Pathophysiology of Late Onset Alzheimer's Disease Research Paper

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Pathophysiology of Late Onset Alzheimer's Disease

The author provides a comprehensive overview of late-onset Alzheimer's disease, including discussions about what is generally known about the disease with regard to heritability, disease progression, and risk factors. Findings from relevant studies on the association of LOAD with genotypes, cellular processes, and patterns of brain deterioration are provided. Brief discussions of pharmacological treatments and future research are included.

Key words: Alzheimer's, late-onset

Alzheimer's disease (AD) is the most common form of dementia and it is both progressive and incurable. Early-onset Alzheimer's disease is considered to be an onset of the symptoms before the age of 65 years of age (Canu, et al., 2010). Compared to late onset AD patients, early onset AD patients show a more rapid cognitive and clinical decline, along with earlier impairment of a multidomain nature that includes language, executive functions, and visuospatial abilities, although memory deficits may be less severe (Canu, et al., 2010). Early onset AD is generally considered to be a more aggressive form of Alzheimer's disease.

It is estimated that 5.3 million Americans have AD, with 10 to 13% of people older than 65 affected by the disease (Buckley & Schub, 2012). Incidence rises to 40% in populations older than 85 years of age (Buckley & Schub, 2012). The prevalence of AD grows higher with advancing age, a factor that drives estimates of new diagnoses of AD to roughly 1 million added each year for the next 40 years or so (Buckley & Schub, 2012). What this means practically, is that 11 to 15 million Americans are expected to have AD by the year 2050 (Buckley & Schub, 2012). The incident rate shows about 10% inherited and about 90% as sporadic, or non-inherited (Buckley & Schub, 2012). Institutionalization of patients is common. The association between years following diagnosis and institutionalization percentage of the patient population, as follows: 20% institutionalized one year after diagnosis, 50% at five years, and close to 90% at eight years (Buckley & Schub, 2012).

Etiology. Alzheimer's disease is evidenced by cognitive deficits in speech and language, memory, and motor skills (Buckley & Schub, 2012). Patients who exhibit this constellation of diminished day-to-day functioning experience significant problems with the social and occupational aspects of life (Buckley & Schub, 2012). The accompanying ramifications for family, friends, and community members are substantive (Buckley & Schub, 2012). The disease progresses differently across patients, however, neurodegenerative complications inevitably make the disease fatal (Buckley & Schub, 2012).

Risk factors. The primary risk factor for AD is advanced age, a risk which doubles for every five years that pass after a person has attained the age of 65 (Buckley & Schub, 2012). Higher than normal risk is associated with having a first-degree relative with AD. Other conditions associated with increased risk include Down syndrome, head trauma, and exposure to certain environmental contaminants such as metals, toxins, infections (Buckley & Schub, 2012). Alzheimer's has also been associated with decreased estrogen levels, cardiovascular disease, cardiovascular risk factors (such as obesity, hypertension, dyslipidemia, insulin resistance), depression, and lifestyle issues such as smoking, poor diet, lack of exercise, and alcohol consumption (Buckley & Schub, 2012). There is some evidence that memory functions are under strong genetic influence in older people whether or not they have AD, suggesting that memory function variability can only partly be attributed to the APOE genotype (Wilson, et al., 2011).

Symptomatology. Alzheimer's disease is characterized by stages: Early, middle, middle-to-late, and final (Buckley & Schub, 2012). The onset of the disease is typically noticed by family members during the early stage, where the patient begins to exhibit mild depression, some difficulty learning, and a progressive loss of intellectual ability (Buckley & Schub, 2012). During the middle stage, the patient exhibits increased moodiness and other personality changes, social withdrawal and disorganized conversation, increased memory loss, and decreased ability to perform daily living activities (Buckley & Schub, 2012). In the middle to late stages of AD, the patient will be significantly dependent on others to complete dialing living activities, wanders, is incontinent, needs repeated instructions for simple tasks, is not be able to recognize objects or family members, and has periodic outbursts of hostility, anger, and paranoia (Buckley & Schub, 2012). In the final stage, the patient has profound memory loss, cannot speak, cannot walk, has dysphagia, is bedridden and may develop ulcers, contractures, respiratory failure, and/or pneumonia (Buckley & Schub, 2012).

