Don A. Davies

Apolipoprotein E (APOE) has three different isoforms, with APOE4 carriers representing a major risk factor for the development of Alzheimer’s disease (AD). AD is the most common form of dementia, and is a relentlessly progressive disorder that afflicts the aged, characterized by severe memory loss. Presently, AD does not have a cure, increasing the urgency for the development of novel therapeutics for the prevention/treatment of AD. The APOE4 isoform is associated with many pathological mechanisms, such as increased neuroinflammation and a reduction in β-amyloid (Aβ) clearance. The accumulation of Aβ plaques in the brain is a hallmark of AD. The presence of APOE4 can increase neuroinflammation via overactivation of the nuclear factor kappa B (NF-κB) pathway. The NF-κB pathway is a family of transcription factors involved with regulating over 400 genes involved with inflammation. AD is associated with sustained inflammation and an overactivation of the NF-κB pathway. Therefore, targeting the APOE4 isoform and suppressing the NF-κB pathway using anti-inflammatory compounds may result in the development of novel therapeutics for the prevention/treatment of AD.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that reduces oxidative stress. When reactive oxygen species (ROS) or reactive nitrogen species (RNS) are detected, Nrf2 translocates from the cytoplasm into the nucleus and binds to the antioxidant response element (ARE), which regulates the expression of antioxidant and anti-inflammatory genes. Nrf2 impairments are observed in the majority of neurodegenerative disorders, including Alzheimer’s disease (AD). The classic hallmarks of AD include β-amyloid (Aβ) plaques, and neurofibrillary tangles (NFTs). Oxidative stress is observed early in AD and is a novel therapeutic target for the treatment of AD. The nuclear translocation of Nrf2 is impaired in AD compared to controls. Increased oxidative stress is associated with impaired memory and synaptic plasticity. The administration of Nrf2 activators reverses memory and synaptic plasticity impairments in rodent models of AD. Therefore, Nrf2 activators are a potential novel therapeutic for neurodegenerative disorders including AD.

The coronavirus disease that presumably began in 2019 (COVID-19) is a highly infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic. Initially, COVID-19 was thought to only affect respiration. However, accumulating evidence shows a wide range of neurological symptoms are also associated with COVID-19, such as anosmia/ageusia, headaches, seizures, demyelination, mental confusion, delirium, and coma. Neurological symptoms in COVID-19 patients may arise due to a cytokine storm and a heighten state of inflammation. The nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) is a central pathway involved with inflammation and is shown to be elevated in a dose-dependent matter in response to coronaviruses. NF-κB has a role in cytokine storm syndrome, which is associated with greater severity in COVID-19-related symptoms. Therefore, therapeutics that reduce the NF-κB pathway should be considered in the treatment of COVID-19. Neuro-COVID-19 units have been established across the world to examine the neurological symptoms associated with COVID-19. Neuro-COVID-19 is increasingly becoming an accepted term among scientists and clinicians, and interdisciplinary teams should be created to implement strategies for treating the wide range of neurological symptoms observed in COVID-19 patients.

Dementia is an umbrella term—caused by a large number of specific diagnoses, including several neurodegenerative disorders. Alzheimer's disease (AD) is now the most common cause of dementia in advanced countries, while dementia due to neurosyphilis was the leading cause a century ago. Many challenges remain for diagnosing dementia definitively. Some of these include variability of early symptoms and overlap with similar disorders, as well as the possibility of combined, or mixed, etiologies in some cases. Newer technologies, including the incorporation of PET neuroimaging and other biomarkers (genomics and proteomics), are being incorporated into revised diagnostic criteria. However, the application of novel diagnostic methods at clinical sites is plagued by many caveats including availability and access. This review surveys new diagnostic methods as well as remaining challenges—for clinical care and clinical research.