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The Search for Answers: Causes, Risk Factors, and Current Research in Neurodegenerative Disorders

Premier Science > The Search for Answers: Causes, Risk Factors, and Current Research in Neurodegenerative Disorders

Amita Kajrolkar ORCiD
Freelance Writer, Mumbai, India
Correspondence to: Amita Kajrolkar, emmydixit@gmail.com

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DOI: https://doi.org/10.70389/PJN.100013

Premier Journal of Neuroscience

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  • Ethical approval: N/a
  • Consent: N/a
  • Funding: No industry funding
  • Conflicts of interest: N/a
  • Author contribution: Amita Kajrolkar – Conceptualization, Writing – original draft, review and editing
  • Guarantor: Amita Kajrolkar
  • Provenance and peer-review:
    Commissioned and externally peer-reviewed
  • Data availability statement: N/a

Keywords: Neurodegenerative disorders, Genetic predispositions, Environmental risk factors, Disease modelling, Biomarker development.

Peer Review
Received: 11 May 2025
Last revised: 11 June 2025
Accepted: 10 August 2025
Version accepted: 2
Published: 8 September 2025

Plain Language Summary Infographic
Plain language infographic on genetic and environmental risks, research, and therapies in neurodegenerative diseases
Abstract

Neurodegenerative disorders represent a global health priority, characterized by the progressive degeneration of neural systems and cognitive or motor function. Although these disorders have different clinical pictures, such as, memory deficits in Alzheimer’s and movement problems in Parkinson’s, it is crucial to identify the causes of these disorders along with risk factors so as to guide intervention efforts. As it is explored in this thorough analysis, the multidimensional causes of key neurodegenerative diseases are studied, in particular, genetic predispositions, environmental contributions, and the interplay of these as a whole. Besides, the article discusses some current research trends, including the development of disease modeling, biomarker identification, and novel therapies. By linking epidemiological data, the molecular mechanisms, and clinical data, this review provides a modern synopsis of the origins of neurodegenerative diseases and locates possible directions for further study and therapeutic development.

Introduction

Neurodegenerative disorders are characterized by a broad spectrum of pathologies characterized by the gradual destruction of neural tissue, which leads to both functional deficits and eventual severe disability.1 Some of the conditions included in this group are Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and multiple sclerosis (MS), which form part of the members of this group2 and present an urgent public health issue given the huge population of older adults across the world. Despite the clinical variability of these disorders, they converge on the molecular and cellular level, sharing core features such as protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, and neuro-inflammation.3 In most cases, neurodegenerative disorders arise from a combination of genetic and environmental causes that act in a complex manner and interact with each other.4 Although disorders like HD have specific genetic causes, much of the neurodegeneration is due to the combined protein modifications from many variations in genes and environmental exposure.5 Understanding these interactions is critical to developing successful ways of preventing, early recognition, and specific treatment of neurodegenerative disorders.6

Within the last few decades, technological breakthroughs in genomics, proteomics, imaging, and computational biology have vastly improved our understanding of the molecular basis of neurodegeneration.7 It is due to the developments in these areas that new disease-associated genes, signaling pathways, and potential therapeutic interventions have been identified.8 At the same time, longitudinal population studies have identified important modifiable risk factors and protective factors, thus providing a solid basis for developing effective preventive measures.9 The primary objective of this article is to provide a detailed overview of modern knowledge regarding the causes and risk factors of major neurodegenerative conditions and the key research efforts to uncover the basic mechanisms of these afflictions. By bringing together the insights of genetics, epidemiology, molecular biology, and clinical research, this review hopes to provide a state-of-the art overview of what scientists in this field already know about neurodegenerative disease mechanisms and outline priority areas for further research and treatment (Table 1).

