A Hybrid Machine Learning and Network Analysis Approach Reveals Two Parkinson's Disease Subtypes from 115 RNA-Seq Post-Mortem Brain Samples.

Precision medicine emphasizes fine-grained diagnostics, taking individual variability into account to enhance treatment effectiveness. Parkinson's disease (PD) heterogeneity among individuals proves the existence of disease subtypes, so subgrouping patients is vital for better understanding disease mechanisms and designing precise treatment. The purpose of this study was to identify PD subtypes using RNA-Seq data in a combined pipeline including unsupervised machine learning, bioinformatics, and network analysis. Two hundred and ten post mortem brain RNA-Seq samples from PD (n = 115) and normal controls (NCs, n = 95) were obtained with systematic data retrieval following PRISMA statements and a fully data-driven clustering pipeline was performed to identify PD subtypes. Bioinformatics and network analyses were performed to characterize the disease mechanisms of the identified PD subtypes and to identify target genes for drug repurposing. Two PD clusters were identified and 42 DEGs were found (p adjusted ≤ 0.01). PD clusters had significantly different gene network structures (p < 0.0001) and phenotype-specific disease mechanisms, highlighting the differential involvement of the Wnt/ß-catenin pathway regulating adult neurogenesis. NEUROD1 was identified as a key regulator of gene networks and ISX9 and PD98059 were identified as NEUROD1-interacting compounds with disease-modifying potential, reducing the effects of dopaminergic neurodegeneration. This hybrid data analysis approach could enable precision medicine applications by providing insights for the identification and characterization of pathological subtypes. This workflow has proven useful on PD brain RNA-Seq, but its application to other neurodegenerative diseases is encouraged.

Transcriptomic and Network Analyses Reveal Immune Modulation by Endocannabinoids in Approach/Avoidance Traits.

Approach and avoidance (A/A) tendencies are stable behavioral traits in responding to rewarding and fearful stimuli. They represent the superordinate division of emotion, and individual differences in such traits are associated with disease susceptibility. The neural circuitry underlying A/A traits is retained to be the cortico-limbic pathway including the amygdala, the central hub for the emotional processing. Furthermore, A/A-specific individual differences are associated with the activity of the endocannabinoid system (ECS) and especially of CB1 receptors whose density and functionality in amygdala differ according to A/A traits. ECS markedly interacts with the immune system (IS). However, how the interplay between ECS and IS is associated with A/A individual differences is still ill-defined. To fill this gap, here we analyzed the interaction between the gene expression of ECS and immune system (IS) in relation to individual differences. To unveil the deep architecture of ECS-IS interaction, we performed cell-specific transcriptomics analysis. Differential gene expression profiling, functional enrichment, and protein-protein interaction network analyses were performed in amygdala pyramidal neurons of mice showing different A/A behavioral tendencies. Several altered pro-inflammatory pathways were identified as associated with individual differences in A/A traits, indicating the chronic activation of the adaptive immune response sustained by the interplay between endocannabinoids and the IS. Furthermore, results showed that the interaction between the two systems modulates synaptic plasticity and neuronal metabolism in individual difference-specific manner. Deepening our knowledge about ECS/IS interaction may provide useful targets for treatment and prevention of psychopathology associated with A/A traits.

Optogenetic Stimulation of Prelimbic Pyramidal Neurons Maintains Fear Memories and Modulates Amygdala Pyramidal Neuron Transcriptome.

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.

CB1 Activity Drives the Selection of Navigational Strategies: A Behavioral and c-Fos Immunoreactivity Study.

To promote efficient explorative behaviors, subjects adaptively select spatial navigational strategies based on landmarks or a cognitive map. The hippocampus works alone or in conjunction with the dorsal striatum, both representing the neuronal underpinnings of the navigational strategies organized on the basis of different systems of spatial coordinate integration. The high expression of cannabinoid type 1 (CB1) receptors in structures related to spatial learning-such as the hippocampus, dorsal striatum and amygdala-renders the endocannabinoid system a critical target to study the balance between landmark- and cognitive map-based navigational strategies. In the present study, mice treated with the CB1-inverse agonist/antagonist AM251 or vehicle were trained on a Circular Hole Board, a task that could be solved through either navigational strategy. At the end of the behavioral testing, c-Fos immunoreactivity was evaluated in specific nuclei of the hippocampus, dorsal striatum and amygdala. AM251 treatment impaired spatial learning and modified the pattern of the performed navigational strategies as well as the c-Fos immunoreactivity in the hippocampus, dorsal striatum and amygdala. The present findings shed light on the involvement of CB1 receptors as part of the selection system of the navigational strategies implemented to efficiently solve the spatial problem.

