Late Onset Alzheimer's Disease Analysis

Late onset Alzheimer’s disease (LOAD) is the most common neurodegenerative disorder characterized by progressive loss of cognitive function that interferes with daily activities [38](Holtzman et al., 2011). The neuropathology involves neurofibrillary tangles, composed of hyperphosphorylated tau proteins, and β-amyloid (Aβ) plaques which obstruct proper synapse function and lead to neuronal cell loss and atrophy [5](Ballard et al., 2011). The most crucial risk factor is age; the risk doubles every five years after the age of 65, with higher prevalence in females than males [5;37](Hirtz et al., 2007;Ballard et al., 2011). There is also a strong genetic component that indicates increased risk of dementia in individuals expressing the E4 isoform …show more content…
FTD constitutes 5-15% of all dementia cases and is the second most common cause of dementia for patients under the age of 65 [57](Rademakers et al., 2012). Unlike LOAD, FTD patients have relative preservation of memory; nonetheless, they experience progressive deterioration in language, behavior, and personality [57](Rademakers et al., 2012). The genetic background of FTD lies on two mutations respectively on the microtubules associated protein tau gene (MAPT) and progranulin (GRN) genes [57](Rademakers et al., 2012). DLB is yet another common type of dementia that is characterized by the presence of Lewy bodies in the brainstem, throughout the amygdala and cortex [75](Wu, 2011). Lewy bodies are composed of accumulated α-synuclein inside the nuclei of neurons [63](Shults, 2006). Symptoms are typically similar to that of AD, although DLB patients experience visual hallucinations, visuospatial deficits, fluctuating cognitive awareness, and parkinsonian symptoms [28;45;75](Wu, 2011;Gomperts et al., 2012;Lebedev et al., 2013). Memory impairment is more pronounced in AD than DLB whereas SPECT and PET scans have demonstrated hypometabolism and hypoperfusion in the primary visual cortex in DLB but not in AD [31](Hampel et al., …show more content…
Oxidative stress has been shown to stimulate sphingomyelinase (SMase), which converts SM to CM [3;49](Alessenko et al., 2004;Malaplate-Armand et al., 2006). CM, a second messenger and regulator of apoptosis, stabilizes β secretase activity [36;36](He et al., 2010). In AD, increased CM levels regulate β and γ secretases and amyloid precursor protein (APP) processing on lipid rafts [69](Vetrivel et al., 2004). Mislocalization of β and γ secretase to lipid rafts in post Golgi rather than lysosomes can promote Aβ accumulation [69](Vetrivel et al., 2004). Sphingosine is associated with apoptosis and is elevated in AD brains [30](Hagen-Euteneuer et al., 2012). Sphingosine also plays a role in vesicle fusion and exocytosis [16;48;59](Rohrbough et al., 2004;Darios et al., 2009;Lutjohann et al., 2012). Increased cholesterol increases the risk of AD and more cholesterol in membranes have been associated with larger lipid raft size and accelerated b and g secretase activity [69;74](Wood et al., 2002;Vetrivel et al.,