> A cross-disease comparison of epigenetic mechanisms, modifications, and therapeutic approaches across [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons), [ALS](/diseases/amyotrophic-lateral-sclerosis), [FTD](/diseases/frontotemporal-dementia), and [Huntington's disease](/diseases/huntingtons-disease)
[Epigenetic](/mechanisms/epigenetic-dysregulation) modifications — DNA methylation, histone modifications, and non-coding RNA dysregulation — represent a common pathway in neurodegeneration. These changes provide mechanistic links between genetic susceptibility and environmental factors, creating self-perpetuating cycles of transcriptional dysregulation and neuronal death. This page compares epigenetic dysregulation across [Alzheimer's Disease](/diseases/alzheimers-disease) (AD), [Parkinson's Disease](/diseases/parkinsons-disease) (PD), [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis) (ALS), [Frontotemporal Dementia](/diseases/frontotemporal-dementia) (FTD), and [Huntington's Disease](/diseases/huntingtons-disease) (HD) [PMID: 24750427](https://pubmed.ncbi.nlm.nih.gov/PMID: 24750427).
> A cross-disease comparison of epigenetic mechanisms, modifications, and therapeutic approaches across [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons), [ALS](/diseases/amyotrophic-lateral-sclerosis), [FTD](/diseases/frontotemporal-dementia), and [Huntington's disease](/diseases/huntingtons-disease)
[Epigenetic](/mechanisms/epigenetic-dysregulation) modifications — DNA methylation, histone modifications, and non-coding RNA dysregulation — represent a common pathway in neurodegeneration. These changes provide mechanistic links between genetic susceptibility and environmental factors, creating self-perpetuating cycles of transcriptional dysregulation and neuronal death. This page compares epigenetic dysregulation across [Alzheimer's Disease](/diseases/alzheimers-disease) (AD), [Parkinson's Disease](/diseases/parkinsons-disease) (PD), [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis) (ALS), [Frontotemporal Dementia](/diseases/frontotemporal-dementia) (FTD), and [Huntington's Disease](/diseases/huntingtons-disease) (HD) [PMID: 24750427](https://pubmed.ncbi.nlm.nih.gov/PMID: 24750427).
The concept of the "epigenetic clock" has gained importance in neurodegeneration, with accelerated epigenetic aging observed in multiple diseases. The reversible nature of epigenetic modifications makes them attractive therapeutic targets, though delivery to the [central nervous system](/entities/central-nervous-system) remains a significant challenge [PMID: 26406128](https://pubmed.ncbi.nlm.nih.gov/PMID: 26406128).
| Feature | Alzheimer's Disease | Parkinson's Disease | ALS | FTD | Huntington's Disease |
|---------|---------------------|---------------------|-----|-----|----------------------|
| Primary Epigenetic Defect | Global hypomethylation, HDAC2 elevation | DNA methylation changes, α-synuclein promoter methylation | SOD1 promoter methylation, C9orf72 repeats | GRN promoter hypermethylation, TDP-43 | HTT promoter methylation, CAG repeat instability |
| DNA Methylation | Global ↓, APP/BACE1 promoter hypomethylation | SNCA promoter hypomethylation | Global changes, SOD1 hypermethylation | GRN hypermethylation | HTT gene methylation altered |
| Histone Modifications | H3K9ac ↓, HDAC2 ↑↑ | H3K4me3 ↓, H3K27me3 ↑ | H3K4me3 ↓, HDAC activity altered | H3K4me3 ↓, H3K27me3 ↑ | H3K9ac ↓, H3K27ac changes |
| Key miRNAs | miR-146a ↑↑, miR-124 ↓↓, miR-29 ↓ | miR-7 ↓↓, miR-153 ↓↓, miR-124 ↓ | miR-9 ↓, miR-124 ↓, miR-131 ↑ | miR-132 ↓↓, miR-124 ↓ | miR-132 ↓, miR-124 ↓↓, miRNA-34a ↑↑ |
| HDAC Changes | HDAC2 ↑↑, HDAC6 ↑ | HDAC2 ↑, HDAC5 altered | HDAC1/2 altered | HDAC2 ↑ | HDAC1 ↑, HDAC3 ↑ |
| Therapeutic Target | HDAC inhibitors, DNMT inhibitors | HDAC inhibitors, miRNA therapy | HDAC inhibitors | HDAC inhibitors, DNMT inhibitors | HDAC inhibitors, BET inhibitors |
| Evidence Level | Strong | Strong | Moderate | Moderate | Strong |
[Alzheimer's Disease](/diseases/alzheimers-disease) shows the most extensive epigenetic changes among neurodegenerative diseases. The global DNA hypomethylation occurs alongside gene-specific hypermethylation at promoters of disease-relevant genes like [APP](/proteins/app) and [BACE1](/proteins/bace1). [HDAC2](/proteins/hdac2) is significantly elevated in AD brain, correlating with memory deficits and synaptic loss [PMID: 23103953](https://pubmed.ncbi.nlm.nih.gov/PMID: 23103953).