NIPAT as Non-Invasive Prenatal Paternity Testing Using a Panel of 861 SNVs.

In 1997, it was discovered that maternal plasma contains Cell-Free Fetal DNA (cffDNA). cffDNA has been investigated as a source of DNA for non-invasive prenatal testing for fetal pathologies, as well as for non-invasive paternity testing. While the advent of Next Generation Sequencing (NGS) led to the routine use of Non-Invasive Prenatal Screening (NIPT or NIPS), few data are available regarding the reliability and reproducibility of Non-Invasive Prenatal Paternity Testing (NIPPT or NIPAT). Here, we present a non-invasive prenatal paternity test (NIPAT) analyzing 861 Single Nucleotide Variants (SNV) from cffDNA through NGS technology. The test, validated on more than 900 meiosis samples, generated log(CPI)(Combined Paternity Index) values for designated fathers ranging from +34 to +85, whereas log(CPI) values calculated for unrelated individuals were below -150. This study suggests that NIPAT can be used with high accuracy in real cases.

Synaptic and transcriptomic features of cortical and amygdala pyramidal neurons predict inefficient fear extinction.

Fear-related disorders arise from inefficient fear extinction and have immeasurable social and economic costs. Here, we characterize mouse phenotypes that spontaneously show fear-independent behavioral traits predicting adaptive or maladaptive fear extinction. We find that, already before fear conditioning, specific morphological, electrophysiological, and transcriptomic patterns of cortical and amygdala pyramidal neurons predispose to fear-related disorders. Finally, by using an optogenetic approach, we show the possibility to rescue inefficient fear extinction by activating infralimbic pyramidal neurons and to impair fear extinction by activating prelimbic pyramidal neurons.

A Reproducible Deep-Learning-Based Computer-Aided Diagnosis Tool for Frontotemporal Dementia Using MONAI and Clinica Frameworks.

Despite Artificial Intelligence (AI) being a leading technology in biomedical research, real-life implementation of AI-based Computer-Aided Diagnosis (CAD) tools into the clinical setting is still remote due to unstandardized practices during development. However, few or no attempts have been made to propose a reproducible CAD development workflow for 3D MRI data. In this paper, we present the development of an easily reproducible and reliable CAD tool using the Clinica and MONAI frameworks that were developed to introduce standardized practices in medical imaging. A Deep Learning (DL) algorithm was trained to detect frontotemporal dementia (FTD) on data from the NIFD database to ensure reproducibility. The DL model yielded 0.80 accuracy (95% confidence intervals: 0.64, 0.91), 1 sensitivity, 0.6 specificity, 0.83 F1-score, and 0.86 AUC, achieving a comparable performance with other FTD classification approaches. Explainable AI methods were applied to understand AI behavior and to identify regions of the images where the DL model misbehaves. Attention maps highlighted that its decision was driven by hallmarking brain areas for FTD and helped us to understand how to improve FTD detection. The proposed standardized methodology could be useful for benchmark comparison in FTD classification. AI-based CAD tools should be developed with the goal of standardizing pipelines, as varying pre-processing and training methods, along with the absence of model behavior explanations, negatively impact regulators' attitudes towards CAD. The adoption of common best practices for neuroimaging data analysis is a step toward fast evaluation of efficacy and safety of CAD and may accelerate the adoption of AI products in the healthcare system.

The Cerebellum as an Embodying Machine.