Table 1: Major neurodegenerative disorders and key clinical features.
DisorderKey SymptomsAffected Brain RegionsTypical Onset AgePrevalence
ADMemory loss, confusion, disorientationHippocampus, cortex>65 yearsHigh
PDTremor, rigidity, bradykinesiaSubstantia nigra>60 yearsModerate
ALSMuscle weakness, paralysisMotor neurons40–70 yearsLow
HDInvoluntary movements, cognitive declineBasal ganglia, cortex30–50 yearsRare
MSVisual problems, fatigue, numbnessWhite matter tracts20–40 yearsModerate
Genetic Architecture: From Monogenic to Complex Risk

Monogenic Forms of Neurodegenerative Disorders

Some neurodegenerative diseases are known to have distinct genetic roots, particularly if they follow Mendelian inheritance.10 HD represents an example of a monogenic neurodegenerative disease due to an expanded CAG trinucleotide repeat within the HTT gene.11 As this expansion lengthens, the age of onset of the disease decreases and the severity increases, describing a relationship between genotype and phenotype.12 Even though familial AD accounts for only 5% of all AD cases, it has provided a key understanding of the mechanism of the disorder.13 Mutations in the APP gene and presenilin 1 and 2 (PSEN1, PSEN2) genes cause autosomal dominant, early-onset AD, primarily because of enhanced production or misprocessing of amyloid-beta (Aβ) peptides.14 Findings on this issue helped develop the amyloid cascade hypothesis, which has determined research on AD since the 1990s.15

Similarly, familial PD, which makes up approximately 10% of all cases, has helped uncover several genes that cause disease formation, including SNCA (which codes α-synuclein), LRRK2, PARK7, PINK1, and PRKN.16 Discovery of these genes has revealed major PD pathways, including protein aggregation, mitochondrial diseases, and intricate cellular clearance processes.17 LRRK2 mutations are the most common genetic cause of both familial and sporadic PD, highlighting the genetic knowledge in nongenetic cases.18 Also, both familial (about 10% of cases) and sporadic forms (19%) of ALS occur. SOD1 mutations were the first genetic cause of familial ALS found, followed by the identification of mutations in the C9orf72, TARDBP (TDP-43), FUS, among others.19 The C9orf72 hexanucleotide repeat expansion is strikingly significant, accounting for approximately 40% of familial ALS cases with 7% of sporadic ALS cases in European populations.20 Besides ALS, C9orf72 mutations cause frontotemporal dementia (FTD); therefore, associating the two conditions given their genetic connection, further supporting the ALS-FTD spectrum concept (Table 2).21

Table 2: Established genetic mutations in neurodegenerative diseases.
DiseaseGene(s)Inheritance PatternClinical Impact
Huntington’sHTT (CAG repeat)Autosomal dominantEarlier onset with longer repeats
Alzheimer’s (familial)APP, PSEN1, PSEN2Autosomal dominantEarly-onset AD
Parkinson’s (familial)SNCA, LRRK2, PARK7VariableProtein aggregation, mitochondrial dysfunction
ALSSOD1, C9orf72, TARDBPAutosomal dominant/recessiveALS-FTD overlap

Complex Genetic Architecture in Sporadic Cases

The majority of neurodegenerative disorders occur due to spontaneous development and lack of identifiable Mendelian inheritance, suggesting that they are the outcome of combined effects of a variety of genetic factors, each having a modest effect, and environmental factors.22 Genome-wide association studies (GWAS) have been pivotal in discovering the genetic risk variants linked to sporadic neurodegenerative disorders.23 The most important genetic determinant of AD risk is the apolipoprotein E (APOE) gene, in which the ε4 allele increases the risk 3–4 times in heterozygotes and up to 12–15 times in homozygotes compared to noncarriers.24 More than 40 additional risk loci have been identified by GWAS (many of these genes are part of the immune function, lipid metabolism, and endocytosis, emphasizing the involvement of numerous pathways for AD pathogenesis unrelated to amyloid processing).25 Several risk loci have been identified in GWAS in PD (there are >90), and these are associated with lysosomal function, autophagy, mitochondrial biology, and immune regulation.26 Interestingly, several of these genetic locations are comparable to those found in other neurodegenerative diseases, thus suggesting that these neurodegenerative diseases might have common underlying causes.27 Recent studies have highlighted the importance of rare variants that have a large effect size, establishing a genetic relationship between monogenic and complex forms of disease.28

