The Brain that Forgets. Alzheimer Mysteries and Treatment Advances

Ageing is a multifactorial process characterized by progressive functional decay and is the main risk factor for neurodegenerative diseases such as Alzheimer’s disease (AD). Demographic changes in the world point to a gradual aging of the population, with the medical and social problems that derive from it. For example, it is estimated that every three seconds someone in the world develops dementia and, although not all dementias are AD, this is the most frequent and devastating. Sporadic or late-onset AD accounts for 95 percent of cases; it is estimated that there are currently 55 million in the world and will be almost 150 million by 2050. From a histopathological point of view [see box], AD is a dual proteinopathy that includes the presence in the brain of amyloid plaques composed of the protein β-amyloid (Aβ) and the intraneuronal accumulation of a biochemically modified form of the tau protein, associated with the cytoskeleton of neurons, which forms neurofibrillary tangles.


Both lesions (the Aβ protein plaques and the accumulation of tau protein) concur with a multitude of alterations that include damage to synapses, dysfunction of neuronal circuits, activation of glial cells (non-neuronal cells that are part of the nervous system), and finally neuronal death, generating a state of gradual loss of memory and other cognitive, sensory, vegetative, and emotional abilities, in a chronic and, so far, irreversible way (Ferrer, 2024). This condition severely limits carrying on daily tasks, work performance, family and social interaction, and ends up disconnecting the patient from their own life history. AD has an uncertain and possibly multifactorial origin, although it is possible that some of the structural and functional changes that are slowly installed in the brain during natural “non-pathological” aging, in the presence of some precipitating factor can evolve into a state of “pathological aging” and even lead to neurodegeneration.

THE REDUCTION OF FACTORS SUCH AS SEDENTARY LIFESTYLE, OBESITY, DEPRESSION, SOCIAL ISOLATION, AMONG OTHERS, COULD PREVENT THE RISK OF DEMENTIA

Is AD an inexorable phase of brain aging or does it occur as a function of a favorable genetic background and its interaction with environmental and lifestyle factors? Is it a condition derived from the great anatomical and functional complexity that 
the human brain has reached throughout evolution? These questions have not yet been resolved, but it has been reported that the reduction of factors such as sedentary lifestyle, hypertension, obesity, hearing loss, reduced cognitive activity, depression, social isolation, among others, could prevent the risk of dementia by up to 40 percent (Livingston et al., 2017). Following the above, our research group has reported the impact of high saturated fat and high fructose diets (HFFD) on the expression of protein and structural markers associated with AD. We have described that the hippocampus, a brain region responsible for the establishment of short-term memory, is particularly sensitive to excess of saturated fat, involved in the development of neuronal insulin resistance, neuroinflammation, and decreased neuronal processes connecting neurons to each other (Calvo-Ochoa et al., 2014).

We also found that one of the most abundant components of the saturated fat we consume, palmitic acid, in high concentrations alters neuronal metabolism and induces biochemical modifications in the tau protein similar to those that occur in the brains of AD patients (García-Cruz & Arias, 2024). Moreover, this saturated fatty acid modifies the transcription of genes related to the inflammatory response in hippocampal neurons (Flores-León et al., 2021). These studies on the effects on the brain of chronic exposure to diets with high energy content and saturated fat open new perspectives to understand some of the mechanisms underlying the effects of an unhealthy lifestyle and their relationship with an increased risk of premature and pathological brain aging.

In addition to metabolic changes, in AD the systems for eliminating or cleaning damaged proteins and organelles are also affected, causing their accumulation inside the neurons. Dysfunctional mitochondria in particular do not appear to be adequately eliminated by a process known as mitophagy. In fact, mitochondria, responsible for generating energy in cells, are severely affected both in patients and in several experimental models of AD. In our laboratory we are described that the mitochondria of the synaptic terminals are particularly sensitive during aging and in a transgenic model of AD, and lose their ability to produce energy efficiently, fragment, swell, and accumulate toxic proteins such as Aβ and modified tau (Espino de la Fuente-Muñoz et al., 2020).

Is it possible to prevent, stop, or reverse the neurodegenerative changes that lead to AD? In terms of prevention, some risk factors on which we are working have already been mentioned; however, stopping or reversing it does not seem to be close yet. Currently, the most common treatments for AD include cognition activators such as cholinesterase enzyme inhibitors that increase levels of the neurotransmitter acetylcholine, and excitatory receptor agonists called NMDA (other neurotransmitters), both of which are involved in memory and neuroplasticity. However, these medications only manage to delay symptoms without stopping their progression. Due to this limitation, new alternatives have emerged. In the last four years, three monoclonal antibodies (laboratory-produced antibodies) have been approved to help eliminate different forms of Aβ and, although they seem effective in cleaning up this protein, their role in slowing cognitive decline has been very modest and, in addition, they have been associated with undesirable side effects (Zhang et al., 2024). Faced with these challenges, some researchers have opted for newer strategies, such as improving mitochondrial function. A particularly innovative proposal is functional mitochondrial transplants, a technique that has shown promising results in animal models and in pilot trials with pediatric patients suffering from heart and mitochondrial diseases. In our laboratory we have developed a method to transfer healthy mitochondria to neurons in culture and in vivo, improving the survival of aged neurons and memory in an animal model of AD.

Despite the advances that have been made in the study of AD, we need additional efforts, new paradigms, and new methodological approaches more refined tools, such as artificial intelligence, multiomics, and demographic research strategies, in search of its origin and its triggers, in order to implement more efficient prevention strategies, develop biomarkers for early diagnosis, and offer better therapeutic tools to combat this devastating condition.

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