Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia

Chao Wang, Monica Xiong, Maud Gratuze, Xin Bao, Yang Shi, Prabhakar Sairam Andhey, Melissa Manis, Caitlin Schroeder, Zhuoran Yin, Charlotte Madore, Oleg Butovsky, Maxim Artyomov, Jason D.Ulrich, David M.Holtzman

Neuron: May 19, 2021

The apolipoprotein E (APOE) gene is a well-known risk factor for Alzheimer’s Disease (AD). Previous research has shown that apoE4 has strong detrimental effects on both tauopathy and tau-mediated neurodegeneration. Wang and colleagues aimed to determine whether removing astrocytic APOE would affect tau pathology, tau-mediated neurodegeneration, and inflammatory response. To test this, the group generated P301S Tau/Aldh1l1-CreERT2/apoE3flox/flox and Tau/Aldh1l1-CreERT2/apoE4flox/flox mice to allow for the specific removal of astrocytic APOE3 or APOE4 via injection with tamoxifen after the onset of tau pathology. The authors found that at 9.5 months of age, the removal of astrocytic APOE4 significantly reduced phosphorylated tau pathology as well as tau-mediated neurodegeneration, specifically decreasing tau-induced synaptic loss and microglial phagocytosis of synaptic elements. Furthermore, single-nucleus RNA sequencing analysis revealed decreased disease associated gene signatures in the neurons, oligodendrocytes, astrocytes, and microglia in the group depleted of astrocytic APOE4. This data suggests that astrocytic apoE plays a role in neurodegeneration and reducing astrocytic APOE4 has therapeutic potential for tau-related neurodegeneration.  

APOE E2/E2 Is Associated with Slower Rate of Cognitive Decline with Age

Benjamin Sweigart, Stacy L. Andersen, Anastasia Gurinovich, Stephanie Cosentino, Nicole Schupf, Thomas T. Perls and Paola Sebastiani

Journal of Alzheimers Disease: August 4, 2021

It is well-known that the E4 allele of apoE is associated with cognitive impairment and increases one’s risk for AD. However, the longitudinal changes in cognitive function associated with the E2 allele are far less understood. It is also unknown whether E2 homozygous versus E2 heterozygous have a differential impact of cognitive function. The authors aim to understand how the E2 allele influences cognitive ability over a period and examine how age modifies the protective effect of E2. Using data from two ongoing longitudinal cohort studies, the Long-Life Family study and the New England Centenarian Study, they found that the common E3/E3 genotype showed a decreased TICS score by 0.15 points per year of age. Participants with E2/E2 genotype showed a decreased TICS score of 0.05 points per year of age, which is a significantly slower rate of decline compared to the common variant. However, there was no protective effect of the E2/E3 genotype on cognitive decline. Lastly, their analysis confirmed a significant negative effect of the E3/E4 and E4/E4 genotypes on TICS score, but there was no significant difference on rate of decline. Overall, these results indicate there is a protective effect of the E2/E2 genotype on cognitive functioning. A major limitation of the study is the cohort size and demographics of study participants. Most of the test subjects had more education compared to the national age cohort, which is associated to promoting longevity and protecting against cognitive decline. Also, there were few participants with E2/E2, E2/E4, and E4/E4 genotypes. Although the authors attempted to adjust for these factors and cofounding variables, results should be replicated in a more homogeneous population.

Association of apolipoprotein E variation with cognitive impairment across multiple neurodegenerative diagnoses

Allison A. Dilliott, Kelly M. Sunderland, Paula M. McLaughlin, Angela C. Roberts, Emily C. Evans, Agessandro Abrahao, MalcolmA. Binnsc, SandraE. Black, Michael Borrie, Leanne.K. Casaubon, Dar Dowlatshahi, Elizabeth Finger, Corinne.E. Fischer, Andrew Franke, Morris Freedmanc , David Grimes, Ayman Hassan, Mandar Jog, Sanjeev Kumar, Donna Kwan, Anthony E. Lang, Jennifer Mandzia, Connie Marras, Mario Masellis, Adam D. McIntyre, Stephen Pasternak, Bruce G. Pollock, Tarek K. Rajji, John F. Robinson, Ekaterina Rogaeva, Demetrios J. Sahlas, Gustavo Saposnik, Christine Sato, Dallas Seitz, Christen Shoesmith, Thomas Steeves, Stephen C. Strother, Richard H. Swartz, Brian Tan, David Tang-Wai, Maria C. Tartaglia, Angela K. Troyer, John Turnbull, Lorne Zinman, ONDRI Investigators, Robert A. Hegele

Neurobiology of Aging; April 24, 2021

It is known that the APOE4 allele is a risk factor for Alzheimer’s disease (AD), through A? accumulation and tau pathology, and Lewy Body Dementia (LBD), through increased ?-synuclein pathology. Thus demonstrating that APOE4 has a major impact on multiple neurodegenerative diseases through various mechanisms. Hegele et al. sought to establish overlapping APOE genotype dependent factors across numerous neurodegenerative and cerebrovascular diseases. This study investigated a cohort of 513 participants who were clinically diagnosed with a neurodegenerative or cerebrovascular disease. Researchers employed a neuropsychological assessment, the results of which were analyzed alongside APOE genotype and disease status to evaluate the effects of APOE genotype function on various neurodegenerative diseases. The study found that E4 carriers generally had significantly lower performance in verbal memory and visuospatial domains than E3/E3 carriers, while E2 carriers displayed similar performance to E3/E3 genotypes. Interestingly, within the frontotemporal dementia (FTD) patients, E4 carriers had better verbal memory performance than E3/E3 carriers, while E2 carriers performed significantly worse in attention and working memory compared to E3/E3 genotypes. These findings suggest that APOE genotype has a significant and complex influence on cognition regardless of disease status, yet the mechanisms that drive such phenotypes remain unclear. Future studies with larger samples sizes, particularly in FTD cohorts, are needed to explore the interesting findings reported in this study.