Multiple risk loci have been identified by GWAS for ALS beyond the established monogenic factors, though with weaker effect sizes compared to AD and PD.29 These findings signify the roles of RNA processing, cytoskeletal organization, and cellular stress response pathways in ALS risk.30 Additional studies using GWAS have shown shared genetic markers between ALS and FTD, suggesting their liability to common etiological mechanisms through overlapping risk loci.31 Technological developments in the process of sequencing have made it possible for a more comprehensive overview of genetic factors in neurodegenerative disorders, revealing implications of aberrant variants, structural changes, and noncoding DNA regions.32 Such studies have evidenced genetic heterogeneity in clinically defined disorders, and as such, traditional boundaries between conditions are blurring, necessitating a reconsideration of nosological classifications.33

Genetic Modifiers and Disease Heterogeneity

Separate from pathogenic and risk-determining genes, genetic modifiers significantly influence the symptoms of a disease, its course, and responsiveness to pharmacological treatment.34 These genetic modifiers also help explain the great variety of clinical manifestations observed in genetically defined disorders and may present ways to modulate the disease process.35 In HD, the number of CAG repeats in the HTT gene accounts for 70% of the variance in age at symptom onset, with other genetic influences accounting for the rest.36 Genome-wide association studies also identified modifier loci that contribute to the time of onset and progression of the disease (examples are genes for DNA repair and processes of the mitochondria).37 Similar modifier effects have also been reported in other polyglutamine disorders, indicating common disease mechanisms and opportunities for therapeutic intervention.38

In AD, some genetic variants that influence cognitive decline and disease progression are found in genes that control inflammation, lipid metabolism, and synaptic function.39 Such modifiers40 may be used in isolation from or combined with primary APOE risk factors.40 Such knowledge is crucial for the organization of clinical trials by patient groups and tailoring particular treatments.41 In PD, the genetic components modify not only the probability of its development, but also the manifestation of certain clinical signs, such as cognitive decline, autonomic problems, and complications of therapy.42 For instance, mutations in GBA not only increase the risk for PD, but also increase the risk for early-onset and progressive cognitive deterioration.43 Such associations between genetic variants and clinical entities are currently being used to determine patient care and the design of clinical trials.44 Genetic pleiotropy, in which a single variation in a gene can influence numerous, apparently unrelated traits, is a vital consideration in neurodegenerative maladies.45 Many neurodegenerative disease-associated genes have pleiotropic effects through multiple organ systems and biological pathways, which helps explain the wide variety of often overlapping clinical features that are presented by these patients.46 Knowledge of this pleiotropy may identify shared roots of disease and give rise to new strategies for repurposing existing treatments.47

Environmental Risk Factors

Aging and Neurodegenerative Risk

Aging is the predominant risk factor across all neurodegenerative diseases, and the rate of sickness accelerates very rapidly as individuals age.48 There are many cellular and molecular changes when the body ages that contribute to increased risk of neurodegeneration, like increased oxidative stress, mitochondrial irregularities, protein synthesis disruption, accumulation of DNA damage, and alterations in immune function.49 Such age-related changes might interact with genetic tendencies to suggest earlier onset and faster course of disease.50 Epigenetic evidence, including alteration in DNA methylation and other markers of biological aging, lends credence to the concept that neurodegenerative disorders underlie accelerated aging processes.51 So epigenetic changes might be a biological bridge between the impacts of the environment and lifestyle that are occurring during aging processes and the emergence of neurological disorders.52 Cellular senescence is defined as a permanent arrest of the cell cycle, accompanied by the secretion of proinflammatory cytokines and other factors (collectively known as the senescence-associated secretory phenotype), and has become a critical entity in neurodegenerative processes.53 As our bodies age, senescent cells accumulate in our brain and cause inflammation, as well as tissue damage.54 Results from preclinical experiments in senescent cell settings of neurological decline promise efficacy with suggestions of upcoming therapeutic potential for neurodegenerative disorders.55