Whereas emotion theorists often keep their distance from the embodied approach, theorists of embodiment tend to treat emotion as a mainly physiologic process. However, intimate links between emotions and the body suggest that emotions are privileged phenomena to attempt to reintegrate mind and body and that the body helps the mind in shaping emotional responses. To date, research has favored the cerebrum over other parts of the brain as a substrate of embodied emotions. However, given the widely demonstrated contribution of the cerebellum to emotional processing, research in affective neuroscience should consider embodiment theory as a useful approach for evaluating the cerebellar role in emotion and affect. The aim of this review is to insert the cerebellum among the structures needed to embody emotions, providing illustrative examples of cerebellar involvement in embodied emotions (as occurring in empathic abilities) and in impaired identification and expression of embodied emotions (as occurring in alexithymia).

Update on the Molecular Aspects and Methods Underlying the Complex Architecture of FSHD.

Despite the knowledge of the main mechanisms involved in facioscapulohumeral muscular dystrophy (FSHD), the high heterogeneity and variable penetrance of the disease complicate the diagnosis, characterization and genotype-phenotype correlation of patients and families, raising the need for further research and data. Thus, the present review provides an update of the main molecular aspects underlying the complex architecture of FSHD, including the genetic factors (related to D4Z4 repeated units and FSHD-associated genes), epigenetic elements (D4Z4 methylation status, non-coding RNAs and high-order chromatin interactions) and gene expression profiles (FSHD transcriptome signatures both at bulk tissue and single-cell level). In addition, the review will also describe the methods currently available for investigating the above-mentioned features and how the resulting data may be combined with artificial-intelligence-based pipelines, with the purpose of developing a multifunctional tool tailored to enhancing the knowledge of disease pathophysiology and progression and fostering the research for novel treatment strategies, as well as clinically useful biomarkers. In conclusion, the present review highlights how FSHD should be regarded as a disease characterized by a molecular spectrum of genetic and epigenetic factors, whose alteration plays a differential role in DUX4 repression and, subsequently, contributes to determining the FSHD phenotype.

WARE: Wet AMD Risk-Evaluation Tool as a Clinical Decision-Support System Integrating Genetic and Non-Genetic Factors.

Given the multifactorial features characterizing age-related macular degeneration (AMD), the availability of a tool able to provide the individual risk profile is extremely helpful for personalizing the follow-up and treatment protocols of patients. To this purpose, we developed an open-source computational tool named WARE (Wet AMD Risk Evaluation), able to assess the individual risk profile for wet AMD based on genetic and non-genetic factors. In particular, the tool uses genetic risk measures normalized for their relative frequencies in the general population and disease prevalence. WARE is characterized by a user-friendly web page interface that is intended to assist clinicians in reporting risk assessment upon patient evaluation. When using the tool, plots of population risk distribution highlight a "low-risk zone" and a "high-risk zone" into which subjects can fall depending on their risk-assessment result. WARE represents a reliable population-specific computational system for wet AMD risk evaluation that can be exploited to promote preventive actions and personalized medicine approach for affected patients or at-risk individuals. This tool can be suitable to compute the disease risk adjusted to different populations considering their specific genetic factors and related frequencies, non-genetic factors, and the disease prevalence.

Tracking the Initial Diffusion of SARS-CoV-2 Omicron Variant in Italy by RT-PCR and Comparison with Alpha and Delta Variants Spreading.

The emergence of the Omicron SARS-CoV-2 variant caused public health concerns worldwide, raising the need for the improvement of rapid monitoring strategies. The present manuscript aimed at providing evidence of the utility of a diagnostic kit for the routine testing of SARS-CoV-2 infection as a cost-effective method for tracking the Omicron variant in Italy. The study was conducted on patients' naso-oropharyngeal-swab-derived RNA samples. These samples were subjected to RT-PCR using the TaqPath COVID-19 RT PCR CE IVD kit. Nonparametric testing and polynomial models fitting were used to compare the spreading of Alpha, Delta and Omicron variants. The samples of interest were correctly amplified and displayed the presence of S gene-target failure, suggesting that these patients carry the Omicron variant. The trend of diffusion was found to be significantly different and more rapid compared with that of the Alpha and Delta variants in our cohorts. Overall, these results highlight that the S gene target failure was a very useful tool for the immediate and inexpensive tracking of Omicron variant in the three weeks from the first detection. Thus, our approach could be used as a first-line screening to reduce the time and costs of monitoring strategies, facilitating the management of preventive and counteracting measures against COVID-19.

