Marcos Vinícius Ferreira Silva, Cristina de Mello Gomide Loures, and Maria das Graças Carvalho
2019
Abstract
Alzheimer’s disease (AD) is the most common type of dementia and ypically manifests through a progressive loss of episodic memory and cognitive function, subsequently causing language and visuospatial skills deficiencies, which are often accompanied by behavioral disorders such as apathy, aggressiveness and depression. The presence of extracellular plaques of insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles (NFT) containing hyperphosphorylated tau protein (P-tau) in the neuronal cytoplasm is a remarkable pathophysiological cause in patients’ brains. Approximately 70% of the risk of developing AD can be attributed to genetics. However, acquired factors such as cerebrovascular diseases, diabetes, hypertension, obesity and dyslipidemia increase the risk of AD development. The aim of the present minireview was to summarize the pathophysiological mechanism and the main risk factors for AD. As a complement, some protective factors associated with a lower risk of disease incidence, such as cognitive reserve, physical activity and diet will also be addressed.
Introduction
Alzheimer’s disease (AD) is the most common type of dementia [1], affecting at least 27 million people and corresponding from 60 to 70% of all dementias cases [2]. The occurrence of this disease also has a huge impact on life of patient’s family, in addition to a high financial cost to society [3]. From an anatomopathological point of view, AD is characterized by two prototypical lesions: 1) senile plaques, composed of a nucleus of β-amyloid protein accumulation (Aβ42), as extra-cellular lesions and 2) neurofibrillary tangles composed of phosphorylated tau protein (P-tau) and which are intraneuronal findings [4]. Deposition of β-amyloid protein can also occur in capillaries walls, arteries and arterioles causing amyloid cerebral angiopathy leading to degeneration of vascular wall componentes and worsening of blood flow, besides predisposing to intraparenchymal hemorrhages [5].
AD typically manifests through a progressive loss of episodic memory and cognitive function, with later deficiency of language and visuospatial abilities. Such changes are often accompanied by behavioral disorders such as apathy, aggressiveness and depression [6]. It should be noted that there is an important subgroup of AD patients who do not present a typically amnestic picture, manifesting non-amnestic deficits from the onset of symptoms [7]. Structural neuroimaging, with a pattern of hippocampal and parietal atrophy in typical cases reinforces the diagnosis [8]. Patients who meet typical disease characteristics, excluding other causes such as vascular and fronto-temporal dementias, have a probable diagnosis of AD [6]. Definitive diagnosis of the disease is usually carried out only through postmortem examination, whose purpose is to demonstrate histologically the neurofibrillary tangles and the senile plaques [9].
Other relevant factors and conclusion
The main pathophysiological mechanisms of AD are amyloidosis and tau-related neurodegeneration, and have specific topographical and chronological pathways. For instance, brain amyloidosis starts in neocortical regions and then affects subcortical structures [137]. On the other hand, neurodegeneration first appear on locus coeruleus and then spreads through ransentorrinal area and neocortical regions [137]. Cognitive and behavioral features of AD are significantly correlated to the topographical distribution of neurofibrillary tangles.
There is great variability in topographical patterns of pathological findings in AD, causing great phenotypical variability [7], with atypical presentations of the disease [138]. It is not clear how risk and beneficial factors may modulate the topographical progression of amyloidosis and neurodegeneration.
The effects of modifiable risk factors on cross-sectional cognition have been the target of multiple WRAP (The Wisconsin Registry for Alzheimer’s Prevention) investigations. This study has investigated risk factors for AD in middle age, since this phase of life is less studied in relation to the later stages of aging. However, this is a critical time because it is when the Alzheimer’s pathology begins and thus, when its trajectory can be modified through pharmacological approaches and / or lifestyle changes. Within this context, the WRAP study, reported by Johnson et al. (2018), suggest that social engagement, physical and cognitive activities, glucose regulation, stress and sleep, in addition to cardiovascular and metabolic risks are interventional parameters that may improve brain health and reduce the likelihood and severity of AD pathology. These authors conclude that a good health and a salutary lifestyle are factors associated not only with better cognition and brain structure but also the lower AD pathophysiologic burden.
The studies of genetic risk factors are important to better elucidate the pathophysiological processes in the development of AD. However, such factors are not passible to any intervention until now. Faced to this scenario, modifiable risk factors such as diabetes, hypertension and dyslipidemia and others previously mentioned should be closely monitored to prevent complications favoring cognitive decline or even to improve the quality of life of patients with AD. In this context, it should also be emphasized that factors considered protective, such as physical exercise, diet and cognitive stimuli should be strongly and widely encouraged, so that such theoretically preventive measures can be adopted by the population contributing to reduce risk of this disease. Since no current drug intervention can modify the pathophysiological mechanisms related to the development of this devastating disease, adoption of these measures constitutes an important strategy for clinical management in order to prevent or postpone cognitive decline.