Environmental Exposures

A number of environmental factors have been associated with increased risks of neurodegenerative disorders, but it is not easy to establish causal relationships as a result of the lag between exposure and symptoms and the complexity of exposure measurement.56 There is good evidence that suggests the risk of PD is associated with pesticide exposure, especially organochlorines, organophosphates, and rotenone.57 Mechanistic studies have provided evidence of how these compounds affect mitochondrial function, protein aggregation, and oxidative stress, which has underscored the observed relations.58 Using metals has been associated with several neurodegenerative diseases.59 It has been shown that in AD, amyloid plaques contain elevated levels of copper, iron, and zinc, processes which may promote Aβ aggregation and cause oxidative damage.60 Lead exposure at early ages is known to correlate with cognitive problems and potentially induce increased susceptibility for neurodegeneration during later life years.61 In addition, people exposed to manganese will be at higher risk of having parkinsonian syndromes because of their impaired mitochondrial function and high levels of oxidative stress.62

More studies report that traffic-related pollution and fine levels of particulate matter are major risk factors for neurodegenerative disorders.63 Many epidemiological studies have found a relationship between long-term exposure to air pollution and an increase in dementia, cognitive impairment, and syndromes of neurodegeneration.64 Mechanisms implicated include neuroinflammation, oxidative stress, and direct entry of ultrafine particles into the brain through the olfactory bulb.65 Traumatic brain injury (TBI) is also an important risk factor for which large association levels were observed for chronic traumatic encephalopathy (CTE), developing following repetitive bouts of head trauma.66 TBI has been associated with increased risks of AD, PD, and ALS, which can be caused by axonal injury, inflammation, and disruption of protein metabolism.67 The relationship between the impact or the frequency of TBI and the possibility of developing neurodegeneration is still under investigation in the current research (Table 3).68

Table 3: Environmental risk factors by disorder.
FactorADPDALSHDMS
Pesticide Exposure✗✔✗✗✗
TBI✔✔✔✗✗
Air Pollution✔✔✗✗✔
Aging✔✔✔✔✗
✔ = strong evidence; ✗ = little/no evidence.

Lifestyle Factors and Modifiable Risks

Increasing scientific evidence shows that this mitigation can be achieved through lifestyle changes to essentially create avenues for proactive measures.69 Physical activity of a regular character is always found to offer protection from cognitive decline and neurodegenerative diseases, particularly those associated with AD and PD.70 The protective effects of the duration on stress may be due to increased flow of blood to the brain, high levels of neurotrophic factors, lower inflammatory responses, and improved insulin sensitivity.71 Also, similar associations have been detected between dietary patterns and the risk of neurodegenerative diseases.72 Compliance with a Mediterranean diet, which is high in fruits, vegetables, whole grains, fish, and olive oil, is linked with reduced risk of cognitive decline and AD.73 Some nutrients, such as omega-3 fatty acids, antioxidants, and B vitamins, contribute to neuroprotection through reducing inflammation, enhancing synaptic plasticity, and protecting against oxidative stress.74 Based on the studies, issues related to sleep (including insomnia, sleep apnea, and disturbance of the natural sleep–wake cycle in the body) have been linked to an increase in the risk of neurodegenerative disorders.75 When asleep, the brain uses the glymphatic system to clear waste, support memory storage, and sustain healthy immunity function.76 Chronic sleep interruptions can interfere with these functions, resulting in enhanced neurodegeneration.77 Targeted improvements of sleep quality can be promising as a preventive and therapeutic measure.78

