Alzheimer’s Disease: Symptoms, Diagnosis, And Treatment Options

Aetiology and Pathogenesis

Discuss about the Alzheimer’s Disease.

Alzheimer’s disease is an irreversible and progressive disorder causing memory loss and disruption of other cognitive functions which severely interferes with daily life activities. It is the most common type of dementia and accounts for up to 75% of all dementia cases worldwide. It has been estimated that about 25 million people worldwide are affected by dementia of some kind (Qiu, Kivipelto & von Strauss, 2009). The incidence of Alzheimer’s disease is strongly although not solely associated with ageing. The majority of affected individuals age above 65 years, however, early onset of Alzheimer’s is also been observed. There are more than 413,106 Australians suffering from dementia among which 55% are female and 45% male (Alzheimer’s Australia | Statistics, 2017). With the world population ageing at a steady rate the frequency of dementia is expected to double by 2030 and hence is considered as a public health priority presently. Further, the global societal cost of Alzheimer’s disease is quite high, both in terms of direct burdens (medical and social care) as well as indirect burdens (unpaid caregiving by family and friends). This clinical update aims to address several aspects of the disease including prevailing diagnostic methods, distinction between different types of dementia, pathophysiology, prognosis and potential treatment options.

Scientists believe that Alzheimer’s is a multifactorial disease resulting from the culmination of a range of different factors, of which increasing age is the most potent risk factor of all. The strong association of the disease with old age is an indication of complex interaction of other risk factors such as genetic susceptibility, psychosocial factors, lifestyle and environmental factors experienced over the lifespan of the patient. Alzheimer’s is caused by brain cell death like all other types of dementia. Thus it is a progressive neurodegenerative disorder resulting in shrinkage of the overall brain size and decrease in nerve cells and connections between the same. Damage and changes to the brain start occurring from as long as a decade or more before the appearance of any clinical symptoms. Abnormal deposits of a protein called beta-amyloid causes amyloid plaques. Disintegration of another protein called tau tangles which as the name suggest tangles with different neurons of the brain. These beta plaques and tau tangles affects the normal functioning of the neurons and the neurons start losing neural connections (Swerdlow, Burns & Khan, 2014). In the initial stages the hippocampus is only affected which is associated with memory functioning. In the later stages as the disease progresses other parts of the brain are affected and brain tissues shrink considerably (Fjell et al., 2014). However, the exact reason of why these plaques and tangles form and the onset of the disease mostly at an old age are still undiscovered. Researches provide several theories and age-related changes like mitochondrial dysfunction, inflammation, production of increased levels of free radicals, etc. which requires further investigation to treat and cure the disease.

Risk and Protective Factors of Alzheimer’s Disease

The disease progresses through three main stages namely Preclinical, Mild Cognitive Impairment and finally Dementia. During the preclinical stage no cognitive or memory impairment is observed, however changes in the brain tissue proceeds. In Mild Cognitive Impairment there are some signs disruption in cognitive functioning may appear but it does not interfere with normal daily activities of the patient (Vos et al., 2015). As the disease further progresses to severe cognitive impairment dementia and memory loss is observed.

Several lines of risk factors are associated with Alzheimer’s. Table. 1 summarizes some of the established risk factors and protective associated with the disease.

Aetiological Hypothesis	Risk Factors/ Protective Factors	Epidemiological Evidence
Genetic	Risk factors: APOE ?4 allele (Late-onset Alzheimer’s) Inherited genetic changes (Early-onset Alzheimer’s)	Strong
Vascular	Risk Factors: Hypertension, high BMI, diabetes, Cardiovascular disorders, cerebrovascular disorders and smoking. Protective Factors: Light to moderate alcohol consumption, antihypertensive therapy.	Moderate or Sufficient
Psychosocial	Protective Factors: High level of education, persistent cognitive and mental stimulating activities, increased social and physical activity.	Moderate or Sufficient
Nutritional and Dietary	Risk Factors: Folate, Vitamin B12 and antioxidant deficiency. Protective Factors: Omega-3 fatty acids and vegetable consumption.	Insufficient or Limited.
Other (Toxic or inflammatory factors, etc.)	Risk Factors: Head injuries, exposure to toxins and electromagnetic fields, depression and hormone replacement theory. Protective Factors: Non-steroidal anti-inflammatory drugs,	Insufficient or Limited.

