Alzheimer’s- An Introduction towards the memory loss Alzheimer’s disease (AD) is the most common type of dementia and typically 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, affecting at least 27 million people and corresponding from 60 to 70% of all dementias cases. 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. From an anatomopathological point of view, AD is characterized by two prototypical lesions: 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 . 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. 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 . 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. Structural neuroimaging, with a pattern of hippocampal and parietal atrophy in typical cases reinforces the diagnosis . Patients who meet typical disease characteristics, excluding other causes such as vascular and fronto-temporal dementias, have a probable diagnosis of AD . 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 Pathophysiology of Alzheimer’s disease The presence of extracellular plaques of insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles (NFT) of P-tau in neuronal cytoplasm is the hallmark of AD . Although the mechanisms by which these changes lead to cognitive decline are still debated, these deposits are believed to lead to atrophy and death of neurons resulting from excitotoxicity processes [excessive stimulation of neurotransmitter receptors in neuronal membranes], collapse in calcium homeostasis, inflammation and depletion of energy and neuronal factors. As a result of this process, damage to neurons and synapses involved in memory processes, learning and other cognitive functions lead to the aforementioned cognitive decline. According to amyloid cascade theory (one of the most accepted theories about AD pathogenesis, although still debated), the cerebral accumulation of Aβ peptide, resulting from the imbalance between production and clearance of this protein, is the main event causing the disease, being other events observed (including the formation of NFT) resulting from this process. The Aβ peptide, which has 36 to 43 aminoacids, is derived from amyloid precursor protein (APP) enzymatic proteolysis, a physiologically produced protein that plays important roles in brain homeostasis. The APP gene is located on chromosome 21, which explains the higher incidence of early-onset AD in individuals with 21 trisomy (Down Syndrome) and in individuals with APP gene locus duplication [a rare form of early onset of familial origin]. It is believed that overexpression of APP results in an increase of cerebral Aβ peptide, and consequently, in its deposition. Two main pathways for APP processing are now recognized: a nonamyloidogenic α-secretase-mediated pathway and an amyloidogenic β-and γsecretase-mediated pathway. Cleavage of APP by α-secretase results in a soluble molecule, sAPPα, which has probable neuroprotective function, playing important roles in the plasticity and survival of neurons and protection against excitotoxicity. The Aβ peptide is produced by APP cleavage by a β-secretase (mainly BACE1 enzyme). In this pathway, APP is cleaved by β-secretase to give a APP soluble fragment (sAPPβ, a mediator related to neuronal death), and a carboxy-terminal complex linked to cell membrane. The latter is cleaved by a γsecretase complex composed by 4 proteins: presenilin 1 or 2, nicastrin, APH-1 (formerly pharynx-defective-1) and and PEN-2 (presenilin enhancer-2), to give rise to the Aβ peptide. Aβ peptides ranging in size from 38 to 43 aminoacids are generated with predominance of the 40 aminoacid form (Aβ 40), followed by 42 (Aβ 42) . In physiological conditions, the amyloidogenic and non-amyloidogenic pathways coexist in equilibrium, the latter being favored preferentially. The Aβ42 peptide is more prone to aggregation than Aβ40. Immunohistochemical analyses indicate that Aβ42 is initially deposited and found at higher concentrations in the amyloid plaques observed in AD patients . Several studies showed that CSF Aβ42 levels are surrogate markers of underlying brain amyloidosis . On the contrary, the correlation between serum Aβ42 levels and cerebral amyloidosis is not yet demonstrated. A decrease in Aβ42 levels is observed in cerebrospinal fluid of AD subjects, which can be explained in part by higher deposition of β-amyloid plaques . As additional evidence of Aβ42 peptide and the AD pathophysiology, it is further noted that mutations in APP and presenilin genes, which give rise to early-onset familial AD forms, lead to a relative increase in Aβ42 levels. Aβ peptides, under physiological conditions, are produced primarily in monomeric forms with synapses protective function. However, the accumulation of this protein leads to formation of fibrils that accumulate in senile plaques. High levels of Aβ may lead to oligomeric products formation (dimers, trimers, tetramers) leading to neuronal toxicity and degeneration (both by interaction with cell membranes and their receptors, and by direct interference in intracellular processes), interfering with the function and survival of cholinergic, serotonergic, noradrenergic and dopaminergic neurons, reducing their control over the amyloidogenic pathway and favoring the accumulation of insoluble Aβ peptide. The exact mechanism by which deposition of Aβ peptide promotes NFT formation of hyperphosphorylated tau protein is not known. Blurton-Jones & Laferla (2006) suggest four basic mechanisms: The Aβ peptide promotes the activation of specific kinases (GSK3β, e.g.) that catalyze the hyperphosphorylation of tau