Morphometric Inverse Divergence Networks Combined with HYDRA Identify Parkinson's Disease Subtypes with Distinct Transcriptomic and Serum Biomarker Profiles.

Cognitive impairment is a key feature of Alzheimer’s disease (AlzD) and related dementias [,]. The role of acetylcholine in memory has led to the development of therapeutic agents that inhibit its degradation by acetylcholinesterase (AChE) or activate its synaptic nicotinic (nAChR) or muscarinic receptors []. These sites affect neuronal excitability and plasticity, often by modulating glutamate release [,]. Several of these compounds are in clinical use, including donepezil [], rivastigmine [], varenicline [] and tropisetron []. Galantamine is often used for its ability to inhibit AChE and to potentiate nAChR activity, although the latter claim has been disputed []. Memantine, which is primarily an antagonist at N-methyl-D-aspartate (NMDA) receptors, is also in clinical use, often in conjunction with an AChE inhibitor [], while agonists at AMPA-sensitive glutamate receptors (‘ampakines’) are also of potential value []. Amyloid-β (Aβ), which features prominently in AlzD pathophysiology, suppresses synaptic activity partly by interacting with the α-7nAChR and glutamate-NMDA receptors []. Dissociating Aβ from these receptors partially normalizes their function. Upregulation of α-7-nAChR in astrocytes correlates with Aβ pathology [], while antibodies to Aβ such as aducanumab [] and lecanemab [], have modest activity in early AlzD and have been clinically approved in some countries. Other neuroactive compounds implicated in AlzD include γ-aminobutyric acid (GABA), with down-regulation of GABA transaminase, loss of GABAergic neurons and altered GABA receptor function []. Serotonin (5-hydroxytryptamine, 5-HT) may also be involved since low levels of 5-HT and its membrane transporters have been reported in AlzD, with a loss of 5-HT-releasing neurons [,].