From: hounddog23x@gmail.com   
      
   The Causes Of Alzheimer's Disease - An Overview   
      
   by Sara Adaes, PhD (c) | June 30, 2015   
      
      
      
      
   Dementia is characterized by a progressive and debilitating decline in   
   cognition, function and behavior. Its numbers are staggering: according to the   
   World Health Organization, the total number of people with dementia worldwide   
   in 2010 was estimated at    
   35.6 million and predicted to nearly double every 20 years, to 65.7 million in   
   2030 and 115.4 million in 2050.   
   Each year, there are around 7.7 million new cases of dementia, implying one   
   new case every four seconds. Its incidence rate increases exponentially with   
   age, with the highest increase occurring after 70 years of age.   
   Alzheimer's disease (AD) is the most common form of dementia worldwide,   
   accounting for around 70% of dementia cases, with North America and Western   
   Europe having the highest prevalence and incidence rates.   
   Healthcare costs for AD are massive: in the US alone, the estimated healthcare   
   costs are of $172 billion per year. Despite these striking numbers and the   
   extensive amount of research being conducted on AD, its exact pathological   
   mechanisms remain to be    
   determined, with a number of theories having been proposed. Risk factors for   
   AD development include genetic factors, cerebrovascular disease, traumatic   
   brain injury, hypertension, type 2 diabetes, obesity, and smoking.   
   Neuroprotective factors include    
   adequate diets, exercise and intellectual activity.   
   Hallmarks of the disease   
   There are some pathological features in AD brain tissue that are considered   
   hallmarks of the disease. Specifically, amyloid plaques - extracellular   
   deposits of the amyloid-beta (A-beta) peptide - and neurofibrillary tangles,   
   intracellular accumulations    
   of the hyperphosphorylated tau (p-tau), a microtubule assembly protein. Other   
   characteristic changes include increased microglial reactivity and widespread   
   loss of neurons, white matter and synapses.   
   Despite considerable controversy, the predominant line of research in AD has   
   followed the amyloid hypothesis for the pathophysiology of AD, which claims   
   that it is the A-beta peptide that causes AD and that neu-rofibrillary   
   tangles, cell loss, vascular    
   damage and dementia are a direct consequence of A-beta deposition.   
   However, evidence supporting this theory is not totally clear. In May, Nature   
   Neuroscience published an interesting perspective article that overviews the   
   arguments for and against this theory.   
   Supporting the amyloid hypothesis   
   According to the mentioned article, the strongest evidence supporting the role   
   of A-beta as AD initiator comes from human genetics. There is a form of   
   familial AD that is caused by mutations in genes which are directly involved   
   in A-beta production,    
   namely the gene that encodes the precursor to A-beta, the amyloid precursor   
   protein (APP), and the genes that encode Presenilin 1 and 2, subunits of the   
   complex that cleaves APP to generate A-beta. These mutations induce an   
   enhanced accumulation of    
   amyloid plaques.   
   In sporadic forms of AD the strongest genetic risk factor is apolipoprotein E   
   (ApoE), mainly produced by astrocytes in the brain, and that is responsible   
   for transporting cholesterol to neurons via ApoE receptors. There are   
   different alternative forms of    
   the APOE gene, each having different effects in the risk of AD development.   
   ApoE3 is the most common form, ApoE2 decreases the risk of AD development, and   
   ApoE4 is known to increase the risk for AD.   
   An estimated 20-25% of the population carries at least one copy of ApoE4,   
   having an increased risk of AD of around 4-fold; in the  2% of the population   
   that carries two E4 copies, on the other hand, the increased risk is of around   
   12-fold. Experimental    
   studies have shown that ApoE4 does indeed promote A-beta aggregation and   
   deposition and that the reduction of ApoE levels can decrease amyloid plaque   
   development.   
   Against the amyloid hypothesis   
   The tau protein is regarded as essential for AD-associated neurodegeneration.   
   Arguments against the amyloid theory stem from the fact that there are   
   anatomic and temporal mismatches between A-beta pathology, p-tau aggregation   
   and neurodegeneration in AD.   
   For instance, A-beta deposition occurs first and most severely in regions that   
   do not match those where neuronal death is first observed, whereas tau   
   pathology correlates much more closely with neuronal loss, not only   
   anatomically, but also temporally,    
   since many clinically asymptomatic individuals are known to already have   
   extensive amyloid plaque pathology.   
   One explanation presented in the mentioned article is that, in addition to   
   amyloid plaques, A-beta can be present in the form of small molecular   
   complexes (oligomers) that can mediate AD pathol-ogy. These oligomeric A-beta   
   molecules can actually be found    
   in brain regions showing extensive neuronal loss, and their presence seems to   
   correlate more extensively with the development of dementia than the presence   
   of amyloid plaques. Indeed, A-beta oligomers seem to accumulate with age, and   
   be correlated with    
   tau pathology in humans.   
   Therefore, a proposed model for AD pathology places A-beta as the primary   
   initiator of AD: age-associated factors may induce oligomeric and fibrillar   
   A-beta accumulation, leading to the appearance of the first plaques; after   
   several years of A-beta    
   aggregation, it somehow triggers the tau pathology, with neurofibrillary   
   tangles, as well as other toxic proteins such as synuclein beginning to   
   accumulate, prompting increased neurodegeneration. At this point, the   
   degenerative changes become extensive,    
   with neuronal loss, oxidative damage, inflammation, and clinical symptoms   
   becoming evident.   
   What seems unclear is what induces the aggregation and accumulation of A-beta   
   in the first place and how it is related to age. It is possible that multiple   
   factors that may enhance A-beta production and aggregation or suppress its   
   clearance can    
   contribute to this throughout life.   
      
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