Table 1: Risk and Protective Factors of Alzheimer’s Disease (Qiu, Kivipelto & von Strauss, 2009)

The public health impact of Alzheimer’s is profound. As the disease is costly in terms of both personal suffering and economic loss it has become an important facet of public health and health care delivery. Although the immediate clinical symptoms of the disease is limited to memory loss and other cognitive impairments, several non-cognitive secondary clinical features like behavioural disturbances, depression, disruption of daily life activities (Wimo et al., 2013). Several studies have estimated the financial burden of the disease by using self-report and observational tools. One study estimates the cost of the disease to be $38,000 per patient per year although estimates ranging from 50% lower to 50% higher have also been reported (Sloane et al., 2002). The main burden of care is upon informal caregivers. Time spent providing care ranges from 5.9 hours per week for patients with lower severity to 35.2 hours per week for patients with severe cognitive impairments and limitations (Wittenauer, Smith & Aden, 2013). Hospitalization incurs the highest financial burden for patients with severe to moderate form of the disease.

Several signs and symptoms are associated with Alzheimer’s disease. Affected individuals may experience one or more of these symptoms to be diagnosed with the disease. Appropriate evaluation of the symptoms is essential for early diagnosis by medical practitioners. The symptoms often vary according to the severity of the disease i.e. mild, moderate and severe. Almost all the symptoms are related to memory and cognitions. Patients suffer from worsened ability to remember and process new information like conversations, appointments, navigations routes, etc. Impairments regarding reasoning, judgements and complex tasks such as inability to make appropriate decisions, manage finances or plan complex sequential activities. Vision is often affected in patients with Alzheimer’s disease causing moderate to severe visuospatial functioning impairments. Difficulty in reading, judging distances, determining colour, recognising familiar faces and objects and implementing tasks that involve some sort of orientation are early symptoms of disease prognosis (Ismail et al., 2016). Further, behavioural changes are also extensively observed in Alzheimer’s patients. Mood swings, lack of interest and motivation, apathy, social withdrawal, compulsive and obsessive behaviour. Memory loss is the most common of all the symptoms and is associated with manifestation of all the other related symptoms. People are often diagnosed at mild stage of the disease which is most prominently characterised by mild cognitive impairment (Geda et al., 2013). At the initial stages it does not interfere with daily living activities but older people with the condition have higher risk of developing Alzheimer’s. As the disease progresses from mild to severe the brain ceases to work and the body shuts down.

Clinical Manifestations

Various guidelines for Alzheimer’s dementia and mild cognitive impairment can be used for general practice. To diagnose the disease the initial step is a medical assessment of the patient. Early diagnosis is crucial for providing appropriate treatment and intervention and restricts the prognosis of the disease as direct cure of the disease is yet to be discovered. A medical assessment should include examination of the patient’s family and medical history. Whether dementia runs in the family or any incidence relating to head injury can be high risk factors and might aid in early diagnosis. Physical examinations including measurement of blood pressure and other cardiovascular parameters must be performed to assess the effects of the same on progression of the diseased condition. Neurological tests like assessment of balance, sensory functions, reflexes, eye movements and other neurological functions may help in assessing the overall function ability of the patient and diagnose the disease. In the preclinical stage several biological and physiological changes are underway but no noticeable clinical symptoms are visible in the patient. Studies predict that the onset of this preclinical stage may begin years ever decades before any manifestation of the disease symptoms and hence diagnosis of this stage becomes somewhat difficult for medical practitioners and physicians. The diagnosis of this stage mostly depends on the identification of certain biomarkers that may signal the inception of these biological changes within the brain (Olsson et al., 2016). The most efficient biomarkers of Alzheimer’s disease brain imaging studies using biophysical techniques like magnetic resonance imaging (MRI), positron imaging tomography (PET) and estimation of several proteins present in the brain and cerebrospinal fluid. To assess mild and severe symptoms, established guidelines must be followed. Memory and cognitive skills, behavioural changes, degree of memory or cognitive impairment and the cause of symptoms are evaluated for such diagnosis (Hayne, Lim & Donnelly, 2014). The practitioner must rule out other factors that can cause similar symptoms by thoroughly studying patient history. Parkinson’s disease, depression, past strokes and other medical conditions must be considered prior to diagnosing the patient with Alzheimer’s disease.

