Alzheimer’s Disease: An Overview
Shivangi Sharma, Aaliya Bari, Javed Akhtar, Meenu Yadav, Rishi Pal and Rajendra Nath*
Department of Pharmacology & Therapeutics, King George’s Medical University, India
Submission: August 09, 2019; Published: September 06, 2019
*Corresponding author: Rajendra Nath, department of Pharmacology & Therapeutics, King George’s Medical University, Lucknow (UP), India
How to cite this article: Shivangi Sharma, Aaliya Bari, Javed Akhtar, Meenu Yadav, Rishi Pal, Rajendra Nath. Alzheimer’s Disease: An Overview. Open Access J Neurol Neurosurg. 2019; 11(4): 555816. DOI: 10.19080/OAJNN.2019.11.555816.
Abstract
Alzheimer’s disease presently is a huge burden on society and the situation is only going to worsen in coming years. Today more than 25 million people in the world are affected by dementia and more than 75% of all dementia cases are due to Alzheimer’s Disease (AD) and this number is bound to increase in coming years. AD is a neurodegenerative disorder where the loss of hippocampal and cortical neurons leads to impairment of memory and cognitive ability. The main neurochemical disturbance in AD is a deficiency of ACh. In AD there is protein accumulation as neuritic plaques containing amyloid beta protein (Aβ), NeuroFibrillary Tangles (NFTs) composed of hyperphosphorylated tau filaments which induce neuronal dysfunction and death by various mechanisms currently under study like-direct impairment of synaptic transmission and plasticity (AMPA receptors), excitotoxicity, oxidative stress, and neuroinflammation. Mutations in Amyloid beta (Aβ) Precursor Protein (APP), presenilin1 (PSEN1), presenilin2 (PSEN2) genes have been identified as causes of autosomal dominant, early onset AD, also inheritance of ε4 allele of APOE gene increases the risk for AD. Recent advances in diagnosis of AD include use of fluid biomarkers and imaging biomarkers like FDG PET scan, Amyloid PET scan, Tau PET scan. Currently there is no cure for AD. Drugs available provide only symptomatic relief that too for a short duration. There is a intensive research going on for creating drugs for prevention, cure or delay of progression of AD, though more of extensive research and trials are required for faster positive Conclusion in favor of AD.
Keywords: Dementia; Neurodegenerative disorder; Amyloid beta protein; Hyperphosphorylated tau filaments; APP; PSEN1; PSEN2 genes; Fluid and Imaging biomarkers
Opinion
Alzheimer’s disease is a prototypical neurodegenerative disorder where the loss of hippocampal and cortical neurons leads to impairment of memory and cognitive ability. Neurodegenerative disorders are disorders that are characterized by progressive and irreversible neuronal dysfunction and loss of neurons from specific regions of the brain. There are other prototypical neurodegenerative disorders which include Parkinson disease, Huntington disease, Amyotrophic lateral sclerosis apart from Alzheimer’s disease, where a specific area of brain is involved in each one of these diseases [1]. AD begins in the entorhinal region of the medial temporal lobe, spreads to the hippocampus, and then moves to lateral and posterior temporal and parietal neocortex, eventually causing a more widespread degeneration and atrophy [2] (Figure1).
AD-A proteinopathy
AD like other major neurodegenerative diseases has specific protein accumulations. In AD there is protein accumulation as neuritic plaques containing amyloid beta protein (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau filaments. Aβ protein is also accumulated in blood vessel walls in cortex and leptomeninges [3]. Clinically AD has three major stages:1).A “preclinical” stage (before symptoms appear) - accumulation of Aβ and tau begins,2).A MCI stage(mild cognitive impairment)with episodic memory loss (repeated questions, misplaced items, etc.) that is not severe enough to impair daily function.3).A dementia stage with progressive loss of functional abilities. Death usually occurs within 6–12 years of onset of disease and usually due to a complication of immobility of patient such as pneumonia or pulmonary embolism [4].
Epidemiology of Alzheimer’s disease
More than 25 million people in the world today are affected by dementia. More than 75% of all dementia cases are due to Alzheimer’s disease. In both developed and developing nations, Alzheimer’s disease has tremendous impact on not just the affected individuals, but also on caregivers and society [5].
Determinants of Alzheimer’s disease
Alzheimer’s disease is a multifactorial disease, in which the most important risk factors are-old age and a positive family history or genetic susceptibility [5] (Table1).
Prevalence of AD
Worldwide, the global prevalence of dementia is estimated to be 3.9% in people aged 60+ years. The age-specific prevalence of AD almost doubles every 5 years after aged 65 (Figure 2&3).