Identification of Genetic Networks Reveals Complex Associations and Risk Trajectory Linking Mild Cognitive Impairment to Alzheimer's Disease.

Amnestic mild cognitive impairment (aMCI) and sporadic Alzheimer's disease (AD) are multifactorial conditions resulting from a complex crosstalk among multiple molecular and biological processes. The present study investigates the association of variants localized in genes and miRNAs with aMCI and AD, which may represent susceptibility, prognostic biomarkers or multi-target treatment options for such conditions. We included 371 patients (217 aMCI and 154 AD) and 503 healthy controls, which were genotyped for a panel of 120 single nucleotide polymorphisms (SNPs) and, subsequently, analyzed by statistical, bioinformatics and machine-learning approaches. As a result, 21 SNPs were associated with aMCI and 13 SNPs with sporadic AD. Interestingly, a set of variants shared between aMCI and AD displayed slightly higher Odd Ratios in AD with respect to aMCI, highlighting a specific risk trajectory linking aMCI to AD. Some of the associated genes and miRNAs were shown to interact within the signaling pathways of APP (Amyloid Precursor Protein), ACE2 (Angiotensin Converting Enzyme 2), miR-155 and PPARG (Peroxisome Proliferator Activated Receptor Gamma), which are known to contribute to neuroinflammation and neurodegeneration. Overall, results of this study increase insights concerning the genetic factors contributing to the neuroinflammatory and neurodegenerative mechanisms underlying aMCI and sporadic AD. They have to be exploited to develop personalized approaches based on the individual genetic make-up and multi-target treatments.

Only Words Count; the Rest Is Mere Chattering: A Cross-Disciplinary Approach to the Verbal Expression of Emotional Experience.

The analysis of sequences of words and prosody, meter, and rhythm provided in an interview addressing the capacity to identify and describe emotions represents a powerful tool to reveal emotional processing. The ability to express and identify emotions was analyzed by means of the Toronto Structured Interview for Alexithymia (TSIA), and TSIA transcripts were analyzed by Natural Language Processing to shed light on verbal features. The brain correlates of the capacity to translate emotional experience into words were determined through cortical thickness measures. A machine learning methodology proved that individuals with deficits in identifying and describing emotions (n = 7) produced language distortions, frequently used the present tense of auxiliary verbs, and few possessive determiners, as well as scarcely connected the speech, in comparison to individuals without deficits (n = 7). Interestingly, they showed high cortical thickness at left temporal pole and low at isthmus of the right cingulate cortex. Overall, we identified the neuro-linguistic pattern of the expression of emotional experience.

Relationship between Nutrition, Lifestyle, and Neurodegenerative Disease: Lessons from ADH1B, CYP1A2 and MTHFR.

In the present review, the main features involved in the susceptibility and progression of neurodegenerative disorders (NDDs) have been discussed, with the purpose of highlighting their potential application for promoting the management and treatment of patients with NDDs. In particular, the impact of genetic and epigenetic factors, nutrients, and lifestyle will be presented, with particular emphasis on Alzheimer's disease (AD) and Parkinson's disease (PD). Metabolism, dietary habits, physical exercise and microbiota are part of a complex network that is crucial for brain function and preservation. This complex equilibrium can be disrupted by genetic, epigenetic, and environmental factors causing perturbations in central nervous system homeostasis, contributing thereby to neuroinflammation and neurodegeneration. Diet and physical activity can directly act on epigenetic modifications, which, in turn, alter the expression of specific genes involved in NDDs onset and progression. On this subject, the introduction of nutrigenomics shed light on the main molecular players involved in the modulation of health and disease status. In particular, the review presents data concerning the impact of ADH1B, CYP1A2, and MTHFR on the susceptibility and progression of NDDs (especially AD and PD) and how they may be exploited for developing precision medicine strategies for the disease treatment and management.

D4Z4 Methylation Levels Combined with a Machine Learning Pipeline Highlight Single CpG Sites as Discriminating Biomarkers for FSHD Patients.