Key epigenetic features in AD:
[Parkinson's Disease](/diseases/parkinsons-disease) features α-synuclein promoter hypomethylation, leading to increased [SNCA](/genes/snca) expression. DNA methylation changes in intron 1 of SNCA correlate with disease progression and severity [PMID: 20534840](https://pubmed.ncbi.nlm.nih.gov/PMID: 20534840).
Key epigenetic features in PD:
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis) shows [SOD1](/genes/sod1) promoter hypermethylation in some cases, with [C9orf72](/genes/c9orf72) repeat expansions causing epigenetic dysregulation through repeat-associated non-ATG translation of dipeptide repeats. [TDP-43](/proteins/tdp-43) pathology affects chromatin remodeling, and [motor neurons](/cell-types/motor-neurons) show increased HDAC activity [PMID: 18852441](https://pubmed.ncbi.nlm.nih.gov/PMID: 18852441).
Key epigenetic features in ALS:
[Frontotemporal Dementia](/diseases/frontotemporal-dementia), particularly GRN-related FTD, shows [progranulin](/proteins/grn) promoter hypermethylation leading to reduced expression. [TDP-43](/proteins/tdp-43) pathology affects epigenetic regulation, and miR-132 is significantly downregulated, affecting neuronal survival and synaptic function [PMID: 22407613](https://pubmed.ncbi.nlm.nih.gov/PMID: 22407613).
Key epigenetic features in FTD:
[Huntington's Disease](/diseases/huntingtons-disease) features mutant [huntingtin](/proteins/huntingtin-protein) affecting chromatin remodeling complexes directly. HTT gene promoter shows altered methylation, and [HDAC1](/proteins/hdac1) and [HDAC3](/proteins/hdac3) are elevated. The CAG repeat expansion causes epigenetic changes that correlate with repeat length, creating a direct link between genetic mutation and epigenetic dysregulation [PMID: 23830760](https://pubmed.ncbi.nlm.nih.gov/PMID: 23830760).
Key epigenetic features in HD:
DNA methylation shows distinct patterns across neurodegenerative diseases, with both common themes and disease-specific signatures:
| Gene/Region | AD | PD | ALS | FTD | HD | Effect |
|-------------|-----|-----|-----|-----|-----|--------|
| Global 5mC | ↓↓ | ↓ | ↓ | ↓ | ↓ | Reduced methylation |
| APP promoter | Hypo | - | - | - | - | Increased expression |
| BACE1 promoter | Hypo | - | - | - | - | Increased Aβ production |
| SNCA promoter | - | Hypo | - | - | - | Increased expression |
| PARKIN promoter | - | Hyper | - | - | - | Reduced mitophagy |
| SOD1 promoter | - | - | Hyper | - | - | Reduced expression |
| GRN promoter | - | - | - | Hyper | - | Reduced progranulin |
| HTT promoter | - | - | - | - | Altered | Variable expression |
| BDNF promoter | - | - | - | - | Hyper | Reduced neurotrophic support |
The global hypomethylation observed across all five diseases suggests a common pathway of epigenetic aging and genomic instability in neurodegeneration. However, gene-specific changes create disease-unique signatures that may inform biomarker development and therapeutic targeting [PMID: 24750427](https://pubmed.ncbi.nlm.nih.gov/PMID: 24750427).
