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Dementia in Alzheimer's disease - What's going on?
Last reviewed: 07.07.2025
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Macroscopic changes in Alzheimer's disease include diffuse brain atrophy with a decrease in the volume of convolutions and widening of sulci. Pathohistological examination of patients with Alzheimer's disease reveals senile plaques, neurofibrillary tangles, and a decrease in the number of neurons. Similar changes are possible in normal brain aging, but Alzheimer's disease is characterized by their quantitative expression and localization, which have diagnostic significance.
Cholinergic systems
In Alzheimer's disease, the functioning of cholinergic systems in the brain is disrupted. A negative correlation has been found between the postmortem activity of acetylcholine transferase (an enzyme responsible for the synthesis of acetylcholine) and the severity of dementia determined using special scales shortly before death. Selective death of cholinergic neurons has been noted in Alzheimer's disease. A negative effect of anticholinergic drugs on the performance of memory tests has been found in both laboratory animals and humans. At the same time, the administration of drugs that enhance cholinergic activity led to improved test performance in laboratory animals and humans with structural changes in the brain or exposed to anticholinergic drugs. The role of weakened cholinergic system activity in the pathogenesis of Alzheimer's disease is also confirmed by the positive results of clinical trials of cholinesterase inhibitors, an enzyme that ensures the metabolic degradation of acetylcholine.
Adrenergic systems
Neurochemical changes in Alzheimer's disease are complex. Changes in cholinergic activity may be potentiated by dysfunction of other neurotransmitter systems. Clonidine, being an agonist of presynaptic alpha2-adrenergic receptors, can disrupt the function of the frontal cortex. Alpha2-adrenergic receptor antagonists (eg, idazoxan) increase the release of norepinephrine by blocking presynaptic receptors. Animal studies have shown that cholinesterase inhibitors enhance learning ability, and blockade of presynaptic alpha2-adrenergic receptors can potentiate this effect. Thus, an increase in learning ability was noted in laboratory animals that were administered a subthreshold dose of acetylcholinesterase inhibitors in combination with alpha2-adrenergic receptor antagonists. Clinical trials of this combination of drugs are currently underway.
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Mechanisms of neuronal death
Excitatory amino acids
Excitatory amino acids (EAAs) may play an important role in the pathogenesis of Alzheimer's disease. It has been established that apoptosis (programmed cell death) may result from increased activity of the glutamatergic systems of the brain. High concentrations of glutamate and aspartate are detected in the hippocampus, cortico-cortical and cortico-striatal projections. Activation of glutamate receptors leads to long-term potentiation, which may underlie the formation of memory traces. Hyperstimulation of these receptors may cause a neurotoxic effect. Three types of ionotropic EAA receptors have been identified: NMDA, AMPA and icainate. NMDA receptors, which play an important role in memory and learning processes, can be stimulated by glutamate and aspartate, while NMDA itself is a chemical analogue of glutamic acid. The effect of glutamate stimulation of the NMDA receptor is allosterically modulated by receptor sites that interact with polyamine and glycine. The calcium channel associated with the NMDA receptor is blocked by magnesium ions in a voltage-dependent manner. NMDA receptor antagonists, which act only after receptor activation, also have a binding site within the ion channel. Neuroprotective properties of both NMDA and AMPA receptor antagonists have been demonstrated in laboratory animals.
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Oxidative stress
Oxidation with formation of free radicals may be responsible, at least in part, for neuronal damage in Alzheimer's disease and other neurodegenerative diseases. It is suggested that the toxic effect of B-amyloid in Alzheimer's disease is mediated by free radicals. Free radical scavengers and other drugs that inhibit oxidative damage to neurons (e.g., immunosuppressants that inhibit transcription of factors involved in the neurodegenerative process) may play a role in the treatment of Alzheimer's disease in the future.
Calcium
Calcium is a chemical messenger that plays a vital role in neuronal function. Moreover, neuronal damage can be caused by disruption of calcium homeostasis. In studies conducted on both laboratory animals and humans, nimodipine (but not other calcium channel blockers) has been shown to improve memory and learning.