No drug has been formulated yet that can completely protect neurons from degenerative effects however pharmacological treatment primarily depends on inhibition of acetylcholine degradation in the nerve synapses. Acetylcholinesterase inhibitors are the only drugs that have been used to treat Alzheimer’s. They act by slowing down the process of degradation of neurotransmitters. Another group of drug, N-methyl D-aspartate receptor antagonist are also used that regulate the activity of glutamate and help in the proves of cell signalling.

References

Alzheimer’s Australia | Statistics. (2017). Fightdementia.org.au. Retrieved 2 September 2017, from https://www.fightdementia.org.au/statistics

Fjell, A. M., McEvoy, L., Holland, D., Dale, A. M., Walhovd, K. B., & Alzheimer’s Disease Neuroimaging Initiative. (2014). What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus. Progress in neurobiology, 117, 20-40.

Geda, Y. E., Schneider, L. S., Gitlin, L. N., Miller, D. S., Smith, G. S., Bell, J., … & Rosenberg, P. B. (2013). Neuropsychiatric symptoms in Alzheimer’s disease: past progress and anticipation of the future. Alzheimer’s & dementia, 9(5), 602-608.

Hayne, D. J., Lim, S., & Donnelly, P. S. (2014). Metal complexes designed to bind to amyloid-β for the diagnosis and treatment of Alzheimer’s disease. Chemical Society Reviews, 43(19), 6701-6715.

Ismail, Z., Smith, E. E., Geda, Y., Sultzer, D., Brodaty, H., Smith, G., … & Area, I. N. S. P. I. (2016). Neuropsychiatric symptoms as early manifestations of emergent dementia: provisional diagnostic criteria for mild behavioral impairment. Alzheimer’s & Dementia, 12(2), 195-202.

Olsson, B., Lautner, R., Andreasson, U., Öhrfelt, A., Portelius, E., Bjerke, M., … & Wu, E. (2016). CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. The Lancet Neurology, 15(7), 673-684.

Qiu, C., Kivipelto, M., & von Strauss, E. (2009). Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues in clinical neuroscience, 11(2), 111.

Sloane, P. D., Zimmerman, S., Suchindran, C., Reed, P., Wang, L., Boustani, M., & Sudha, S. (2002). The public health impact of Alzheimer’s disease, 2000–2050: potential implication of treatment advances. Annual review of public health, 23(1), 213-231.

Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014). The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1842(8), 1219-1231.

Vos, S. J., Verhey, F., Frölich, L., Kornhuber, J., Wiltfang, J., Maier, W., … & Frisoni, G. B. (2015). Prevalence and prognosis of Alzheimer’s disease at the mild cognitive impairment stage. Brain, 138(5), 1327-1338.

Wimo, A., Jönsson, L., Bond, J., Prince, M., Winblad, B., & International, A. D. (2013). The worldwide economic impact of dementia 2010. Alzheimer’s & Dementia, 9(1), 1-11.

Wittenauer, R., Smith, L., & Aden, K. (2013) Update on 2004 Background Paper Written by Saloni Tanna, Pharm. D. MPH Background Paper, 6.