Alzheimer’s Relevance in the Neuroscience Community: A Collaborative Neuronline Perspective
The following article is a collaboration between members of the 2024 Neuronline Community Leaders program. The program is a group of active SfN members who are interested in cultivating the sharing and discussion of resources among SfN members on the Neuronline Community.
Alzheimer’s Disease (AD) and Alzheimer’s Disease-Related Dementias (ADRD) are debilitating diseases that take away an individual's identity, self, and devastate their loved ones. In addition to family and communities, AD and ADRD pose social and economic burdens globally, affecting economies, policies, and healthcare systems. This burden of dementia is also projected to disproportionately affect low- and middle-income countries.
Periodic reports indicate that several risk factors for AD and ADRD are preventable, and there is hope in the recent FDA approvals for potentially disease-modifying therapies, despite the controversy surrounding them. More recently, in the United States, the National Alzheimer’s Project Act Reauthorization and the Alzheimer’s Accountability and Investment Acts have been signed into law by the president, providing further hope for continued investment to prevent, treat, and even cure AD and ADRD.
Advocacy efforts leading to increased funding of AD research combined with the progress made in the field has resulted in several Neuronline Community Leaders wanting to share our perspectives and enthusiasm for AD research. This collaborative approach allowed us to also share in each other’s work more closely and we hope that many of you are inspired to collaborate across disciplines towards your common goals.
Identifying Environmental Risk Factors for Neurodegenerative Diseases – Japhet Kineze
Understanding how environments interact with our brains is key to exploring the complex cultural practices that contribute to brain health in different regions. This field of study delves into the biological and social factors shaping human behavior. By integrating a neural network model with sensors analyzing bioenvironmental data (e.g., pollution, noise levels, natural disaster occurrences, crime rates, and infrastructure) alongside brain activity (EEG, fMRI), we can identify and predict responses of the brain to environmental factors that heighten the risk of neurodegenerative diseases like strokes, Alzheimer's or Parkinson's Disease.
While urbanization has its benefits, it can also introduce challenges that adversely affect health outcomes via substandard infrastructure, constrained resources, inadequate healthcare, pollution, and social insecurity. Environmental factors are increasingly recognized as playing a significant role in the development and progression of neurodegenerative diseases; an estimated 12.6 million deaths occur annually due to unhealthy environmental conditions.
I am working on a project that proposes a bioenvironmental sensor embedded in a BCI (EEG) device that combines biological marker detection, cognitive assessment, and lifestyle monitoring to identify individuals in urban and rural areas at risk for neurodegenerative diseases. The sensor wouldn't directly "read" the brain but would monitor various factors that may provide clues about brain health.
This study proposes a three-pronged approach to address these challenges and improve well-being in urban and rural areas: (i) utilizing neural networks for analysis of bioenvironmental data, (ii) simulating brain activity using advanced computational techniques, and (iii) improving access to resources to empower individuals via mobile technologies. By combining these data points, I am excited about the prospect of potentially identify individuals at risk for neurodegenerative diseases earlier, allowing for earlier intervention and management.
Biomarker Discovery for Early Detection and Treatment – Sai Lavanya Patnala
Understanding pathophysiology at a molecular level and identifying potential therapeutic targets can change the way complex diseases like AD are treated in the future. Currently, AD can be detected early using CSF levels of amyloid beta and CSF-P-Tau. PET imaging is used for confirmation upon onset of symptoms. Given the high costs of such methods, it is crucial to identify reliable and affordable diagnostic markers that can be detected through blood tests. There is an urgent need to develop cost-effective and accessible solutions for large-scale screening, early detection, and potential treatment of AD, rather than merely slowing its symptoms.
Recent research has highlighted microRNAs (miRNAs) as potential biomarkers for early diagnosis and as therapeutic targets. In human subjects, miR-4722-5p and miR-615-3p were found upregulated in blood samples collected from AD patients compared to healthy controls. Dysregulated miR-485-5p or miR-485-3p was found in plasma, CSF, and postmortem tissues of the brain in patients with AD. miR-455–3p was also identified in postmortem AD brains, B-lymphocytes, and fibroblasts. Experiments in mouse models have shown miR-485-3p and miR 128 to be upregulated and miR-132, miR-455–3p, miR-340 and miR-132 to be downregulated. Anti-sense oligonucleotide treatment to inhibit miR-485-3p reduced Aβ plaque accumulation, tau pathology development, neuroinflammation, and cognitive decline in transgenic mouse models and miR-132 replacement in adult mice restored hippocampal neurogenesis and memory deficits. Engineered nanoliposomes carrying miR-195, modified to improve blood-brain barrier penetration and cell membrane permeability have been developed. When used in combination with Donepezil, miR-195 significantly slowed cognitive decline in mouse models without causing notable side effects.
