Current Alzheimer Research - Volume 22, Issue 7, 2025

Dementia is a set of acquired and progressive neuropsychiatric disorders. The most common types of dementia include Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD). Early intravital diagnosis of both types of dementia is difficult. Both molecular and neuroimaging markers are important for the diagnosis of different types of dementia.

This review employed freely accessible databases, including PubMed, Google Scholar, and ScienceDirect, using keywords such as molecular parameters, neuroimaging factors, dementia, FTD, Alzheimer’s disease, and fMRI.

Among the molecular markers of dementia, there are parameters common to its various types and enabling their differentiation. These parameters include both genetic and biochemical factors. Markers include genetic factors that help differentiate AD (APP, PSEN1, PSEN2) from FTD (e.g., TARDBP, FUS, MAPT). Simultaneously, there are important biochemical parameters differentiating AD (amyloid-beta (Aβ), neurofibrillary tangles) from FTD (TDP-43, FUS, and different forms of tau protein aggregates). Currently, there is growing interest in neuroimaging studies in the differential diagnosis of dementia. Positron Emission Tomography (PET) imaging enables the quantification and localization of Aβ deposits in the brain through the selective binding of the Pittsburgh Compound-B (PiB) ligand. This method has become the standard in AD diagnostics. In the context of magnetic resonance imaging studies, it is worth noting the search for structural differences between AD (mainly affecting the temporal lobe, including the hippocampus and entorhinal cortex, and the parietal lobe) and FTD (primarily involving the prefrontal cortex, anterior temporal lobes, and subcortical structures, as well as exhibiting an anteroposterior gradient of atrophy). However, the method of the future appears to be functional Magnetic Resonance Imaging (fMRI), especially since functional changes precede structural changes in the development of dementia.

The review encompasses the basic diagnostic criteria for AD and FTD dementia, as well as molecular and neuroimaging parameters important for the intravital diagnosis of these dementias. It seems that the use of fMRI can contribute to both early diagnosis and early introduction of targeted treatment in developing dementia. Although it is not yet widely used clinically, its diagnostic value is increasingly recognized.

The benefits of fMRI studies complementing molecular markers in the diagnosis of dementia were highlighted.

This study aims, to trace the history of age-associated dementia from the earliest historical periods to the beginning of the modern age.

Since the medical literature prior to the early 19th century is relatively scarce, the near absence of senile dementia has been hypothesized.

Verify the prevalence of senile dementia across different historical periods.

Beyond the medical literature, reviewed papers addressing legal and social aspects were examined to provide a comprehensive overview of the subject.

While the medical literature on the subject is limited, there are a greater abundance of sources discussing social and legislative aspects. The scientific study of dementia had began only in the early 1800s.

In ancient times, dementia was not particularly rare, but it was often overlooked, as it was considered an inevitable consequence of aging.

Khat (Catha edulis (Vahl) Forssk. ex Endl.), a stimulant plant native to Africa and Asia, contains psychoactive compounds such as cathinone and cathine that affect the central nervous system. This study aims to investigate the potential neurotoxicological risks associated with these compounds, particularly focusing on their possible relationship with neurodegenerative disorders like Alzheimer's disease (AD). The primary objective was to evaluate the toxicity of khat's main compounds and examine their molecular interactions with Monoamine Oxidase A (MAO-A), an enzyme implicated in the pathology of AD.

The toxicological profiles of cathinone, cathine, amphetamine, and the AD medication Donepezil were assessed using the Protox-3 server, which predicted toxicity class, potential for liver damage, carcinogenicity, immunotoxicity, mutagenicity, and cytotoxicity. Molecular docking studies were conducted to analyse the binding interactions of these compounds with MAO-A (PDB ID: 2Z5X). Binding affinities and key interacting residues were identified. The steric effects of the ligands within the enzyme's binding site were quantified by calculating the buried volume (%VBur) using the centroid of centres method.