Incidence of AD
The pooled incidence rate of AD among people 65+ years of age in Europe was 19.4 per 1000 person-years. The pooled data from two large-scale community-based studies of people aged 65+ years in the US yielded an incidence rate for AD of 15.0per 1000 person-years. Studies have shown that AD incidence in developing countries is generally lower than in developed countries. Incidence in India is 3.2 per 1000 personyears [5]. Posttranslational modifications of tau, including phosphorylation, proteolysis, and other changes, increase tau’s propensity to aggregate. Mechanisms by which Aβ and tau induce neuronal dysfunction and death may include direct impairment of synaptic transmission and plasticity, excitotoxicity, oxidative stress, and Neuroinflammation [4]. Recently newer hypothesis have been proposed regarding pathogenesis of AD. It is hypothesized that Peroxisome Proliferator-Activated Receptors (PPAR) are nuclear receptors that have potential role in having neuroprotective effects in various neurodegenerative disorders, especially AD. They are implicated to play a key role in Aβ clearance and show potential use in AD therapy [6-8] (Figure 4).
Another hypothesis proposes that cerebral glucose metabolism is perturbed in the pathogenesis of AD. Abnormality of glucose transportation contributes to intracellular glucose catabolism dysfunction resulting in neuronal degeneration and consequently cognitive deficits in AD patients [8]. Genetics of AD [4] Mutations in three genes have been identified as causes of autosomal dominant, early onset AD.1) APP-encoding Amyloid beta(Aβ)precursor protein.2) PSEN1-encoding presenilin 1.3) PSEN2- encoding presenilin 2 .All three genes are involved in the production of Aβ peptides.
Neurochemistry Of AD
The main neurochemical disturbance in AD is a deficiency of ACh. This is due to atrophy and degeneration of subcortical cholinergic neurons. There is destruction of not only cholinergic neurons but also the cortical and hippocampal targets that receive cholinergic inputs [4]. Basal forebrain provides the major cholinergic innervations to the neocortex, hippocampus and amygdala. There is dramatic loss of neurons and synapses in these areas [8].
Diagnosis of AD
Alzheimer disease remains a clinical diagnosis, based on the presence of memory impairment and other cognitive impairments that are insidious, progressive, and not well explained by another disorder
a. Screening tools: Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MOCA), and Cognistat can be used to capture dementia and follow progression. In most patients with MCI and some with clinically apparent AD, bedside screening tests may be normal, and a more challenging and comprehensive set of neuropsychological tests will be required.
b. Neuropsychological tests: When the etiology for the dementia syndrome remains in doubt, a specially tailored evaluation should be performed that includes tasks of working and episodic memory, executive function, language, and visuospatial and perceptual abilities.
c. A functional assessment: should also be performed to help the physician determine the day-to-day impact of the disorder on the patient’s memory, community affairs, hobbies, judgment, dressing, and eating.
d. Neuropsychiatric assessment: is important for diagnosis, prognosis, and treatment [4,9] (Figure 5).
Current Treatment modalities for AD
a. The existing therapy for AD are neurochemical, aiming to compensate for acetyl cholinergic neurotransmitter systems that are selectively impaired or to boost acetyl cholinergic transmission. The drugs used for this purpose are Cholinesterase inhibitors. These are-Three drugsdonepezil, rivastigmine, and galantamine. All three are reversible antagonists of cholinesterase’s and are first-line therapy. Useful only for symptomatic relief of cognitive impairments. Useful mainly in mild or moderate AD. There is no dramatic improvement in symptoms but rather a 6- to 12-month delay in progression of symptoms, after which clinical deterioration resumes. These drugs are usually well tolerated, most common side effects-GI distress, muscle cramping, and abnormal dreams, but must be used with caution in patients with bradycardia or syncope.
b. Memantine. It is a noncompetitive antagonist of the NMDA type glutamate receptor. Used as either an adjunct or an alternative to cholinesterase inhibitors in AD. Useful mainly in later stages of dementia, not much efficacious earlier. Delays clinical deterioration in moderate-to-severe AD. Adverse effects-mild headache or dizziness. Excreted by the kidneys so dosage should be reduced in patients with renal failure.
Treatment of behavioural symptoms of AD
In addition to cognitive decline, behavioural and psychiatric symptoms in dementia (BPSD) are common, particularly in middle stages of the disease. These symptoms include-Irritability, Agitation, Paranoia, Delusional thinking, Wandering, Anxiety, Depression, Social withdrawal, Sleep disturbance [4]. Treatment of BPSD can be difficult, and non-pharmacological approaches should generally be first line. A variety of pharmacological options are also available-most useful are SSRIs [4].
Recent Advances in Treatment of AD
The goal of much current research is to identify therapies [6].
a. that are neuroprotective.
b. that modify the underlying neurodegenerative process.
Neuroprotective therapies-Excitotoxicity
a. Role of Glutamate [6]
b. Glutamate is used as a neurotransmitter to mediate most excitatory synaptic transmission in the mammalian brain. The presence of excessive amounts of glutamate can lead to excitotoxic cell death.
c. Glutamate antagonists have been developed as neuroprotective therapies for neurodegeneration, with two such agents- Memantine and Riluzole, currently in clinical use.
d. Aging is the most important risk factor for all of the neurodegenerative diseases, and a likely contributor to the effect of age is the progressive impairment in the capacity of neurons for oxidative metabolism with consequent production of reactive compounds such as hydrogen peroxide and oxygen radicals. This has led to pursuit of drugs that can enhance cellular metabolism (Mitochondrial cofactor coenzyme Q10) and antioxidant strategies as treatments to prevent or retard degenerative diseases [6].