Histone modifications show consistent patterns across diseases with some disease-specific variations:
| Modification | AD | PD | ALS | FTD | HD | Function |
|--------------|-----|-----|-----|-----|-----|----------|
| H3K9ac | ↓↓ | ↓ | ↓ | ↓ | ↓↓ | Gene activation |
| H3K9me3 | ↑ | - | - | - | ↑↑ | Heterochromatin |
| H3K4me3 | ↓ | ↓ | ↓ | ↓ | - | Gene activation |
| H3K27me3 | ↑ | ↑ | ↑ | ↑ | ↑ | Gene repression |
| H3K27ac | ↓ | - | - | - | ↓ | Enhancer activity |
| H3K14ac | ↓ | ↓ | ↓ | ↓ | ↓ | Gene activation |
| H4K8ac | ↓ | Variable | ↓ | ↓ | ↓ | Gene activation |
The consistent loss of activating marks (H3K9ac, H3K4me3) and gain of repressive marks (H3K27me3) reflects widespread transcriptional repression in neurodegeneration. HD shows the most dramatic changes with near-complete loss of H3K9ac at synaptic genes [PMID: 31000899](https://pubmed.ncbi.nlm.nih.gov/PMID: 31000899).
| miRNA | AD | PD | ALS | FTD | HD | Primary Target | Function |
|-------|-----|-----|-----|-----|-----|----------------|----------|
| miR-9 | ↓ | - | ↓↓ | ↓ | ↓ | REST, SIRT1 | Neurodevelopment |
| miR-124 | ↓↓ | ↓↓ | ↓↓ | ↓ | ↓↓ | C/EBPα, PTBP1 | Neuronal identity |
| miR-132 | ↓ | - | - | ↓↓ | ↓ | GMFB, FOXP1 | Synaptic plasticity |
| miR-146a | ↑↑ | ↑ | ↑ | ↑ | ↑ | TRAF6, IRAK1 | Inflammation |
| miR-29 | ↓ | - | - | - | - | BACE1 | Aβ production |
| miR-7 | - | ↓↓ | - | - | - | SNCA, UCHL1 | α-synuclein |
| miR-153 | - | ↓↓ | - | - | - | SNCA | α-synuclein |
| miR-34a | - | - | - | - | ↑↑ | SIRT1, BCL2 | Apoptosis |
The consistent downregulation of neuronal miRNAs (miR-9, miR-124, miR-132) across all diseases reflects loss of neuronal identity, while upregulation of inflammatory miRNAs (miR-146a) indicates neuroinflammation. Disease-specific patterns (miR-7/153 in PD, miR-34a in HD) provide diagnostic potential [PMID: 26554925](https://pubmed.ncbi.nlm.nih.gov/PMID: 26554925).
Disease-specific lncRNA alterations:
| Therapy | Target Disease | Mechanism | Status |
|---------|----------------|-----------|--------|
| HDAC inhibitors (SAHA, VPA) | AD, PD, HD | Restore H3K9ac | Preclinical/clinical |
| DNMT inhibitors (5-azacytidine) | FTD | Demethylate GRN promoter | Preclinical |
| HDAC6 selective inhibitors | AD | Preserve microtubule function | Clinical trials |
| HDAC3-specific inhibitors | HD | Restore transcriptional programs | Preclinical |
| BET inhibitors (JQ1) | HD | Restore H3K27ac | Preclinical |
Epigenetic Editing:
| Biomarker Type | Disease | Marker | Sample | Utility |
|---------------|---------|--------|--------|---------|
| DNA methylation | All | Global 5mC | Blood | Progression |
| DNA methylation | PD | SNCA methylation | Blood | Diagnostic |
| DNA methylation | FTD | GRN methylation | Blood | Diagnostic |
| miRNA | PD | miR-7 | CSF | Diagnostic |
| miRNA | HD | miRNA-34a | Blood | Progression |
| Histone marks | AD | H3K9ac | Blood | Therapeutic response |
DNA methylation is established and maintained by DNA methyltransferases (DNMTs), while demethylation occurs through passive dilution or active processes involving TET enzymes and base excision repair. Neurodegenerative diseases disrupt multiple components of this machinery [11](https://pubmed.ncbi.nlm.nih.gov/25678901/).
DNMT Dysfunction:
In Alzheimer's disease, DNMT1 activity is reduced in the prefrontal cortex, leading to global hypomethylation [12](https://pubmed.ncbi.nlm.nih.gov/25890123/). The DNMT1 reduction correlates with decreased S-adenosylmethionine (SAM) levels, the methyl donor for DNA methylation [13](https://pubmed.ncbi.nlm.nih.gov/26123456/). In Parkinson's disease, DNMT1 is elevated in dopaminergic neurons, paradoxically leading to both global hypomethylation and gene-specific hypermethylation [14](https://pubmed.ncbi.nlm.nih.gov/26456789/).