Research shows that regular cognitive activity and formal education are associated with lower incidences/slower onset of dementia, including AD.79 Such interferences can buffer cognitive reserve, the brain’s ability to withstand pathological changes but still retain optimal function in the presence of subclinical disease.80 Higher cognitive reserve correlates with higher neural efficiency, adaptive neuroplasticity, and lower probability of accumulating pathological changes.81 Social isolation and loneliness are widely acknowledged as significant risk factors for cognitive decline and dementia.82 Psychological distress, lack of appropriate cognitive activity, bad habits, and physiological changes such as inflammation and disharmony in the hormonal balance are some of the ways that these social determinants may influence cognition.83 Through interventions, promoting social involvement may supplement or aid in strengthening preexisting strategies for prevention.84

Gene–Environment Interactions and Epigenetics

Genetic predisposition and environmental exposures are likely relevant for accounting for significant differences in neurodegenerative disease risks and symptoms.85 These interactions may express themselves in various ways, such as increased exposure effects among persons with genetic predisposing factors, altered gene expression induced by environmental exposures, or shared biological pathways that are modified by both genetics and the environment.86 The combination of genetic variations and pesticide exposure in PD provides for these connections.87 Individuals who carry genetic variations in such genes that are involved in processing xenobiotics, for example, CYP2D6, may face a greater risk of pesticide-associated parkinsonism.88 In the same way, a person with genes mutated in parts, such as PRKN, which are important for mitochondrial function, and who is exposed to environmental toxins affecting these structures, e.g., rotenone or MPTP.89

The APOE genotype has an impact on the impact of different environmental exposures and life habits on the risk of AD.90 Individuals with the APOE ε4 gene variant may be more susceptible to the adverse consequences of head trauma, smoking, and inactivity on cognitive function, but they may benefit more from interventions such as exercise and a healthy diet.91 This finding emphasizes the necessity of a personalized prevention program that analyzes genetic risk profiles. Epigenetic processes, including DNA methylation and histone modification processes, as well as the action of noncoding RNAs, serve as intermediaries to connect environmental factors to the expression of the genome.92 Exposure to environmental factors is capable of creating epigenetic changes that last for long periods, and may even extend over generations to explain later life manifestations of early experiences.93 It has been established that there are epigenetic modifications in various neurodegenerative conditions and may play a role in whether the disease develops and the rate at which it develops.94

The gut microbiome is also a possible mediator of the gene–environment interplay, playing a role in the formation of neurodegenerative diseases.95 A new study shows reciprocity between the gut microbiome and the central nervous system, which might contribute to neuroinflammation, accumulation of protein, and neuronal activity.96 That is, hereditary factors and environmental exposures, especially dietary options, influence the structure of a microbiome, which might have to do with a change in neurodegenerative risk via this linkage.97 Advances in computational skills, including machine learning and systems biology, have come to play a pivotal role in the synthesis of genetic, environmental, and clinical data to explain complex biological relationships.98 Such methods can help to develop comprehensive models of risk assessment and personalized preventive measures that take into account hereditary and changeable risk factors.99

Current Research Frontiers

Disease Modeling and Mechanisms

New advances in disease modeling have greatly increased our capacity to explore neurodegenerative processes and assess treatment strategies.100 Generated from patients, induced pluripotent stem cells allow the production of human neurons and other CNS cells with disease-relevant genetic backgrounds.101 These models have provided a unique understanding of the exact pathogenic processes associated with various genetic variants and have permitted the screening of a large selection of potential therapeutic compounds.102 Three-dimensional culture approaches like brain organoids and assembloids act as superior platforms to traditional in vitro modeling applications.103 These models better simulate the developmental stages of the brain and the cellular organization than conventional two-dimensional cultures, allowing for studies on cell-cell interactions and complex pathophysiological conditions.104 Scientists have recently made progress in the development of vascularized brain organoids and the use of microfluidic systems to mimic the function of the blood–brain barrier.105