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Inflammation
The involvement of inflammatory mechanisms in the pathogenesis of Alzheimer's disease is evidenced by epidemiological data, detection of inflammatory factors in areas of neurodegeneration, as well as data obtained in vitro and on laboratory animals. Thus, it has been established that Alzheimer's disease is less common in patients who have been taking nonsteroidal anti-inflammatory drugs (NSAIDs) for a long time, as well as those treated for rheumatoid arthritis. A prospective study in Baltimore (USA) revealed a lower risk of developing Alzheimer's disease in individuals taking NSAIDs for more than 2 years compared to an age-matched control group, and the longer they took NSAIDs, the lower the risk of the disease. In addition, in discordant pairs of twins at risk of Alzheimer's disease, the use of NSAIDs reduced the risk of developing the disease and delayed the moment of its manifestation.
Among the markers of the inflammatory process in the areas of neurodegeneration in Alzheimer's disease, interleukins IL-1 and IL-6, activated microglia, Clq (an early component of the complement cascade), and acute phase reactants are detected. Studies on tissue cultures in vitro and on laboratory animals confirm the concept that inflammatory factors can participate in the pathogenesis of AD. For example, in a transgenic mouse model, it was shown that increased production of IL-6 is associated with the development of neurodegeneration, and the toxicity of β-amyloid is enhanced by Clq, which interacts with it and promotes its aggregation. In various cell cultures, IL-2 increases the production of amyloid precursor protein and enhances the toxic effect of β-amyloid 1-42.
Amyloid protein metabolism
According to the amyloid cascade hypothesis proposed by Selkoe, amyloid formation is the initiating stage in the pathogenesis of Alzheimer's disease. Neuritic plaques containing amyloid are present in Alzheimer's disease in those areas of the brain that are involved in memory processes, and the density of these plaques is proportional to the severity of cognitive impairment. Moreover, genetic mutations underlying Alzheimer's disease are associated with increased production and deposition of amyloid. In addition, patients with Down syndrome who develop Alzheimer's disease by the age of 50 have amyloid deposits in the brain at an early age - long before the development of other pathomorphological changes characteristic of Alzheimer's disease. In vitro, beta-amyloid damages neurons, activates microglia and inflammatory processes, and blockade of β-amyloid formation prevents the toxic effect. Transgenic mice that have been given a mutant human gene for the amyloid precursor protein develop many of the pathological features of Alzheimer's disease. From a pharmacological perspective, the initial step of the amyloid cascade is a potential target for therapeutic intervention in Alzheimer's disease.
Tau protein metabolism
Neurofibrillary tangles are another characteristic histopathological marker of Alzheimer's disease, but they are also found in a number of other neurodegenerative diseases. Tangles consist of paired filaments formed as a result of pathological aggregation of tau protein. They are predominantly found in axons. Pathological phosphorylation of tau protein can disrupt the stability of the microtubule system and participate in the formation of tangles. Phosphorylated tau protein is detected in the hippocampus, parietal and frontal cortex, that is, in those areas affected by Alzheimer's disease. Drugs that affect the metabolism of tau protein can protect neurons from the destruction associated with the formation of tangles.
Genetics and Molecular Biology
Some cases of Alzheimer's disease are associated with mutations in the genes encoding presenilin-1, presenilin-2, and amyloid precursor protein. Other genotypes, such as APOE-e4, are associated with an increased risk of developing Alzheimer's disease. There are three alleles of the apolipoprotein E (APOE) gene, located on chromosome 19: APOE-e2, APOE-e3, and APOE-e4. The APOE-e4 allele is found with increased frequency in elderly people placed in nursing homes. In some studies, the presence of the APOE-e4 allele among patients with late-onset Alzheimer's disease was associated with an increased risk of developing the disease, an earlier age at death, and a more severe course of the disease, but these data were not confirmed by other researchers.