptomatic E4FAD mice, and there were pharmacogenetic differences between the E3FAD and E4FAD mice. As the multi-modal MRI methods used in the study are readily to be used in humans and rapamycin is FDA-approved, our results may pave a way for future clinical testing of the pharmacogenetic responses in humans with different APOE alleles, and potentially using rapamycin to prevent AD for asymptomatic APOE4 carriers.

Dataset Information

APOE ?4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease.

Publications

APOE ε4 genotype-dependent cerebrospinal fluid proteomic signatures in Alzheimer's disease.

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