Recent Advances in Alzheimer Research

Alzheimer’s disease (AD) is a neurodegenerative condition which is highly prevalent. According to the World Health Organization (WHO) estimates, the overall projected prevalence in worldwide will reach 132 million patients by 2050. Amyloid hypothesis described in 90´s by Hardy et al, is the main therapeutic target. Since acetylcholinesterase inhibitors as symptomatic treatment, drug development for AD has been disappointing. All drugs in completed phase 2 and phase 3 trials have failed.

So, the question is, what´s wrong about this hypothesis and the immunotherapy approach? These compounds aimed at reducing Aβ formation and plaques do not restore cognition although removes amyloid plaques in PET amyloid scans.

This paper tries to discuss all the aspects and describe the current situation and the future goals.

In recent years, the research of Alzheimer’s disease (AD) has shifted from the classic paradigm of grey matter disorders as the central and most relevant events of the pathophysiology, to a broader perspective that takes into account the role of white matter and brain connectivity. In the pre-AD stage, the mild cognitive impairment, we can find with Magnetoencephalography a pattern of desynchronization among some regions related with brain disconnection and hyper synchronization probably as a compensatory mechanism. In addition, the study of brain white matter tracts by diffusion tensor imaging by MRI provides sufficient discriminative capacity to allow its use in the prognosis of the evolution of subjects within early stages of the disease. Along these lines, we expect to show the alterations of white matter tracts in early phases of the disease, and the possibility of using them as a predictor of the development of AD. The study of connectivity alterations not only allows us to know the physio pathogenic basis of the disease but also to increase targets in the search for earlier markers of this neurodegenerative disorder.

Pain assessment in the different stages of Alzheimer's disease can become complex, especially in the final stages of the disease due to the inability of patients to express the different characteristics of the pain, so it is necessary to use observational scales to detect pain “equivalents”.

Patients with Alzheimer's disease may have dysphagia with greater frequency and severity in advanced stages of the disease. This can lead to complications such as dehydration, weight loss, malnutrition and aspiration pneumonia. Therefore, it is necessary to know the problem, identify it and treat it early. We can use postural modifications, changes in the volume and viscosity of food and ultimately the placement of a percutaneous endoscopic gastrostomy.

Neurodegeneration in Alzheimer’s disease starts several years before clinical manifestations are present; they make it possible to establish the clinical diagnosis of the disease. In this continuum of neurodegeneration there are still unknown factors to solve, although much progress has been made in identifying neuropathological, biochemical and genetic signs that help to diagnose the disease in the early stages (mild cognitive impairment) in order to start earlier an effective treatment.

There are several biomarkers proposed for the diagnosis of Alzheimer's disease such as neuroimaging with measurement of brain atrophy; also those related to glucose tracers, beta-amyloid and tau protein in (PET) Positron Emission Tomography; and in recent years, cerebrospinal fluid with the determination of beta-amyloid, tau, p-Tau and other proteins is being studied.

Alzheimer's disease (AD) is a neurological degenerative disease that causes a progressive cognitive deterioration, being the main cause of dementia in elderly people at present. The diagnosis of Alzheimer's disease can be made with great precision through the use of clinical, neuropsychological and imaging evaluations, being of vital importance an early diagnosis to establish a treatment that improves the prognosis in these patients. From the neuroimaging point of view, magnetic resonance imaging (MRI) or computed tomography (CT) is recommended for the routine assessment of AD. MRI sequences in the coronal plane assess entorhinal and hippocampal cortical atrophy, typical at the onset of the disease. MRI volumetric sequences and subtraction are used in the evaluation of the progression of dementia. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are used to evaluate the prognosis of patients and in the differential diagnosis with other dementias. PET also serves to assess small visible alterations in very early stages, asymptomatic inclusions of the disease and in patients with predisposing genes to suffer AD.

In patients with advanced dementia, eating problems followed by infections were the most common complications. Several scales (NHO, ADEPT, PALIAR) have been proposed to estimate 6-months survival. In these patients, a better quality of life could be achieved with palliative care rather than with continued aggressive medical interventions. There is no evidence enough to suggest that enteral tube feeding is beneficial in these patients so careful hand feeding should be offered to them. There is a lack of randomized trials that had examined the effects of antibiotics both on survival and on symptom relief, so caution regarding the initiation of antimicrobial treatment in these patients is recommended. Pain is difficult to assess so it is frequently underdiagnosed and undertreated. No conclusive data are available to support the use of antidementia drugs in patients at stage 7 on the GDS scale. Palliative sedation is indicated in patients with advanced or terminal dementia that present a refractory suffering or symptoms. Midazolam is the first-line choice in palliative sedation in all prevailing symptoms, except delirium, in which case levomepromazine is the first-line choice. In dying patients, current medication should be assessed and non-essentials drugs should be discontinued. At the end of life, drugs needed to be continued should be switched to the subcutaneous route. If appropriate, a syringe driver may be used for continuous infusion. In dying patients, inappropriate interventions (e.g. intravenous fluids, antibiotics, blood tests, measurement of vital signs...) should be stopped.

The pathophysiology of Alzheimer’s disease is complex. Both genetic and environmental factors are considered to be involved. Among the latter, nutrition may play a major role. Longitudinal cohort studies have found that people who closely follow the Mediterranean diet, the DASH diet, and the MIND diet undergo less cognitive decline over time and have lower rates of dementia and Alzheimer’s disease. However, interventional studies are needed to establish a causal relationship. In this connection, clinical studies based on the Mediterranean diet have reported positive results for cognitive performance. The beneficial results obtained by certain diets have not been achieved by supplementation with individual nutrients, suggesting that added benefit may be derived through the association of foodstuffs, for instance as occurs in the diet, as opposed to when they are administered separately. Research into nutrients beneficial to brain function has been carried out, and medical foods with good safety and tolerability profiles have been designed and have yielded promising results in the treatment of mild Alzheimer’s disease.

The behavioral and psychological symptoms of dementia are very frequent, appearing during the evolution of the different types of dementia, generating stress for both the patient and their caregivers. They include a wide group of symptoms: agitation, irritability, aggression, hallucinations, delusions, depression, anxiety or insomnia, and need to make an individual assessment of each patient. The management of these situations requires non-pharmacological measures such as education of caregivers, physical and sensory stimulation or music therapy.

When these measures are not effective and the situation is stressful we must resort to pharmacological treatment. Different medications may be useful, but the most frequently used are antipsychotics. Having to start with low doses and evaluate efficacy and safety, and maintaining the necessary time to control the symptoms, and then schedule their progressive withdrawal.

In Alzheimer’s disease, the person may suffer a significant cognitive impairment, and one of the most common problems within them is memory loss, which may be seriously compromised. Usually, retrograde amnesia occurs at an advanced stage of the disease. However, anterograde amnesia usually occurs in early episodes of the process, and must have strategies to decrease its progression. People affected by Alzheimer’s, due to the characteristics of the pathology, will need continued care in the course of the disease and, moreover, the nurses should have training in this area to help patients improve their prospective memory. In an exhaustive review of the literature, there are interventions that the nurses can do independently with the patient, and other interventions that can do in an interdisciplinary way, along with other professionals.