Protox-3 classified cathine and amphetamine as Class 3 toxicants (moderate toxicity), while cathinone and Donepezil were assigned to Class 4 (lower toxicity). Cathinone also demonstrated a moderate probability (0.64) of carcinogenicity. Molecular docking revealed that khat compounds had an average binding affinity of -5.81 ± 0.27 kcal/mol, which was lower than that of amphetamine (-6.10 ± 0.27 kcal/mol) and Donepezil (-7.80 ± 0.38 kcal/mol). Buried volume analysis indicated that khat compounds and amphetamine were more deeply embedded in the MAO-A binding site, correlating with stronger binding affinity.

The computational results suggest that khat compounds exhibit moderate neurotoxic potential and interact with MAO-A in a manner that could be relevant to AD pathology. Although the binding affinities are lower than those of Amphetamine and Donepezil, they point to possible molecular-level interactions significant for neurodegeneration. Steric hindrance, as quantified by %VBur, appeared to influence binding strength, highlighting the importance of molecular fit within the active site.

This study presents evidence of a potential molecular link between khat consumption and an increased risk of Alzheimer's disease. The findings underscore the necessity for further in vivo and epidemiological research, particularly in regions with high rates of khat use, to assess its long-term neurotoxic effects.

Type 2 diabetes mellitus (T2D) is a known risk factor for developing Alzheimer’s disease (AD). Recent research shows that both diseases share complex and related pathophysiological processes. Network medicine approaches can help to elucidate common dysregulated processes among different diseases, such as AD and T2D. Thus, the aim of this work was to determine differentially expressed genes (DEGs) in AD and T2D and to apply a network medicine approach to identify the microRNAs (miRNAs) involved in the AD-T2D association.

Gene expression microarray data sets consisting of 384 control samples and 399 samples belonging to AD and T2D disease were analyzed to obtain DEGs shared by both diseases; the miRNAs associated with these DEGs were predicted using a network medicine approach. Finally, potential small molecules targeting these potentially deregulated miRNAs were identified.

AD and T2D shared a subset of 82 downregulated DEGs. These genes were significantly associated (p < 0.01) with the ontology terms of chemical synaptic deregulation. DEGs were associated with 12 miRNAs expressed in specific tissues for AD and T2D. Such miRNAs were also primarily associated with the ontology terms related to synaptic deregulation and cancer, and AKT signaling pathways. Steroid anti-inflammatory drugs, antineoplastics, and glucose metabolites were predicted to be potential regulators of the 12 shared miRNAs.

The network medicine approach integrating DEGs and miRNAs enabled the identification of shared, potentially deregulated biological processes and pathways underlying the pathophysiology of AD and T2D. These common molecular mechanisms were also linked to drugs currently used in clinical practice, suggesting that this strategy may inform future drug repurposing efforts. Nonetheless, further in-depth biological validation is required to confirm these findings.

Network medicine allowed identifying 12 miRNAs involved in the AD-T2D association, and these could be drug targets for the design of new treatments; however, the identified miRNAs need further experimental confirmation.

Alzheimer's disease (AD) is a neurodegenerative disorder of the central nervous system characterized by complex pathological manifestations and an unclear pathogenesis. Lithium chloride (LiCl) exhibits certain neuroprotective effects. However, its performance and mechanisms in different types of AD models remain unclear.

The streptozotocin (STZ)-induced AD rat model was used to evaluate the ameliorating effects of LiCl. LiCl was administered orally for one month, and then evaluations were conducted in terms of nerve electrophysiology, behavioral science, and molecular biology.

In this study, STZ was found to significantly affect the electrophysiological functions and behavioral performances of rats. However, LiCl was able to mitigate these effects. Specifically, it led to the restoration of electrophysiological functions, with long-term potentiation (LTP) being successfully induced. LiCl also demonstrated favorable therapeutic effects in rats, as confirmed by the nest-building tests, Y-maze, and Morris water maze. Further research revealed that LiCl promoted the phosphorylation of GSK-3β in the hippocampal region of rats.

These findings indicated that LiCl demonstrated beneficial effects on AD-like pathological changes in STZ-induced AD rats, possibly by activating GSK-3β phosphorylation in the hippocampus, improving electrophysiological functions, and further restoring behavioral characteristics.

In conclusion, LiCl demonstrated therapeutic potential for AD by improving neurophysiological and behavioral deficits via hippocampal GSK-3β phosphorylation.