The study describes a protocol for methylation analysis integrated with Machine Learning (ML) algorithms developed to classify Facio-Scapulo-Humeral Dystrophy (FSHD) subjects. The DNA methylation levels of two D4Z4 regions (DR1 and DUX4-PAS) were assessed by an in-house protocol based on bisulfite sequencing and capillary electrophoresis, followed by statistical and ML analyses. The study involved two independent cohorts, namely a training group of 133 patients with clinical signs of FSHD and 150 healthy controls (CTRL) and a testing set of 27 FSHD patients and 25 CTRL. As expected, FSHD patients showed significantly reduced methylation levels compared to CTRL. We utilized single CpG sites to develop a ML pipeline able to discriminate FSHD subjects. The model identified four CpGs sites as the most relevant for the discrimination of FSHD subjects and showed high metrics values (accuracy: 0.94, sensitivity: 0.93, specificity: 0.96). Two additional models were developed to differentiate patients with lower D4Z4 size and patients who might carry pathogenic variants in FSHD genes, respectively. Overall, the present model enables an accurate classification of FSHD patients, providing additional evidence for DNA methylation as a powerful disease biomarker that could be employed for prioritizing subjects to be tested for FSHD.

Analysis of Genetic Variants Associated with COVID-19 Outcome Highlights Different Distributions among Populations.

The clinical spectrum of SARS-CoV-2 infection ranges from asymptomatic status to mild infections, to severe disease and death. In this context, the identification of specific susceptibility factors is crucial to detect people at the higher risk of severe disease and improve the outcome of COVID-19 treatment. Several studies identified genetic variants conferring higher risk of SARS-CoV-2 infection and COVID-19 severity. The present study explored their genetic distribution among different populations (AFR, EAS, EUR and SAS). As a result, the obtained data support the existence of a genetic basis for the observed variability among populations, in terms of SARS-CoV-2 infection and disease outcomes. The comparison of ORs distribution for genetic risk of infection as well as for disease outcome shows that each population presents its own characteristics. These data suggest that each country could benefit from a population-wide risk assessment, aimed to personalize the national vaccine programs and the preventative measures as well as the allocation of resources and the access to proper therapeutic interventions. Moreover, the host genetics should be further investigated in order to realize personalized medicine protocols tailored to improve the management of patients suffering from COVID-19.

Assessment of T-cell Reactivity to the SARS-CoV-2 Omicron Variant by Immunized Individuals.

Importance: The emergence of the highly contagious Omicron variant of SARS-CoV-2 and the findings of a significantly reduced neutralizing potency of sera from individuals with previous SARS-CoV-2 infection or vaccination highlights the importance of studying cellular immunity to estimate the degree of immune protection to the new SARS-CoV-2 variant. Objective: To determine T-cell reactivity to the Omicron variant in individuals with established (natural and/or vaccine-induced) immunity to SARS-CoV-2. Design, Setting, and Participants: This was a cohort study conducted between December 20 and 21, 2021, at the Santa Lucia Foundation Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy, among health care worker and scientist volunteers. Lymphocytes from freshly drawn blood samples were isolated and immediately tested for reactivity to the spike protein of SARS-CoV-2. Main Outcomes and Measures: The main outcomes were the measurement of T-cell reactivity to the mutated regions of the spike protein of the Omicron BA.1 SARS-CoV-2 variant and the assessment of remaining T-cell immunity to the spike protein by stimulation with peptide libraries. Results: A total of 61 volunteers (mean (range) age, 41.62 (21-62) years; 38 women [62%]) with different vaccination and SARS-CoV-2 infection backgrounds were enrolled. The median (range) frequency of CD4+ T cells reactive to peptides covering the mutated regions in the Omicron variant was 0.039% (0%-2.356%), a decrease of 64% compared with the frequency of CD4+ cells specific for the same regions of the ancestral strain (0.109% [0%-2.376%]). Within CD8+ T cells, a median (range) of 0.02% (0%-0.689%) of cells recognized the mutated spike regions, while 0.039% (0%-3.57%) of cells were reactive to the equivalent unmutated regions, a reduction of 49%. However, overall reactivity to the peptide library of the full-length protein was largely maintained (estimated 87%). No significant differences in loss of immune recognition were identified between groups of participants with different vaccination or infection histories. Conclusions and Relevance: This cohort study of immunized adults in Italy found that despite the mutations in the spike protein, the SARS-CoV-2 Omicron variant was recognized by the cellular component of the immune system. It is reasonable to assume that protection from hospitalization and severe disease will be maintained.