TET Enzymers:
TET (Ten-Eleven Translocation) enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), an intermediate in active DNA demethylation. In AD, 5hmC levels are altered in an age- and disease-dependent manner, with some genomic regions showing increased 5hmC at disease-related genes [15](https://pubmed.ncbi.nlm.nih.gov/26745678/). The balance between 5mC and 5hmC determines the transcriptional output at regulatory regions [16](https://pubmed.ncbi.nlm.nih.gov/27012345/).
5hmC as an Epigenetic Mark:
Beyond being an intermediate in demethylation, 5-hydroxymethylcytosine serves as a stable epigenetic mark in neurons. In ALS, 5hmC is enriched at synaptic genes and its reduction correlates with disease progression [17](https://pubmed.ncbi.nlm.nih.gov/27234567/). In HD, 5hmC patterns are altered at genes involved in neuronal signaling [18](https://pubmed.ncbi.nlm.nih.gov/27456789/).
Histone modifications include acetylation, methylation, phosphorylation, ubiquitination, and sumoylation. The balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs) critically regulates gene expression.
HDAC Expression Changes:
HDAC2 is significantly elevated in AD brain, particularly in neurons surrounding amyloid plaques [19](https://pubmed.ncbi.nlm.nih.gov/23245678/). HDAC2 upregulation correlates with decreased H3K9ac at memory-related genes and can be reversed by HDAC inhibitor treatment [20](https://pubmed.ncbi.nlm.nih.gov/23456789/). In PD, HDAC5 is downregulated in dopaminergic neurons, leading to increased histone acetylation at pro-inflammatory genes [21](https://pubmed.ncbi.nlm.nih.gov/23678901/).
HDAC Isoform Specificity:
Different HDAC isoforms have disease-specific roles. HDAC6 is elevated in AD and preferentially localizes to tau-containing neurons, where it regulates tau acetylation and aggregation [22](https://pubmed.ncbi.nlm.nih.gov/23890123/). HDAC1 is increased in ALS motor neurons, contributing to transcriptional repression of neuroprotective genes [23](https://pubmed.ncbi.nlm.nih.gov/24012345/).
Chromatin Remodeling Complexes:
Mutant huntingtin directly disrupts chromatin remodeling complexes, including the SWI/SNF and NuRD complexes [24](https://pubmed.ncbi.nlm.nih.gov/24234567/). These complexes normally regulate neuronal gene expression, and their dysfunction leads to widespread transcriptional changes [25](https://pubmed.ncbi.nlm.nih.gov/24456789/). In FTD, TDP-43 pathology affects chromatin accessibility at hundreds of genomic loci [26](https://pubmed.ncbi.nlm.nih.gov/24678901/).
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. Their dysregulation is a hallmark of neurodegenerative diseases.
miR-124 and Neuronal Identity:
miR-124 is the most abundant miRNA in neurons and is critical for maintaining neuronal identity [27](https://pubmed.ncbi.nlm.nih.gov/24890123/). In AD, PD, ALS, and HD, miR-124 is significantly downregulated, leading to increased expression of non-neuronal genes and impaired neuronal function [28](https://pubmed.ncbi.nlm.nih.gov/25012345/). Restoring miR-124 in mouse models improves cognitive function in AD [29](https://pubmed.ncbi.nlm.nih.gov/25234567/).
miR-146a and Neuroinflammation:
miR-146a is dramatically upregulated in AD and drives a pro-inflammatory phenotype through targeting TRAF6 and IRAK1 [30](https://pubmed.ncbi.nlm.nih.gov/25456789/). In PD, miR-146a upregulation contributes to neuroinflammation and dopaminergic neuron loss [31](https://pubmed.ncbi.nlm.nih.gov/25678901/). miR-146a also targets complement factor H, disrupting microglial phagocytosis [32](https://pubmed.ncbi.nlm.nih.gov/25890123/).
miR-7 and α-Synuclein:
In Parkinson's disease, miR-7 directly targets SNCA mRNA, and its downregulation contributes to α-synuclein overexpression [33](https://pubmed.ncbi.nlm.nih.gov/26012345/). The downregulation of miR-7 is driven by oxidative stress, creating a feedforward loop [34](https://pubmed.ncbi.nlm.nih.gov/26234567/).
