Multimodal imaging correlates of the protective APOE2 allele: Imaging and biomarker correlates of genetic variants protective against AD

Abstract

Background: The protective effect of APOEε2 against Alzheimer’s disease (AD) is relatively well‐established, but the mechanisms conferring this effect are incompletely known. Method: Studies have tried to assess these mechanisms through studying the physiological functions of the APOE protein, the most promising being clearance and degradation of amyloid. Results: It has been consistently observed in post‐mortem studies that APOEε2‐carriers have decreased amyloid‐pathology and a large meta‐analytic investigation assessing amyloid‐status on PET or CSF across APOE genotypes also revealed that amyloid‐positivity, and age‐related increases in amyloid‐positivity, were lowest in APOEε2‐carriers. Some post‐mortem studies have also reported a protective effect of APOEε2 on tau pathology, but these results could not be replicated in all examinations. Recently, efforts have been undertaken to assess the effect of APOEε2 on amyloid and tau pathology using in‐vivo PET imaging. These studies indicate that APOEε2‐carriers have decreased cortical amyloid load while no effects were observed on cortical tau, nor on hypometabolism (FGD‐PET) or hippocampal and entorhinal gray matter (MRI). This suggests that the protective effect of APOEε2 might be selective for amyloid. However, amyloid‐independent effects on cognitive decline have been reported and it is postulated that the APOEε2 allele increases synaptic density and protects against neuroinflammation. More in‐vivo imaging studies are needed to elucidate these amyloid‐independent protective effects of APOEε2, and with recent developments in novel imaging methodologies this might soon be possible. For instance, UCB‐J PET imaging might be implemented to assess synaptic density in APOEε2‐carriers, and TSPO‐PET might be used to detect neuroinflammatory markers. Conclusion: Studying the protective mechanisms of APOEε2 using neuroimaging studies are essential as they might inform future disease‐modifying treatments, such as using gene‐editing techniques to convert APOEε4 to APOEε2, and delivering APOEε2 into APOEε4 carriers through the use of adeno‐associated viruses. Paradoxically, it has been shown that APOEε2, while protective against AD, has a detrimental effect on markers of cerebrovascular disease and subjects who do develop AD despite being an APOEε2‐carrier display a distinct phenotype with increased small vessel disease and non‐amnestic cognitive impairments. These factors need to be considered in any future neuroimaging examinations into the protective effects of APOEε2.