Animal models are still very important in neurodegenerative research, with the recent advances in genetic manipulation techniques greatly contributing to these models.106 CRISPR-Cas9 technology has made it possible to generate models within a short time that possess disease-associated mutations, especially for nonhuman primates whose brains are more complex than those of humans.107 These models complement in vitro methods, enabling researchers to examine system-level effects and accompanying behaviors in animals.108 Progress in the use of single-cell technologies, including transcriptomics, proteomics, and epigenomics, has significantly enhanced our understanding of the diversity of cells in neurodegenerative diseases.109 These techniques have revealed distinctive weaknesses in particular cell types, identified novel cell populations that were previously unaware of being implicated in disease, and enabled labeled monitoring of disease development in the past.110 This is complemented with spatial information obtained using methods such as spatial transcriptomics and offers deeper insights into the cellular and molecular patterning of neurodegenerative diseases.111

The progress in structural biology, where this technology (cryo-electron microscopy) has played a pivotal role, has enabled us to perceive the details of pathogenic protein aggregates, including Aβ fibrils, tau filaments, as well as α-synuclein complexes.112 Such investigations have revealed unique structural conformations connected to various disease states and subtypes, which may explain observed differences in clinical characteristics and dissemination patterns.113 Knowledge of these structural details instills influence on the creation of customized antibodies and small molecules designed to bind to specific conformations for diagnosis and treatment.114

Biomarker Development and Precision Medicine

Developing biomarkers for diagnostic purposes in neurodegenerative disorders is a rapidly developing field for early diagnosis, disease progression monitoring, and stratified patient selection for clinical trials (Table 4).115 In clinical settings, AD is associated with levels of Aβ42, total tau, and phosphorylated tau in the cerebrospinal fluid, which is increasingly considered to reflect underlying pathology and has been validated for clinical use.116 Huge strides have also been made in blood-based biomarkers such as plasma phosphorylated tau (p-tau181, p-tau217), which have shown tremendous potential in screening and monitoring due to their accuracy in detecting AD pathology.117

Table 4: emerging biomarkers and their applications.
Biomarker TypeExampleUtilityDisease
FluidPlasma p-tau217Early diagnosisAD
ImagingTau positron emission tomography (PET)Pathology trackingAD, FTD
DigitalGait analysis via smartphoneDisease monitoringPD
GeneticAPOE ε4Risk stratificationAD

The same is true for neuroimaging biomarkers, which enhance the detection and monitoring of neurodegenerative processes over time.118 Important pathological changes can be visualized in living patients (in vivo) using PET with ligands that bind to amyloid, tau, and α-synuclein.119 Information on the structural, connectivity, and biochemical functional changes is obtained using advanced magnetic resonance imaging (MRI) techniques like diffusion tensor imaging, functional MRI, and magnetic resonance spectroscopy.120 Digital biomarkers from wearable devices, smartphones, and other technology provide new avenues for the constant and objective assessment of neurological functioning.121 Digital biomarker systems will be able to identify subtle shifts in an individual’s gait, movement patterns, voice features, and cognitive performance in real-world environments, allowing for potentially earlier detection of disease occurrence or progression.122 Digital biomarkers, when combined with traditional clinical and biological measures, can allow for more individualized monitoring of disease trajectory.123

Precision medicine—delivering prevention strategies or treatments tailored to the individual’s characteristics—is a concept that has been applied to neurodegenerative disorders with increased frequency.124 Precision medicine approaches typically stratify patients based on their genetic, biomarker, and clinical profiles to then identify patients who are most likely to benefit from specific interventions.125 Recent clinical trials with participants enrolled with AD and other neurodegenerative disorders explored biomarker-based patient selection and monitoring, and suggest impending evidence of feasibility and effectiveness of precision medicine approaches.126 Integrating multiple biomarkers, which combines fluid biomarkers, imaging, digital measures, and clinical measures, is a positive approach to establish comprehensive disease characterization.127 New computational methods, including machine learning and artificial intelligence, can aid in integrating and interpreting these data-heavy models.128 This will allow for more accurate diagnosis, prognosis, and treatment based on individuals who represent their own disease signatures rather than classifying them into a diagnostic category of disease.129