protein, leading to its conformation change and formation of NFT; Neuroinflammation promoted by the deposition of Aβ peptide leads to the production of proinflammatory cytokines that stimulate the phosphorylation of tau protein; Reduced capacity of degradation of tau protein by the proteasome, in a process induced by Aβ peptide; Defects in axonal transport promoted by Aβ peptide lead to inadequate localization of tau protein and its messenger RNA, which can lead to hyperphosphorylation and aggregation in NFT. Tau protein is a microtubule-associated protein, produced by alternative splicing of the MAPT gene, located on chromosome 17 (17q21). Six isoforms of tau protein are produced by this process . The main known physiological functions of this protein are the stimulation of tubulin polymerization, microtubules stabilization and intracellular organelles transport by microtubules. Once hyperphosphorylated, the protein loses its functions in the synthesis and stabilization of microtubules, leading to neuronal damage and promoting cytotoxicity . Histological analyses demonstrate that both the load and the distribution of NFT in brain tissue correlate better with the severity of cognitive deficit than the Aβ peptide deposits. Genetic risk factors AD can be classified by the age of onset of the first symptoms. Early-onset AD affects individuals under 65 years of age, accounting for about 4–6% of cases of AD, while the late form AD affects individuals aged 65 years or older. Besides the age of onset of symptoms, the early and late forms of AD differ in other clinical, neuropsychological, neuropathological and neuroimaging variables. According to Ballard et al. (2011) about 70% of the risk of developing AD can be attributed to genetics. Early AD usually occurs due to mutations in genes APP, PSEN1 and PSEN2 (genes of amyloid precursor protein, presenilin 1 and presenilin 2, respectively), whereas late-form AD is mainly associated with a polymorphism in APOE gene (apolipoprotein E gene), especially the presence of ε4 allele . More than 30 dominant mutations have already been found in APP gene (located in chromosome 21q21) and are associated with about 15% of cases of early-onset autosomal dominant AD. Mutations in PSEN1 gene (located at 14q24.3) are associated with 80% of cases of early-onset AD, whereas 5% of cases are associated with PSEN2 mutations (located at 1q31-q42). Most of APP gene mutations, as well as PSEN1 mutations, lead to an increase in Aβ42: Aβ40 ratio, either by Aβ42 increased expression, reduction of Aβ40, or both. This deregulation favors early Aβ deposition in brain tissue favoring the amyloidogenic cascade . It is believed that there are other genes besides APP, PSEN1 and PSEN2 involved in the pathogenesis of early-onset AD, as demonstrated by Campion et al. (1999) . Apolipoprotein E (ApoE) is a protein involved in lipid metabolism encoded by APOE gene, located on chromosome 19. There are three APOE alleles described (ε2, ε3 and ε4, giving rise to apoE2, apoE3 and apoE4 isoforms), present in population at different frequencies (ε2: 5–10%, ε3: 65–70% and ε4: 15–20%). A study by Corbo and Scacchi (1999) showed that there is a great variability in the APOE allele distribution among the different populations, with ε2 frequencies varying from 0.0 in some Native American populations up to 0.145 in Papuans. The ε 4 frequencies obtained by the authors range from 0.052 (Sardinians) to 0.407 (Pygmies). The ε4 allele is the main risk factor for late-onset AD. The presence of ε4 in heterozygosity increases 3-fold the risk of AD developing, whereas in homozygosis, the risk is increased 12-fold. Conversely, the presence of ε2 allele reduces the risk of AD developing . The causes of the association between apoE are not yet fully understood, although some mechanisms have been proposed, and presented consistent results in clinical and in vitro studies. Among these studies, some show that apoE is able to bind to Aβ peptide. While the apoE4 isoform binds to Aβ peptide promoting its polymerization in fibrils and its deposition, apoE2 and apoE3 forms are more efficient in promoting the clearance of this peptide, reducing its deposition in brain tissue . ApoE has neuroprotective effects and is able to act on neurons development, with apoE2 and apoE3 performing better than apoE4. Additionally, it is observed that protease-generated apoE fragments have toxic effects, which may lead to neuronal injury and favor Aβ peptide deposition . More recently it was observed that rare alterations in the triggering receptor expressed on myeloid cells 2 (TREM2) gene elevated the risk ratio by 2.9% for AD development. The pathophysiological mechanism by which the deficiency in the gene increases the risk ratio for AD still needs to be better clarified. The gene is located on chromosome 6p21 and the TREM2 protein is a highly expressed receptor on the surface of microglia, phagocytic cells of central nervous system, and has the function of modulating phagocytic and inflammatory responses in central nervous system . Activation of microglia through the interaction of TREM2 and DAP12 stimulates the production of CCL19 and CCL21 chemokines and phagocytosis . In knockout models for the TREM2 receptor it was observed that phagocytic capacity of apoptotic neuronal cell bodies was deficient . Thus the accumulation of these cellular debris would promote a proinflammatory microenvironment . Xiang observed that the removal capacity of Aβ peptide deposits is impaired in TREM2 receptor deficiency and would favor amyloid plaques accumulation.