INS NYC 2024 Program

Poster	Poster Session 02 Program Schedule 02/15/2024 08:00 am - 09:15 am Room: Shubert Complex (Posters 1-60) Poster Session 02: Aging \| MCI \| Neurodegenerative Disease - PART 1 Final Abstract #8 Associations Among APOE Genotype, Plasma Neurofilament Light Chain (NfL) and Cognition in Autosomal Dominant Alzheimer’s Disease Kyra Bonta, Yale University, New Haven, United States Stephanie Langella, Massachusetts General Hospital, Boston, United States Yinghua Chen, Banner Alzheimer’s Institute, Phoenix, United States Yi Su, Banner Alzheimer’s Institute, Pheonix, United States Daniel Vasquez, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia David Aguillon, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia Natalia Acosta-Baena, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia Ana Baena, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia Gloria Garcia-Ospina, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia Margarita Giraldo-Chica, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia Victoria Tirado, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia Claudia Muñoz, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia Silvia Ríos-Romenets, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Universidad de Antioquia, Medellin, Colombia Claudia Guzman-Martínez, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia Jeremy Pruzin, Banner Alzheimer’s Institute, Pheonix, United States Valentina Ghisays, Banner Alzheimer’s Institute, Pheonix, United States Joseph Arboleda-Velasquez, Schepens Eye Research Institute of Mass Eye and Ear, Department of Ophthalmology at Harvard Medical School, Boston, United States Kenneth Kosik, University of California Santa Barbara, Santa Barbara, United States Eric Reiman, Banner Alzheimer’s Institute, Phoenix, United States Francisco Lopera, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, United States Yakeel Quiroz, Massachusetts General Hospital, Harvard Medical School, Boston, United States Category: Dementia (Alzheimer's Disease) Keyword 1: dementia - Alzheimer's disease Keyword 2: apolipoprotein E Keyword 3: cognitive functioning Objective: Presenilin-1 (PSEN1) E280A mutation carriers develop early-onset autosomal dominant Alzheimer’s disease (AD) with near 100% certainty. Recently, we showed that the APOE-e4 allele, the strongest genetic risk factor for sporadic AD, influences age-related cognitive trajectories in PSEN1 E280A carriers. However, the relationship between APOE genotype and disease-related neurodegeneration remains unclear in autosomal dominant AD. Neurofilament light chain (NfL), a protein specific to axonal injury, is a known biomarker of neurodegeneration and is increased in PSEN1 E280A carriers decades before clinical onset. Research investigating the association between plasma and CSF NfL and APOE e4 in sporadic AD has yielded conflicting results. Therefore, we aimed to (1) evaluate age-related trajectories of plasma NfL as a function of APOE genotype in PSEN1 E280A carriers and non-carriers and (2) examine how APOE and NfL are associated with cognitive performance. Participants and Methods: A total of 1,428 participants (778 PSEN1 carriers and 650 non-carriers) underwent APOE genotyping and blood draws to quantify plasma NfL concentrations. Within PSEN1 carriers, 169 participants had at least one APOE e4 allele (APOE e4+) while 609 had none (APOE e4-), and 114 participants had at least one e2 allele (APOE e2+) while 664 had none (APOE e2-). Separate analyses were conducted in APOE e2 and APOE e4 groups. To quantify age-related trajectories, a cubic spline model was used to plot cross-sectional log-transformed NfL concentrations across age. Using the Markov chain Monte Carlo method, model parameters were approximated as a function of APOE genotype. A subset of participants (n=1,267) had complete cognitive data. A cognitive composite score was calculated using MMSE total score, CERAD word list delayed recall, CERAD praxis delayed recall, Raven's, and phonemic fluency (FAS) total score. Linear regressions were conducted using log-transformed NfL, APOE genotype, and their interaction as the independent variables and cognitive composite score as the dependent variable. Analyses were performed separately in PSEN1 carriers and non-carriers. Results: Age-related plasma NfL increases in APOE e4+ PSEN1 carriers began to diverge from APOE e4- PSEN1 carriers at age 47.4. Age-related trajectories did not differ by APOE e2 genotype. There was no effect of APOE genotype on age-related NfL accumulation in PSEN1 non-carriers. In PSEN1 carriers, higher NfL was associated with poorer scores on the cognitive composite measure, and the APOE e2+ genotype was associated with better cognitive composite scores. Additionally, the APOE e2+ genotype mitigated the negative effect of NfL on cognitive performance in PSEN1 carriers. There was a non-significant trend for APOE e4 genotype moderating the negative effect of NfL on cognitive performance in PSEN1 carriers. Conclusions: The APOE e4 allele was associated with accelerated age-related increases in plasma NfL levels beginning prior to dementia onset in PSEN1 E280A carriers. The APOE e2 allele attenuated the negative effect of NfL on cognition in PSEN1 carriers. Future longitudinal studies of PSEN1 carriers are needed to confirm and validate these findings and further clarify the impact of APOE genotype on cognitive decline and clinical progression in the prodromal and dementia stages in this population.