e. Currently there are no approved therapies that directly target the disease proteins i.e. Aβ and tau, However, there is intensive research to bring disease-modifying treatments that do directly target these proteins, such as passive immunotherapy with antibodies, into clinical care [6]. Vaccination against Aβ42 has proved highly efficacious in mouse models of AD, helping clear brain amyloid and preventing further amyloid accumulation. In human trials, this approach led to life threatening complications, including meningoencephalitis in a minority of patients [3].
f. Several retrospective studies suggest that nonsteroidal anti-inflammatory agents and 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitors (statins) may have a protective effect on dementia if used prior to the onset of disease but do not influence clinically symptomatic AD [3].
g. There is now also a strong interest in the relationship between diabetes and AD, and insulin regulating studies are being conducted [3].
h. Another experimental approach to AD treatment: β and γ secretase inhibitors that diminish the production of Aβ42, but the first two placebo-controlled trials of γ secretase inhibitors, tarenflurbil and semagacestat, were negative, and semagacestat may have accelerated cognitive decline compared to placebo [3].
i. Ginkgo biloba-Ginkgo biloba is potentially beneficial for the improvement of cognitive function, activities of daily living, and global clinical assessment in patients with mild cognitive impairment or Alzheimer’s disease. Ginkgo biloba is thought to have both antioxidant and anti-inflammatory properties, to protect cell membranes and to regulate neurotransmitter function [10].
Ayurvedic medicinal plants proven beneficial for Alzheimer’s disease
Ashwagandha (Withania somnifera)-It contains steroidal compounds, such as the ergostane-type steroidal lactones. A subset of these components (withanamides) has been shown to scavenge free radicals generated during the initiation and progression of AD. Neuronal cell death triggered by amyloid plaques was also blocked by withanamides [11,12-17]. Turmeric (Curcuma longa)-The active constituents are thought to be turmerone oil and water soluble curcuminoids[18].Curcumin is the principal curcuminoid and is responsible for the yellow color of the turmeric root [18-20].Epidemiologic studies show a 4.4- fold lower incidence of AD in Southeast Asian countries where turmeric is commonly used as a dietary spice [21,22].It is shown to reduce the amount of plaque deposition [23-25],reduced oxidative damage and reversed the amyloid pathology in an AD transgenic mouse [24,25]. Brahmi (Bacopa monnieri)-It is commonly used in Ayurvedic medicine as a nerve tonic, diuretic, and cardiotonic The principal constituents of Bacopa Monnieri (BM) are saponins and triterpenoid bacosaponins that include bacopa sides III to V, bacosides A and B, and bacosaponins A, B, and C.[26-28].BM also inhibited cholinergic degeneration and displayed a cognition-enhancing effect in a rat model of AD [29- 35].
Shankhpushpi (Convolvulus pluricaulis)-Various species for Shankapushpi, including Convolvulus pluricaulis (CP), Convolvulus microphyllus, Evolvulus alsinoides, and Clitoria ternatea (CT), have been described. The whole plant is used in various formulae as a nervine tonic for improvement of memory and cognitive function [36-41]. Guggulu-It is an oleogum resin exuding from the bark from several different plant species, including Commiphora mukul, C. molmol, C. abyssinica, C. Burseraceae, and C. whighitii. Guggulipid is reported to significantly lower both serum LDL cholesterol and triglyceride levels [42-44].MOA is that guggul is an effective antagonist of the bile acid receptor farnesoid X receptor [42,45].Epidemiologic and biochemical data suggest a link between cholesterol, APP processing, and AD [46-51].
Dietary Supplements known to have Preventive benefits for AD-1)
a. Omega-3 fatty acids.
b. Plant Polyphenols like-Resveratrol in red wine, grape skin extracts and raspberries, Green tea etc.
c. B vitamins (Folic acid, vitamin B6 and B12).
d. Antioxidant vitamins (vitamin E, C, A and beta carotenes).
e. Vitamin D
Conclusion
AD affects the life of not only the patients but also adversely impacts the life of caregivers. There is required to be increased awareness about AD among the general masses regarding the disease symptoms. The care providers need to be well informed. Nonprofit organizations, Alzheimer’s societies like organizations are required to spread awareness and to provide counselling to both the patients and the care givers. A lot of support can be provided this way and quality of life of both patient and care giver made easy. Awareness, counselling and support groups become even more important as at present there is no cure for AD. There is lot of research going on and a lot more needed for prevention, delaying disease progression and for the cure. Results of research on beneficial effect on AD of antioxidants, statins, mitochondrial cofactor coenzyme Q10, antibodies against Aβ42, NSAIDS, β and γ secretase inhibitors, insulin regulating studies, ginkgo biloba and extract of various ayurvedic medicinal plants (like Ashwagandha, Shankhpushpi, Brahmi, Turmeric etc. ), role of Peroxisome Proliferator-Activated Receptors (PPAR) in the pathophysiology of AD have been controversial so far with these novel and alternative methods showing both positive and negative effects, which need to be further analyzed and explored till we actually come up with a positive solution with minimal side effects [52-66].
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