So far, miR-485-5p, miR-485-3p and miR-455–3p have been identified as potential peripheral biomarkers and miR-125b, miR-146a, miR-9, and miR-103 have shown high sensitivity and specificity. There is also an increasing understanding of mitochondrial dysfunction in CNS, leading to weaker synapses which leads to worsening of memory and cognitive deficits highlighting the potential of mitochondrial miRNAs. These studies highlight the great promise of blood-based miRNA biomarkers and how targeted therapies may change the way AD is managed in the clinic.
As an aspiring neurologist, I am eager to see the advancements that miRNA research will bring. Challenges to this promising avenue lie in drug delivery, highlighting the need for novel engineered delivery systems such as liposomes to overcome these issues. I believe that with advancements in biotechnology, new drugs and blood biomarkers will become available for clinical use in the coming decades. My hope is to see these novel solutions lead to more equitable dementia care.
Novel Approaches to Target Neurodegeneration – Daisy Gallardo
A proposed avenue for targeting the neuropathology of Alzheimer's Disease (AD) is the mammalian target of Rapamycin (mTOR) pathway. The mTOR signaling pathway is key in a multitude of biological processes, including regulating protein synthesis and cell growth. Due to the pathway being multifaceted, it is widely discussed amongst many nonscientists and scientists alike. It is of interest to athletes for its role in metabolism and protein synthesis, as well as a topic of discussion for its role in longevity and aging.
In the context of AD, most reports on the mTOR pathway have focused on its role in a lysosome-dependent process termed autophagy. Activation of the mTOR signaling pathway leads to the suppression of autophagy. One prevailing idea suggests that overactivation of mTOR in AD results in an accumulation of aberrant proteins, due to a decrease in autophagy. A proposed therapeutic approach is to use pharmacological mTOR kinase inhibitors to potentially ameliorate the neuropathological hallmarks of AD.
The idea of inhibiting the mTOR pathway has gained a lot of popularity in the AD field, but in the spinal cord injury (SCI) field the activation of mTOR is being studied. Although the two fields differ significantly, they both involve neurodegeneration. In mature neurons, mTOR is downregulated, leading to inhibition of neuronal growth and a limited ability to regenerate damaged neuronal processes. Activation of mTOR has been investigated as a treatment for SCI to restore neuronal regenerative capabilities.
In summary, the AD field is primarily investigating mTOR inhibition as a treatment for delaying or preventing neurodegeneration, and the SCI field is investigating mTOR activation as a treatment for managing neurodegeneration due to physical trauma. Therefore, novel approaches for targeting neurodegeneration in AD might be found by exploring approaches being used in other domains, such as the SCI field. With aging being the biggest risk factor for AD, inducing a “younger” cell growth state in a neuron, through mTOR activation, may be beneficial for reducing or delaying neurodegeneration in AD.
Improving Research Rigor and Reproducibility – Jaya Viswanathan
The pipeline of developing a candidate therapeutic for any disease starts with basic research and goes through several phases of research and development before it can be tested in human participants in the clinic. However, many candidate therapeutics that have shown positive results in non-clinical studies when tested in animal models fail in the clinic. While many reasons exist for this gap in translation of promising therapeutics to the clinic colloquially known as the “valley of death”, one major reason is the lack of standardized and rigorous methodology as well transparent reporting of findings in preclinical animal studies.
The Alzheimer’s Disease Preclinical Efficacy Database (AlzPED) was developed and launched to improve translation by serving the research community in 3 ways: (i) to provide the research community with an easy way to survey the research landscape of preclinical efficacy studies as well as the rigor of these published studies via a Rigor Report Card, (ii) to provide a framework to design rigorous experiments as well as to identify critical gaps in study design in published studies, and (iii) to mitigate the bias towards publishing positive findings by providing a platform to house preprints of studies with negative findings.
I am a curator for AlzPED, and one of my roles as a contractor at the National Institute on Aging is to survey the published literature to assess the rigor of these studies as well as help inform policy changes to improve research practices. It can be disheartening to see that studies published as recently as 2023 or 2024 that tested candidate therapeutics do not report having conducted the most basic and yet critical elements of reproducible research such as ensuring that studies are powered well enough to be able to answer the hypothesis or randomizing animals to treatment or placebo arms.
However, this highlights the need for funders, journals, professional science societies, and the research community to come together to ensure rigorous research and transparent reporting. As an example, congruent journal and funder policies to report conflicts of interest has markedly improved the reporting of this over the last 10 years and might provide a template for how our communities can come together to set standards for research and publishing. Further work needs to be done to improve the research incentives and infrastructure, but I am heartened by all the people I know who are working towards and champion research rigor.
To achieve our common goals to prevent, treat, and cure AD and ADRD equitably, we need to move towards open science practices, data sharing models and rigorous science that informs us of the disease heterogeneity, avenues to reduce preventable risk factors, advance biomarker and therapeutic discovery, for a better tomorrow.
Introduction & organization: Jaya Viswanathan
Section Contributors: Japhet Kineze, Sai Lavanya Patnala, Daisy Gallardo, Jaya Viswanathan
About the Contributors
