Marian Shahid1, Jeehyun Kim1, Katherine Leaver2, Taylor Hendershott1, Delphine Zhu1, Brenna Cholerton3, Victor W Henderson4, Lu Tian5, Kathleen L Poston6. 1. Stanford University, Department of Neurology and Neurological Sciences, 300 Pasteur Dr. Room H3144, MC 5235, Stanford, CA 94305, United States of America. 2. Stanford University, Department of Neurology and Neurological Sciences, 300 Pasteur Dr. Room H3144, MC 5235, Stanford, CA 94305, United States of America; Mount Sinai Beth Israel, Department of Neurology, 10 Union Square East, New York, NY 10003, United States of America. 3. Stanford University, Department of Pathology, 300 Pasteur Dr Rm L235, MC 5324, Stanford, CA 94305, United States of America. 4. Stanford University, Department of Neurology and Neurological Sciences, 300 Pasteur Dr. Room H3144, MC 5235, Stanford, CA 94305, United States of America; Stanford University, Department of Health Research and Policy (Epidemiology), 259 Campus Drive, MC 5405, Stanford, CA 94305, United States of America. 5. Stanford University, Department of Biomedical Data Science, 150 Governor's Lane, Room T160C, MC 5464, Stanford, CA 94305, United States of America. 6. Stanford University, Department of Neurology and Neurological Sciences, 300 Pasteur Dr. Room H3144, MC 5235, Stanford, CA 94305, United States of America; Stanford University, Department of Neurosurgery, 300 Pasteur Dr. Room H3144, MC 5235, Stanford, CA 94305, United States of America. Electronic address: klposton@stanford.edu.
Abstract
OBJECTIVE: Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (Aβ-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF Aβ-42 compared to patients with normal levels. METHODS: The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF Aβ-42 determinations, and neuropsychological assessments. We used linear mixed effects models in three PD groups (PD participants with low CSF Aβ at baseline, PD participants with normal CSF Aβ, and both groups combined). Having at least one copy of the APOE ɛ4 allele, time, and the interaction of APOE ɛ4 and time were predictor variables for cognitive change, adjusting for age, gender and education. RESULTS: 423 de novo PD participants were followed up to 5 years with annual cognitive assessments. 103 participants had low baseline CSF Aβ-42 (39 APOE ε4+, 64 APOE ε4-). Compared to participants with normal CSF Aβ-42, those with low CSF Aβ-42 declined faster on most cognitive tests. Within the low CSF Aβ-42 group, APOE ε4+ participants had faster rates of decline on the Montreal Cognitive Assessment (primary outcome; 0.57 points annual decline, p = .005; 5-year standardized change of 1.2) and the Symbol Digit Modalities Test (1.4 points annual decline, p = .002; 5-year standardized change of 0.72). DISCUSSION: PD patients with low CSF Aβ-42 and APOE ε4+ showed a higher rate of cognitive decline early in the disease. Tests of global cognition (Montreal Cognitive Assessment) and processing speed (Symbol Digit Modalities Test) were the most sensitive to early cognitive decline. Results suggest that CSF Aβ-42 and APOE ε4 might interact to promote early cognitive changes in PD patients.
OBJECTIVE: Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (Aβ-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PDpatients with low CSF Aβ-42 compared to patients with normal levels. METHODS: The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PDparticipants, which includes APOE genotyping, CSF Aβ-42 determinations, and neuropsychological assessments. We used linear mixed effects models in three PD groups (PDparticipants with low CSF Aβ at baseline, PDparticipants with normal CSF Aβ, and both groups combined). Having at least one copy of the APOE ɛ4 allele, time, and the interaction of APOE ɛ4 and time were predictor variables for cognitive change, adjusting for age, gender and education. RESULTS: 423 de novo PDparticipants were followed up to 5 years with annual cognitive assessments. 103 participants had low baseline CSF Aβ-42 (39 APOE ε4+, 64 APOE ε4-). Compared to participants with normal CSF Aβ-42, those with low CSF Aβ-42 declined faster on most cognitive tests. Within the low CSF Aβ-42 group, APOE ε4+ participants had faster rates of decline on the Montreal Cognitive Assessment (primary outcome; 0.57 points annual decline, p = .005; 5-year standardized change of 1.2) and the Symbol Digit Modalities Test (1.4 points annual decline, p = .002; 5-year standardized change of 0.72). DISCUSSION: PDpatients with low CSF Aβ-42 and APOE ε4+ showed a higher rate of cognitive decline early in the disease. Tests of global cognition (Montreal Cognitive Assessment) and processing speed (Symbol Digit Modalities Test) were the most sensitive to early cognitive decline. Results suggest that CSF Aβ-42 and APOE ε4 might interact to promote early cognitive changes in PDpatients.
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