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Epidemiology. Eikelenboom, et al. (2011) suggest that late-onset Alzheimer's is a multifactorial disease that is based on the interaction between environmental factors and susceptible genes. Various environmental factors are known to induce acute and chronic systemic inflammation, which is associated with increased decline in cognitive function (Eikelenboom, et al., 2011). Some of the suspect environmental factors are surgical intervention, infection, traumatic brain injuries, and vascular problems. Recent studies in genetics, epidemiology, and neuropathology suggest that innate immunity is an element of late-onset AD etiology (Eikelenboom, et al., 2011). For example, Studies of offspring of parents with late-onset AD suggest that a proinflammatory genotype with a the capacity to produce higher levels of proinflammatory cytokines acts as a genetic risk factor of AD (Eikelenboom, et al., 2011).

Pathogenesis. The pathology of AD occurs in two phases: the earlier phase is characterized by the oligomers and the later phase is associated with the development of plaques (Chiarini, 2009). The aging human brain becomes progressively less able to dispose of the synapse targeting soluble amyloid oligomers that are released from normal neuronal activity (Chiarini, 2009). Rising oligomer levels result in targeted and eliminated synapses and the prevention of synaptic function, which erodes memory formation and other cognitive functions (Chiarini, 2009). For awhile, the affected neurons remain alive, but they are shortly overcome when calcium-sensing receptors on the astrocytes bind to the oligomers, which induces mitogen activated protein kinase causes damage to release large amounts of nitric oxide which is converted to peroxynitrite (Chiarini, 2009). The oligomers aggregate into fibrillar plaques that attract microglial macrophages that produce proinflammatory cytokines and reactive oxygen species (Chiarini, 2009). As with other cellular processes involving inflammation, the process tends to escalate, ultimately effectively destroying both normal and functionally impaired neurons (Chiarini, 2009).

Belbin, et al. (2011) conducted a study on 15 of the top LOAD candidate genes in which they conclude that there is association of LOAD with GAB2 and LOC651924 (6q24.1). Additionally, their study provided suggestive evidence in their large case-control series that two genes (PGBK1 and EBF3) may be associated with the age-at-onset of LOAD (Belbin, et al., 2011). In their research on the impact of mitochondrion and nuclear DNA variants, Maruszak, et al. (2011) found that haplogroup H. And HV cluster were both associated with an increased risk of LOAD. Conversely, their research indicates that haplogroup associated with OXPHOS uncoupling decrease LOAD risk. This research supports theories on the role of coupling-uncoupling halogroups in neurodegenerative disorders factor (Maruszak, et al., 2011). Moreover, their study showed a significant interaction between TFAM rs1937 and APOEA status as a LOAD influencing risk factor (Maruszak, et al., 2011).

The pathophysiology of AD is known to be influenced by the lower expression levels of sorting-protein receptor (sorLa) (Olgiati, et al., 2012). A meta-analysis of published samples and from two independent South-European centers (Greek-Italy Genetic Association Study on Late-Onset Alzheimer's Disease, or GIGAS_LOAD) sought to confirm the association between SORL1 SNPs and LOAD (Olgiati, et al., 2012). No association was found for the GIGAS_LOAD sample and SORL1 genotypes (Olgiati, et al., 2012).

Many research studies are associated with damage to the gray matter of the brains of AD patients (Canu, et al., 2010). Recent studies indicate that there is also damage to the white matter in the brain (Canu, et al., 2010). Losses are primarily attributed to the posterior portion of the brain (corpus callosum, cingulum, and temporoparietal regions) (Canu, et al., 2010). Early onset AD patients have been shown to evidence a widespread pattern of posterior white matter atrophy, while late onset AD patients experienced a selective parahippocampal white matter loss (Canu, et al., 2010).

Pharmocology. Most disease-modifying treatments of AD are directed at the amyloid cascades that are a primary pathogenic feature of AD (Woodward, 2012). Other treatment targets include inflammation, tau pathology, neurogenesis, and oxidative stress (Woodward, 2012). The currently approved pharmacological treatments for AD include central cholinesterase inhibitors and mematine (Greenspan, 2012). The benefits of these two treatments are well documented, but they are modest. Progress with clinical trials for disease modifying drugs has not been promising (Greenspan, 2012). Research is being conducted with drugs that can clear, reduce, or block certain brain chemicals (Abeta, hyperphosphorylation of tau) (Greenspan, 2012). Antidepressants have been suggested as an early stage treatment for behavioral symptoms, particularly in light.....

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