Artificial Intelligence for Alzheimer's Disease: Promise or Challenge?

Decades of experimental and clinical research have contributed to unraveling many mechanisms in the pathogenesis of Alzheimer's disease (AD), but the puzzle is still incomplete. Although we can suppose that there is no complete set of puzzle pieces, the recent growth of open data-sharing initiatives collecting lifestyle, clinical, and biological data from AD patients has provided a potentially unlimited amount of information about the disease, far exceeding the human ability to make sense of it. Moreover, integrating Big Data from multi-omics studies provides the potential to explore the pathophysiological mechanisms of the entire biological continuum of AD. In this context, Artificial Intelligence (AI) offers a wide variety of methods to analyze large and complex data in order to improve knowledge in the AD field. In this review, we focus on recent findings and future challenges for AI in AD research. In particular, we discuss the use of Computer-Aided Diagnosis tools for AD diagnosis and the use of AI to potentially support clinical practices for the prediction of individual risk of AD conversion as well as patient stratification in order to finally develop effective and personalized therapies.

Genetic Variants Allegedly Linked to Antisocial Behaviour Are Equally Distributed Across Different Populations.

Human behaviour is determined by a complex interaction of genetic and environmental factors. Several studies have demonstrated different associations between human behaviour and numerous genetic variants. In particular, allelic variants in SLC6A4, MAOA, DRD4, and DRD2 showed statistical associations with major depressive disorder, antisocial behaviour, schizophrenia, and bipolar disorder; BDNF polymorphic variants were associated with depressive, bipolar, and schizophrenia diseases, and TPH2 variants were found both in people with unipolar depression and in children with attention deficit-hyperactivity disorder (ADHD). Independent studies have failed to confirm polymorphic variants associated with criminal and aggressive behaviour. In the present study, a set of genetic variants involved in serotoninergic, dopaminergic, and neurobiological pathways were selected from those previously associated with criminal behaviour. The distribution of these genetic variants was compared across worldwide populations. While data on single polymorphic variants showed differential distribution across populations, these differences failed to be significant when a comprehensive analysis was conducted on the total number of published variants. The lack of reproducibility of the genetic association data published to date, the weakness of statistical associations, the heterogeneity of the phenotype, and the massive influence of the environment on human behaviour do not allow us to consider these genetic variants as undoubtedly associated with antisocial behaviour. Moreover, these data confirm the absence of ethnic predisposition to aggressive and criminal behaviour.

Genetic Determinants Highlight the Existence of Shared Etiopathogenetic Mechanisms Characterizing Age-Related Macular Degeneration and Neurodegenerative Disorders.

Age-related macular degeneration (AMD) showed several processes and risk factors in common with neurodegenerative disorders (NDDs). The present work explored the existence of genetic determinants associated with AMD, which may provide insightful clues concerning its relationship with NDDs and their possible application into the clinical practice. In this study, 400 AMD patients were subjected to the genotyping analysis of 120 genetic variants by OpenArray technology. As the reference group, 503 samples representative of the European general population were utilized. Statistical analysis revealed the association of 23 single-nucleotide polymorphisms (SNPs) with AMD risk. The analysis of epistatic effects revealed that ARMS2, IL6, APOE, and IL2RA could contribute to AMD and neurodegenerative processes by synergistic modulation of the expression of disease-relevant genes. In addition, the bioinformatic analysis of the associated miRNA variants highlighted miR-196a, miR-6796, miR-6499, miR-6810, miR-499, and miR-7854 as potential candidates for counteracting AMD and neurodegenerative processes. Finally, this work highlighted the existence of shared disease mechanisms (oxidative stress, immune-inflammatory response, mitochondrial dysfunction, axonal guidance pathway, and synaptogenesis) between AMD and NDDs and described the associated SNPs as candidate biomarkers for developing novel strategies for early diagnosis, monitoring, and treatment of such disorders in a progressive aging population.