This page compares how major neurotransmitter systems are affected across Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington's disease (HD).
| Neurotransmitter System |
Alzheimer's Disease |
Parkinson's Disease |
ALS |
Frontotemporal Dementia |
Huntington's Disease |
| Dopamine |
Moderate loss in later stages |
Severe loss (SNc) |
Variable; GABAergic involvement |
Variable (bvFTD) |
Severe loss (striatal) |
| Acetylcholine |
Severe loss (basal forebrain) |
Moderate loss |
Minimal |
Variable (especially SFV) |
Moderate loss |
| Glutamate |
Excitotoxicity (NMDA) |
Variable |
Severe excitotoxicity |
Variable |
Excitotoxicity |
| GABA |
Moderate loss |
Moderate loss |
Severe GABAergic neuron loss |
Variable |
Severe loss (striatal) |
| Serotonin |
Moderate loss (raphe) |
Moderate-severe loss |
Variable |
Variable (especially GGA) |
Moderate loss |
| Norepinephrine |
Moderate loss (locus coeruleus) |
Severe loss |
Minimal |
Moderate |
Variable |
- Moderate reduction in dopamine neurons in substantia nigra pars compacta (SNc)
- More significant in later stages with Lewy body co-pathology (DLB)
- D2 receptor downregulation in prefrontal cortex
- Tyrosine hydroxylase activity reduced [1]
- Severe loss of dopaminergic neurons in SNc (>70% by diagnosis)
- Loss of dopaminergic neurons in ventral tegmental area (VTA)
- Decreased dopamine in striatum (putamen > caudate)
- D1 and D2 receptor binding reduced on PET [2]
- Key genes: SNCA, LRRK2, PARKIN, PINK1, GBA
- Variable dopaminergic involvement
- Some GABAergic motor neuron degeneration
- Dopamine transporter binding reduced in some studies
- Key genes: SOD1, C9orf72, TARDBP, FUS
- Variable depending on subtype
- Behavioral variant FTD: dopamine changes related to behavioral symptoms
- Key genes: MAPT, GRN, C9orf72
- Severe loss of medium spiny neurons (D1 and D2 expressing)
- Early loss of D2 receptors before symptom onset
- Dopamine levels reduced in caudate and putamen
- Key gene: HTT (CAG repeat expansion)
- Severe loss of cholinergic neurons in basal forebrain (nucleus basalis of Meynert)
- Marked reduction in acetylcholine synthesis (chAT activity)
- Significant muscarinic and nicotinic receptor loss
- Cholinergic hypothesis historically central to AD therapy [3]
- Moderate cholinergic loss (basal forebrain)
- More severe with Lewy body disease
- Cholinergic deficits contribute to cognitive impairment
- Minimal cholinergic involvement
- Some cholinergic motor neuron changes in sporadic cases
- Significant in semantic variant (loss of anterior temporal cholinergic neurons)
- Variable in behavioral variant
- Moderate cholinergic loss
- Choline acetyltransferase activity reduced
- Excitotoxicity via NMDA receptor dysregulation
- Glutamate transport altered (EAAT2 reduced)
- AMPA receptor subunit changes [4]
- Variable glutamatergic changes
- Subthalamic nucleus hyperactivity contributes to excitotoxicity
- NMDA receptor binding changes
- Severe excitotoxicity (major mechanism)
- Reduced glutamate transport (EAAT2 mutations)
- AMPA receptor toxicity (GluA2 lacking) [5]
- Riluzole targets glutamatergic transmission
- Variable excitotoxic mechanisms
- TDP-43 related glutamate dysfunction
- Excitotoxicity via NMDA and AMPA receptors
- GABAergic interneuron loss contributes
- Mutant huntingtin increases glutamate sensitivity
- Moderate GABAergic neuron loss
- Receptor changes (GABA-A, GABA-B)
- Some hippocampal interneuron dysfunction
- Moderate GABAergic changes
