Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human-based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and exciting tools to enhance and forward AD research. In particular, these methods are helping advance AD research by contributing multifactorial and multidimensional perspectives, especially considering the crucial role played by lifestyle risk factors in the determination of AD risk. In addition to research techniques, we also consider related pitfalls and flaws in the current research funding system. Conversely, we identify encouraging new trends in research and government policy. In light of these new research directions, we provide recommendations regarding prioritization of research funding. The goal of this document is to stimulate scientific and public discussion on the need to explore new avenues in AD research, considering outcome and ethics as core principles to reliably judge traditional research efforts and eventually undertake new research strategies.

SUMMARYPurpose: The kindling of seizures with stimulation of brainstem sites has been reported inconsistently in the literature. The characteristics of the kindling observed, involving high intensities of stimulation and immediate onset of generalized tonic-clonic convulsions, raise questions regarding the nature of kindling from these sites. Methods: We implanted chronic electrodes in either the nucleus reticularis pontis oralis (RPO), mesencephalic reticular formation (MRF), dorsal periaqueductal gray (dPAG), or ventrolateral periaqueductal gray (vlPAG) in male Long-Evans rats, with a recording electrode in the amygdala. Rats received conventional high-frequency kindling stimulation once daily for 30 days. To test for transfer, we kindled the amygdala beginning 7 weeks after the last brainstem kindling trial. Results: Tonic-clonic seizures were evoked by stimulation from all brainstem sites. Seizures were brief and were associated with characteristic low-amplitude highfrequency afterdischarge (AD). Kindling of the dPAG resulted in the development of classic AD and increased AD duration. Prior kindling of the dPAG facilitated subsequent kindling of the amygdala; however, no transfer was observed with prekindling of other brainstem sites. Discussion: The variability in the response to kindling stimulation suggests that certain brainstem sites are resistant to kindling, whereas other sites are more susceptible to kindling but are still relatively resistant in comparison to sites in the forebrain. The development of classic AD in later trials of dPAG stimulation suggests that epileptogenesis can occur even in the initial absence of classic AD when low-amplitude high-frequency AD is present.

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Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and/or psychological symptoms, remain unclear. In this review, the available knowledge on the neurobiological mechanisms underlying COVID-19 was organized using the AOP framework. Four AOPs leading to neurological adverse outcomes (AO), anosmia, encephalitis, stroke, and seizure, were developed. Biological key events (KEs) identified to induce these AOs included binding to ACE2, blood–brain barrier (BBB) disruption, hypoxia, neuroinflammation, and oxidative stress. The modularity of AOPs allows the construction of AOP networks to visualize core pathways and recognize neuroinflammation and BBB disruption as shared mechanisms. Furthermore, the impact on the neurological AOPs of COVID-19 by modulating and multiscale factors such as age, psychological stress, nutrition, poverty, and food insecurity was discussed. Organizing the existing knowledge along an AOP framework can represent a valuable tool to understand disease mechanisms and identify data gaps and potentially contribute to treatment, and prevention. This AOP-aligned approach also facilitates synergy between experts from different backgrounds, while the fast-evolving and disruptive nature of COVID-19 emphasizes the need for interdisciplinarity and cross-community research.

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Background:The severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) causes various neurological manifestations including neuroinflammation. Neuroinflammation is also present in Alzheimer's Disease and Related Dementias (ADRD).Despite the widespread and devastating impact of these conditions, the full causal mechanisms leading to neuroinflammation and its impact on outcomes remain elusive.Here we examine neuroinflammation in COVID-19 and ADRD in order to identify similarities, differences and interactions that could aid in addressing the biopsychosocial mechanisms and consequences in both conditions.Method: Using an expanded Adverse Outcome Pathway (AOP) approach we constructed a framework to compare the similarities and differences in key events leading to neuroinflammation. The framework is based on a meta-survey of the literature as well as existing AOPs. Key findings were assessed for similarities and differences regarding the clinical presentation, biological mechanisms, risk, protective factors, and treatment interventions. Additionally, we considered health disparities that may contribute to the worsening progression of both COVID-19 and ADRD. Result:The comparison and intersections of COVID-19 and ADRD show various overlapping factors across scales. An overlap of immune system and inflammatory processes exacerbate both conditions, potentially leading to increased mortality rates.Although there are major differences in the initiating events, timelines and molecular cascades, there are significant pathway commonalities across scales. Furthermore, commonalities in underlying conditions, such as obesity, Type 2 diabetes, cardiovascular disease, hypertension, and metabolic disorders, are major risk factors in both COVID-19 and ADRD, which worsen the outcomes. Additionally, lifestyle risk factors, such as poor nutrition, physical inactivity and cognitive status, may further exacerbate the deadly prognosis for both conditions. Conclusion:Given the crucial role of inflammation and immune system functioning in both these conditions, implementing preventative measures to strengthen the immune system and decrease comorbid conditions and lifestyle risk factors is imperative, especially for vulnerable populations. Mapping approaches such as AOPs can be particularly helpful in evaluating the weight of current evidence and knowledge gaps in a rapidly evolving scientific data landscape, such as the COVID-19 pandemic. These approaches can also serve as a foundation to further probe the complexities of multiscale interactions in diseases that may otherwise initially appear unrelated.

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