Therapeutic Approaches and Clinical Trials

Research leading to disease-modifying therapies in neurodegenerative diseases has proven difficult—while there have been numerous promising preclinical results, there have also been numerous clinical trial failures.130 Recent advances in understanding disease mechanisms, biomarker development, and clinical trial design have produced renewed hope in a number of areas.131 Immunotherapeutics aimed at pathological protein aggregates are being looked at as a treatment option in a number of neurodegenerative disorders.132 For example, in AD, several monoclonal antibodies targeting Aβ, including aducanumab and lecanemab, have been shown to have effects on amyloid plaque burden and, in some cases, possible clinical benefit.133 There are other monoclonal antibodies or immunotherapeutic agents being developed which primarily target tau, α-synuclein, and TDP-43, in AD, PD, and ALS, respectively.134

Gene therapy approaches have the potential to directly target the genetic causes or risk factors associated with neurodegenerative diseases.135 Antisense oligonucleotides (ASOs) targeting disease-linked genes have shown promise in both preclinical models and early clinical trials of other neurodegenerative conditions, including HD, ALS, and spinal muscular atrophy.136 AAV virus-based gene delivery systems create the potential for long-term gene expression and have been shown to be safe in a number of applications in the central nervous system.137 Recent CRISPR-based approaches for gene editing are a new frontier technology that can be applied to monogenic forms of neurodegeneration.137 Cellular therapies, which include stem cell transplantation and engineered cell products, are being explored for neurodegenerative diseases.138 These therapies have been proposed to restore lost neurons, provide trophic support, and modulate the inflammatory response.139 Clinical trials using stem cells for ALS using mesenchymal stem cells and fetal dopaminergic neurons for transplantation into PD patients have established feasibility and safety, while efficacy is still under investigation.140

Multitarget approaches seeking to simultaneously address multiple pathogenic mechanisms are gaining interest, given the complex etiology of most neurodegenerative diseases.141 Combination strategies to treat different aspects of a disease’s pathophysiology may provide better results than single-target approaches.142 The same could be said for the repurposing of existing drugs, with established safety profiles and potential for disease-modifying effects in neurodegenerative diseases, as a more efficient development approach.143 Novel clinical trial designs and endpoints are helping improve the efficiency and sensitivity of therapeutic evaluation in the clinic.144 Platform trials that test different interventions simultaneously using a shared control group, adaptive designs, which allow changes to the trial design based on interim results, and basket trials, which enroll patients based on biomarker profiles rather than clinical diagnoses, are all innovative trial designs to accelerate therapeutic development.145 Digital endpoints from wearable devices and home-based assessments are another innovative advancement, with the potential to provide more sensitive, frequent, and ecologically valid measurements of treatment effect (Table 5).146

Table 5: Promising therapeutic approaches by disease.
ApproachTargetDiseaseCurrent Status
Monoclonal antibodiesAβ plaquesADFDA-approved
ASOsSOD1, HTTALS, HDClinical trials
Stem cell therapyDopaminergic neuronsPDExperimental
SenolyticsSenescent gliaADPreclinical
Challenges and Future Directions

Many improvements have been made, but we still face many obstacles to fully understanding and treating neurodegenerative diseases.147 Most of these diseases have lengthy preclinical periods, so treatment can often only occur if identified early. Identifying patients at higher risk before they meet the criteria for symptomatic diagnosis is still a challenge.148 The use of genetic risk profiling, sensitive biomarkers, and advanced modeling of risk may assist in identifying individuals who are at-risk earlier and implement earlier, potentially preventive, interventions.149 Within neurodegenerative diseases, clinical heterogeneity is another major problem.150 Patients diagnosed similarly often differ in terms of pathophysiology, rate of progression, and treatment response.151 Moving from traditional modes of diagnosis to biologically defined disease subtypes may allow for more precision targeting of specific pathogenic mechanisms by developing treatments aimed at a specific biological profile of a patient.152