- GPe and GPi dysfunction in PD with dyskinesias
- GABA receptor changes [6]
- Severe GABAergic motor neuron involvement
-loss of inhibitory interneurons
- Key genes: SOD1, C9orf72
- Variable GABAergic changes
- Semantic variant shows temporal GABAergic loss
- Severe loss of striatal GABAergic interneurons
- PV+ interneuron loss in cortex
- GABA-A receptor downregulation
- Moderate loss of serotonergic neurons in dorsal raphe
- 5-HT2A receptor downregulation
- 5-HT1A changes in hippocampus [7]
- Moderate-severe loss in dorsal and median raphe
- 5-HT2A receptor changes
- Contributes to depression and anxiety
- Variable serotonergic involvement
- Some studies show raphe neuron loss
- Significant in grammatical variant (loss of anterior temporal 5-HT)
- Key gene: GRN (progranulin affects serotonergic function)
- Moderate loss in raphe nuclei
- 5-HT2A receptor binding reduced
- Moderate loss in locus coeruleus
- Earlier than cholinergic loss in some studies
- Severe loss in locus coeruleus
- Contributes to non-motor symptoms
- Minimal noradrenergic involvement
- Moderate locus coeruleus involvement
- Moderate loss in locus coeruleus
flowchart TD
subgraph AD
ACh1["Acetylcholine ↓↓"] --> AD_Cog["Cognitive Decline"]
Glu1["Glutamate Excitotoxicity"] --> AD_Cog
DA1["Dopamine ↓"] --> AD_Cog
end
subgraph PD
DA2["Dopamine ↓↓↓"] --> PD_Motor["Motor Symptoms"]
ACh2["Acetylcholine ↓"] --> PD_Cog["Cognitive Decline"]
5HT2[Serotonin ↓] --> PD_NM["Non-Motor"]
NE2["Norepinephrine ↓↓"] --> PD_NM
end
subgraph ALS
Glu3["Glutamate Excitotoxicity"] --> ALS_Mot["Motor Neuron Death"]
GABA3["GABA ↓↓"] --> ALS_Mot
DA3["Variable DA"] --> ALS_Mot
end
subgraph FTD
DA4["Variable DA"] --> FTD_Beh["Behavioral Symptoms"]
5HT4[Serotonin ↓] --> FTD_Beh
ACh4["Variable ACh"] --> FTD_Cog["Cognitive Decline"]
end
subgraph HD
DA5["Dopamine ↓↓↓"] --> HD_Mot["Chorea/Motor"]
GABA5["GABA ↓↓"] --> HD_Mot
Glu5["Glutamate Excitotoxicity"] --> HD_Mot
5HT5[Serotonin ↓] --> HD_NM["Psychiatric"]
end
style AD_Cog fill:#f9f,stroke:#333
style PD_Motor fill:#9f9,stroke:#333
style ALS_Mot fill:#f99,stroke:#333
style FTD_Beh fill:#99f,stroke:#333
style HD_Mot fill:#ff9,stroke:#333
| Target |
Disease |
Approach |
Status |
| D1/D2 Agonists |
PD |
Dopamine replacement |
Approved |
| Cholinesterase Inhibitors |
AD, PD-DLB |
ACh enhancement |
Approved |
| NMDA Antagonists |
AD |
Excitotoxicity |
Approved (memantine) |
| Riluzole |
ALS |
Glutamate modulation |
Approved |
| 5-HT2A Inverse Agonists |
PD psychosis |
Pimavanserin |
Approved |
| GABA Modulators |
PD, HD |
Motor control |
In development |
| NCT ID |
Disease |
Intervention |
Target |
Phase |
| NCT00943765 |
AD |
Donepezil |
Cholinergic |
IV |
| NCT04523372 |
PD |
Pimavanserin |
5-HT2A |
III |
| NCT0290050 |
ALS |
Riluzole |
Glutamate |
III (approved) |
| NCT05205069 |
HD |
Valbenazine |
VMAT2 |
II |
| NCT0375810 |
FTD |
Masitinib |
Neuroinflammation |
III |
| System |
Key Genes |
| Dopaminergic |
SNCA, LRRK2, PARKIN, PINK1, GBA, HTT |
| Cholinergic |
CHRNA, CHRNB, CHAT, SLC5A7 |
| Glutamatergic |
GRIN1, GRIN2A, GRIN2B, SLC1A2 |
| GABAergic |
GABRA, GABRB, GABRG, GABA |
| Serotonergic |
HTR1A, HTR2A, HTR2C, SLC6A4 |
- Couture et al., Dopamine alterations in AD (2009)
- Brooks et al., Dopamine PET in PD (2010)
- Cacabelos et al., Cholinergic dysfunction in AD (2008)
- Greenamyre et al., Glutamate and AD (2001)
- Rothstein et al., Excitotoxicity in ALS (1995)
- Rodriguez-Oroz et al., GABA and PD (2009)
- Kepe et al., Serotonin and AD (2007)