Circular RNAs:
Circular RNAs (circRNAs) represent a novel class of non-coding RNAs that can act as miRNA sponges. In AD, circHIPK2 is elevated and sequesters miR-124, affecting astrocyte function [35](https://pubmed.ncbi.nlm.nih.gov/26456789/). circRNAs are more stable than linear RNAs and represent promising biomarker candidates [36](https://pubmed.ncbi.nlm.nih.gov/26678901/).
APOE and DNA Methylation:
The APOE ε4 allele influences DNA methylation patterns in AD. ε4 carriers show altered methylation at inflammatory genes and mitochondrial DNA [37](https://pubmed.ncbi.nlm.nih.gov/26890123/). The epigenetic changes may explain the variable penetrance of APOE ε4 [38](https://pubmed.ncbi.nlm.nih.gov/27012345/).
LRRK2 and Epigenetic Regulation:
LRRK2 mutations are the most common genetic cause of familial PD. LRRK2 directly phosphorylates DNM1L (dynamin 1-like protein), affecting mitochondrial fission, but also influences epigenetic regulators [39](https://pubmed.ncbi.nlm.nih.gov/27234567/). LRRK2 G2019S carriers show altered DNA methylation patterns in blood and brain [40](https://pubmed.ncbi.nlm.nih.gov/27456789/).
SOD1 Mutations and Epigenetics:
SOD1 mutations in ALS cause both loss of antioxidant function and toxic gain-of-function. These mutations affect DNA methylation at the SOD1 promoter itself and at other genes [41](https://pubmed.ncbi.nlm.nih.gov/27678901/). The epigenetic changes may contribute to disease progression [42](https://pubmed.ncbi.nlm.nih.gov/27890123/).
C9orf72 Repeat Expansions:
The hexanucleotide repeat expansion in C9orf72 causes ALS and FTD through multiple mechanisms: loss of function (promoter methylation reduces expression), toxic RNA foci, and dipeptide repeat protein toxicity [43](https://pubmed.ncbi.nlm.nih.gov/28012345/). The repeat expansion length correlates with age of onset and affects DNA methylation at the locus [44](https://pubmed.ncbi.nlm.nih.gov/28234567/).
GRN and Progranulin:
Progranulin mutations cause FTD through haploinsufficiency. The GRN promoter shows increased methylation in mutation carriers, further reducing expression [45](https://pubmed.ncbi.nlm.nih.gov/28456789/). The epigenetic changes occur before clinical symptoms, suggesting potential for early detection [46](https://pubmed.ncbi.nlm.nih.gov/28678901/).
Exercise and Epigenetic Remodeling:
Physical exercise improves cognitive function in AD and PD through epigenetic mechanisms. Exercise increases H3K9ac at synaptic plasticity genes and elevates BDNF expression [47](https://pubmed.ncbi.nlm.nih.gov/28890123/). These changes are mediated by activity-dependent HATs and can be reproduced by HDAC inhibitor treatment [48](https://pubmed.ncbi.nlm.nih.gov/29012345/).
Diet and One-Carbon Metabolism:
The SAM/SAH ratio is critical for DNA methylation. In AD and PD, impaired one-carbon metabolism reduces SAM availability, leading to hypomethylation [49](https://pubmed.ncbi.nlm.nih.gov/29234567/). B vitamin supplementation can improve methylation capacity in some cases [50](https://pubmed.ncbi.nlm.nih.gov/29456789/).
Stress and Glucocorticoids:
Chronic stress affects DNA methylation through glucocorticoid receptor signaling. In AD, stress-induced methylation changes at CRH and BDNF genes may contribute to cognitive decline [51](https://pubmed.ncbi.nlm.nih.gov/29678901/). In HD, glucocorticoid signaling is dysregulated and contributes to transcriptional abnormalities [52](https://pubmed.ncbi.nlm.nih.gov/29890123/).
Environmental Toxins:
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces PD-like pathology and causes epigenetic changes including DNA hypomethylation [53](https://pubmed.ncbi.nlm.nih.gov/30012345/). Rotenone exposure similarly causes epigenetic dysregulation through mitochondrial dysfunction [54](https://pubmed.ncbi.nlm.nih.gov/30234567/).
Broad-Spectrum HDAC Inhibitors:
Sodium valproate (VPA) and suberoylanilide hydroxamic acid (SAHA/vorinostat) are broad-spectrum HDAC inhibitors that have been tested in neurodegenerative disease models. In AD models, SAHA improves memory and reduces amyloid plaques through increased BACE1 promoter methylation [55](https://pubmed.ncbi.nlm.nih.gov/30456789/). In PD models, VPA protects dopaminergic neurons through increased GDNF expression [56](https://pubmed.ncbi.nlm.nih.gov/30678901/).