Translating insights from preclinical models of disease to human translations continues to pose challenges, as many promising therapeutic approaches have ultimately met operational failure at clinical trial despite impressive effects at the animal-model level.153 Better disease models that more closely resemble human pathophysiology, including more representative animal models and patient-derived cellular systems, may improve translational replication as well.154 The capacity to more rapidly engage human data through biomarker studies and experimental medicine approaches may also enhance informative power around development decision points.155 The multifactorial nature of most neurodegenerative disorders means that they may require mechanisms that engage the multiple factors simultaneously.156 Combination therapies that may target different aspects of disease pathophysiology, multimodal approaches that involve both pharmacological and nonpharmacological strategies, and personalized approaches with consideration for individual risk profiles and disease presentations all may offer promising leverage points.157

The continued advancement and convergence in technology, particularly AI, digital health technologies, and precision delivery systems, provide potential to revolutionize neurodegenerative disease research and care.158 Specifically, AI-enabled approaches in data integration and pattern recognition and prediction may allow for more accurate diagnoses, effective patient stratification, and development of useful therapies.159 Digital health technologies will allow continuous monitoring and personalized interventions or consequences of interventions can result in remote care delivery; this is particularly practical for patients struggling with mobility.160 Systems for precision delivery, including advances in blood–brain barrier penetrating sciences and methods for targeting delivery to the brain, may enhance the effect of therapeutics while avoiding unwanted systemic effects and increase patient/family adherence and experience.161 Lastly, tackling social determinants of brain health and equitable access to advances in prevention, diagnosis, and treatment are critical challenges.162 Socioeconomic factors play a substantial role in neurodegenerative disease risk and outcomes, with disadvantaged groups experiencing greater prevalence of disease, earlier onset, and poorer access to care.163 Comprehensive ideas of neurodegenerative disorders need to address these issues and reduce disparities with inclusive research, culturally friendly interventions, and fair systems of health care delivery.164

Conclusion

Over the last 40 years or so, there has been tremendous progress in understanding the causes, risk factors, and potential treatments of neurodegenerative diseases. Advances in technology, true collaborative interdisciplinary partnerships, and better acknowledgment of the historically underappreciated social and economic burden of these conditions have ultimately accelerated scientific progress toward better care and a better society. Understanding has shifted from viewing these disorders as inevitable consequences of aging to recognizing them as complex, multifactorial conditions with potential for intervention. As we have become more sophisticated in recognizing these conditions, the treatment of established disease has turned to recognizing prevention, early intervention, and potentially impacting the modifiable risk factors associated with neurodegeneration.

Current frontiers in research, including disease modeling, biomarker development, and therapeutic avenues, represent the best opportunity for transformative science to support changes in our relationship to neurodegeneration. Addressing the global burden of neurodegeneration requires not only scientific excellence but also a commitment to collaborative, inclusive, and translational approaches that improve lives across the spectrum of aging and neurological decline. It is simply not enough to report a research advance in neurodegeneration if we cannot identify a manner in which our advance translates to a meaningful impact on caring for patients with, or those who are at risk of developing neurodegenerative diseases. As we continue to unravel the complexities of neurodegeneration, we should be prepared to respond to this problem with all of the knowledge and capacity we have to understand neurodegenerative diseases as a composite strategy through prevention, early identification, precision treatment, and supportive care, so that we can expect to tackle the growing global burden of these insidious diseases.

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Cite this article as:
Kajrolkar A. The Search for Answers: Causes, Risk Factors, and Current Research in Neurodegenerative Disorders. Premier Journal of Neuroscience 2025;5:100013

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