Poster

02/15/2024
08:00 am - 09:15 am
Room: Shubert Complex (Posters 1-60)

Poster Session 02: Aging | MCI | Neurodegenerative Disease - PART 1

Final Abstract #8

Associations Among APOE Genotype, Plasma Neurofilament Light Chain (NfL) and Cognition in Autosomal Dominant Alzheimer’s Disease

Kyra Bonta, Yale University, New Haven, United States
Stephanie Langella, Massachusetts General Hospital, Boston, United States
Yinghua Chen, Banner Alzheimer’s Institute, Phoenix, United States
Yi Su, Banner Alzheimer’s Institute, Pheonix, United States
Daniel Vasquez, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
David Aguillon, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
Natalia Acosta-Baena, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
Ana Baena, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
Gloria Garcia-Ospina, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
Margarita Giraldo-Chica, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
Victoria Tirado, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
Claudia Muñoz, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
Silvia Ríos-Romenets, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Universidad de Antioquia, Medellin, Colombia
Claudia Guzman-Martínez, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
Jeremy Pruzin, Banner Alzheimer’s Institute, Pheonix, United States
Valentina Ghisays, Banner Alzheimer’s Institute, Pheonix, United States
Joseph Arboleda-Velasquez, Schepens Eye Research Institute of Mass Eye and Ear, Department of Ophthalmology at Harvard Medical School, Boston, United States
Kenneth Kosik, University of California Santa Barbara, Santa Barbara, United States
Eric Reiman, Banner Alzheimer’s Institute, Phoenix, United States
Francisco Lopera, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellin, United States
Yakeel Quiroz, Massachusetts General Hospital, Harvard Medical School, Boston, United States

Category: Dementia (Alzheimer's Disease)

Keyword 1: dementia - Alzheimer's disease
Keyword 2: apolipoprotein E
Keyword 3: cognitive functioning

Objective:

Presenilin-1 (PSEN1) E280A mutation carriers develop early-onset autosomal dominant Alzheimer’s disease (AD) with near 100% certainty. Recently, we showed that the APOE-e4 allele, the strongest genetic risk factor for sporadic AD, influences age-related cognitive trajectories in PSEN1 E280A carriers. However, the relationship between APOE genotype and disease-related neurodegeneration remains unclear in autosomal dominant AD. Neurofilament light chain (NfL), a protein specific to axonal injury, is a known biomarker of neurodegeneration and is increased in PSEN1 E280A carriers decades before clinical onset. Research investigating the association between plasma and CSF NfL and APOE e4 in sporadic AD has yielded conflicting results. Therefore, we aimed to (1) evaluate age-related trajectories of plasma NfL as a function of APOE genotype in PSEN1 E280A carriers and non-carriers and (2) examine how APOE and NfL are associated with cognitive performance.

Participants and Methods:

A total of 1,428 participants (778 PSEN1 carriers and 650 non-carriers) underwent APOE genotyping and blood draws to quantify plasma NfL concentrations. Within PSEN1 carriers, 169 participants had at least one APOE e4 allele (APOE e4+) while 609 had none (APOE e4-), and 114 participants had at least one e2 allele (APOE e2+) while 664 had none (APOE e2-). Separate analyses were conducted in APOE e2 and APOE e4 groups. To quantify age-related trajectories, a cubic spline model was used to plot cross-sectional log-transformed NfL concentrations across age. Using the Markov chain Monte Carlo method, model parameters were approximated as a function of APOE genotype. A subset of participants (n=1,267) had complete cognitive data. A cognitive composite score was calculated using MMSE total score, CERAD word list delayed recall, CERAD praxis delayed recall, Raven's, and phonemic fluency (FAS) total score. Linear regressions were conducted using log-transformed NfL, APOE genotype, and their interaction as the independent variables and cognitive composite score as the dependent variable. Analyses were performed separately in PSEN1 carriers and non-carriers.

Results:

Age-related plasma NfL increases in APOE e4+ PSEN1 carriers began to diverge from APOE e4- PSEN1 carriers at age 47.4. Age-related trajectories did not differ by APOE e2 genotype. There was no effect of APOE genotype on age-related NfL accumulation in PSEN1 non-carriers. In PSEN1 carriers, higher NfL was associated with poorer scores on the cognitive composite measure, and the APOE e2+ genotype was associated with better cognitive composite scores. Additionally, the APOE e2+ genotype mitigated the negative effect of NfL on cognitive performance in PSEN1 carriers. There was a non-significant trend for APOE e4 genotype moderating the negative effect of NfL on cognitive performance in PSEN1 carriers.

Conclusions:

The APOE e4 allele was associated with accelerated age-related increases in plasma NfL levels beginning prior to dementia onset in PSEN1 E280A carriers. The APOE e2 allele attenuated the negative effect of NfL on cognition in PSEN1 carriers. Future longitudinal studies of PSEN1 carriers are needed to confirm and validate these findings and further clarify the impact of APOE genotype on cognitive decline and clinical progression in the prodromal and dementia stages in this population.