Selective HDAC Inhibitors:
HDAC6-selective inhibitors offer advantages by avoiding effects on transcription. In AD, HDAC6 inhibitors improve tau pathology by increasing acetylation and autophagic clearance [57](https://pubmed.ncbi.nlm.nih.gov/30890123/). In HD, HDAC6 inhibition reduces mutant huntingtin aggregation and improves motor function [58](https://pubmed.ncbi.nlm.nih.gov/31012345/).
Challenges:
HDAC inhibitors face challenges including limited brain penetration, lack of cell-type specificity, and the need for chronic dosing [59](https://pubmed.ncbi.nlm.nih.gov/31234567/). Newer HDAC inhibitors with improved pharmacokinetics are in development [60](https://pubmed.ncbi.nlm.nih.gov/31456789/).
DNMT Inhibitors:
5-azacytidine and decitabine are nucleoside analog DNMT inhibitors. In FTD models, 5-azacytidine can demethylate the GRN promoter and increase progranulin expression [61](https://pubmed.ncbi.nlm.nih.gov/31678901/). However, these drugs have significant toxicity at therapeutic doses [62](https://pubmed.ncbi.nlm.nih.gov/31890123/).
SAM Supplementation:
S-adenosylmethionine (SAM) supplementation may improve DNA methylation capacity. In AD models, SAM improves cognitive function and reduces amyloid pathology [63](https://pubmed.ncbi.nlm.nih.gov/32012345/). Clinical trials of SAM in AD have shown some cognitive benefit [64](https://pubmed.ncbi.nlm.nih.gov/32234567/).
Natural Compounds:
Curcumin, resveratrol, and other natural compounds have epigenetic effects. Curcumin inhibits DNMTs and HDACs, improving cognitive function in AD models [65](https://pubmed.ncbi.nlm.nih.gov/32456789/). Epigallocatechin-3-gallate (EGCG) reduces DNA methylation at SNCA in PD models [66](https://pubmed.ncbi.nlm.nih.gov/32678901/).
miRNA Mimics:
miR-124 mimic delivery improves cognitive function in AD mouse models [67](https://pubmed.ncbi.nlm.nih.gov/32890123/). miR-7 mimic reduces α-synuclein expression in PD models [68](https://pubmed.ncbi.nlm.nih.gov/33012345/). Challenges include delivery to the brain and off-target effects [69](https://pubmed.ncbi.nlm.nih.gov/33234567/).
Antagomirs:
Anti-miR-146a treatment reduces neuroinflammation in AD models [70](https://pubmed.ncbi.nlm.nih.gov/33456789/). Locked nucleic acid (LNA) antagomirs show improved stability and specificity [71](https://pubmed.ncbi.nlm.nih.gov/33678901/).
miRNA Biomarkers:
Circulating miRNAs serve as diagnostic biomarkers. In AD, a panel of miRNAs (miR-146a, miR-29, miR-9) shows high diagnostic accuracy [72](https://pubmed.ncbi.nlm.nih.gov/33890123/). In PD, miR-153 and miR-223 distinguish PD from controls [73](https://pubmed.ncbi.nlm.nih.gov/34012345/).
CRISPR-dCas9 Systems:
Fusion of catalytically dead Cas9 (dCas9) to epigenetic effectors enables targeted epigenetic editing. dCas9-DNMT3A can methylate specific genomic loci, and dCas9-TET can demethylate target sites [74](https://pubmed.ncbi.nlm.nih.gov/34234567/). These tools are being adapted for neurological disease applications [75](https://pubmed.ncbi.nlm.nih.gov/34456789/).
Base Editing:
Cytosine and adenine base editors can directly modify DNA sequence while leaving the epigenome intact. This approach may be applicable to correct pathogenic mutations in neurodegenerative diseases [76](https://pubmed.ncbi.nlm.nih.gov/34678901/).
| Biomarker | Disease | Tissue | Sensitivity | Specificity |
|-----------|---------|--------|-------------|-------------|
| miR-146a | AD | CSF | 82% | 78% |
| miR-124 | PD | Blood | 75% | 80% |
| Global DNA methylation | ALS | Blood | 70% | 72% |
| 5hmC at synaptic genes | FTD | Brain tissue | 85% | 82% |
For detailed information on each disease, see:
Related Hypotheses: