A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease
Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-speci...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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FRONTIERS MEDIA SA
2018
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| Online Access: | http://hdl.handle.net/20.500.11937/75016 |
| _version_ | 1848763414445293568 |
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| author | Porter, T. Burnham, S. Savage, G. Lim, Y. Maruff, P. Milicic, L. Peretti, M. Ames, D. Masters, C. Martins, R. Rainey-Smith, S. Rowe, C. Salvado, O. Taddei, K. Groth, David Verdile, Giuseppe Villemagne, V. Laws, Simon |
| author_facet | Porter, T. Burnham, S. Savage, G. Lim, Y. Maruff, P. Milicic, L. Peretti, M. Ames, D. Masters, C. Martins, R. Rainey-Smith, S. Rowe, C. Salvado, O. Taddei, K. Groth, David Verdile, Giuseppe Villemagne, V. Laws, Simon |
| author_sort | Porter, T. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc̅APOE) or excluding APOE (emPRSs̅APOE ). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc̅ APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs̅ APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development. |
| first_indexed | 2025-11-14T11:03:05Z |
| format | Journal Article |
| id | curtin-20.500.11937-75016 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:03:05Z |
| publishDate | 2018 |
| publisher | FRONTIERS MEDIA SA |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-750162019-03-15T02:05:48Z A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease Porter, T. Burnham, S. Savage, G. Lim, Y. Maruff, P. Milicic, L. Peretti, M. Ames, D. Masters, C. Martins, R. Rainey-Smith, S. Rowe, C. Salvado, O. Taddei, K. Groth, David Verdile, Giuseppe Villemagne, V. Laws, Simon Science & Technology Life Sciences & Biomedicine Geriatrics & Gerontology Neurosciences Neurosciences & Neurology polygenic risk score Alzheimer's disease A beta-amyloid cognitive decline episodic memory TRANSCRIPTION FACTOR IMPAIRMENT BETA INDIVIDUALS PREDICTION BIOMARKERS PROTEIN MEF2C Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc̅APOE) or excluding APOE (emPRSs̅APOE ). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc̅ APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs̅ APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development. 2018 Journal Article http://hdl.handle.net/20.500.11937/75016 10.3389/fnagi.2018.00423 English http://creativecommons.org/licenses/by/4.0/ FRONTIERS MEDIA SA fulltext |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Geriatrics & Gerontology Neurosciences Neurosciences & Neurology polygenic risk score Alzheimer's disease A beta-amyloid cognitive decline episodic memory TRANSCRIPTION FACTOR IMPAIRMENT BETA INDIVIDUALS PREDICTION BIOMARKERS PROTEIN MEF2C Porter, T. Burnham, S. Savage, G. Lim, Y. Maruff, P. Milicic, L. Peretti, M. Ames, D. Masters, C. Martins, R. Rainey-Smith, S. Rowe, C. Salvado, O. Taddei, K. Groth, David Verdile, Giuseppe Villemagne, V. Laws, Simon A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease |
| title | A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease |
| title_full | A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease |
| title_fullStr | A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease |
| title_full_unstemmed | A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease |
| title_short | A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease |
| title_sort | polygenic risk score derived from episodic memory weighted genetic variants is associated with cognitive decline in preclinical alzheimer's disease |
| topic | Science & Technology Life Sciences & Biomedicine Geriatrics & Gerontology Neurosciences Neurosciences & Neurology polygenic risk score Alzheimer's disease A beta-amyloid cognitive decline episodic memory TRANSCRIPTION FACTOR IMPAIRMENT BETA INDIVIDUALS PREDICTION BIOMARKERS PROTEIN MEF2C |
| url | http://hdl.handle.net/20.500.11937/75016 |