Stages of Alzheimers disease:
Still now, there have no single diagnostic test to determine the Alzheimers disease. Doctor often applies different types of approaches and tools to assist a diagnosis, with the help of specialists such as neurologists, geriatricians, neuropsychologists and geriatric psychiatrists.
Alzheimers disease patients symptoms can be categorizes in two ways. One is Global Deterioration Scale (GDS), provides caregivers about the overview of the cognitive function stages for those who are suffering from a primary degenerative dementia. This process is classified into 7 different stages. Stages 1-3 are called pre-dementia stages. Stages 4-7 are known as dementia stages (Reisberg et al., 1982).
Table: 7 stages of Alzheimers according to Global Deterioration Scale (GDS)
Source: (Act.alz.org, n.d.)
Another is Mini-Mental State Exam (MMSE) which is used for preliminary screening, diagnosis of cognitive functions (orientation, attention, memory, language and visual-spatial skills) AD patient. As maximum MMSE score is 30 points, if score is 20 to 24 it suggests mild dementia, 13 to 20 indicates moderate dementia, and less than 12 recommends severe dementia. This process is mainly classified into 3 different stages. Alzheimers disease progresses in several stages: preclinical, mild (sometimes called early-stage), moderate, and severe (sometimes called late-stage) (Kraemer et al., 1998).
Table: 4 stages of Alzheimers according to Mini-Mental State Exam (MMSE)
Source: (Ncbi.nlm.nih.gov, n.d.)
Mild Alzheimer’s disease (early stage)
At the early stage, one may feel having memory lapses, forgetting familiar words or the location or objects but he can independently work and can manage the social activities. Its duration is first year or two year.
Common difficulties include:
? Difficulties to memorized the appropriate right word or name
? Dilemma in recall the newly introduced people names
? Challenges come at performing tasks in social or work settings.
? Forgetting the material which one has just read
? Losing or misplacing a valuable object
? Increasing problem with planning or organizing
Figure: Different Stages of AD
Moderate Alzheimer’s disease (middle stage)
It is the longest stage which can lead for many years (second to fourth or fifth years) and prominently shows dementia symptoms. Thats why these patients require a better take care.
At this point, symptoms may include:
? Forgetfulness of events or about one’s own personal history and current information (address or telephone number)
? Feeling moody or withdrawn, particularly in socially or mentally challenging situations
? Confusion about where they are or what day it is
? The need for help choosing proper clothing for the season or the occasion
? Trouble controlling bladder and bowels in some individuals
? Changes in sleep patterns, as sleeping at day and restless at night
? An increased risk of wandering and becoming lost
? Personality and behavioral changes, including suspiciousness and delusions or compulsive, repetitive behavior like hand-wringing or tissue shredding
Severe Alzheimer’s disease (late stage)
At late stage, dementia symptoms become severe. Individuals will lose their ability to respond to their situation, a conversation and, sooner or later, lose the control movement. Its duration is fifth year and after that.
At this stage, individuals may:
? Need round-the-clock assistance with daily activities and personal care
? Lose awareness of recent experiences as well as of their surroundings
? Experience changes in physical abilities, including the ability to walk, sit and, eventually, swallow
? Have increasing difficulty communicating
? Become vulnerable to infections, especially pneumonia
Risk factors for Alzheimers
A. Age: Age is the greatest risk factor. Percentage of Alzheimers patient increases significantly with age:
? 3 % of people age 65-74,
? 17 % of people age 75-84 and
? 32 % of people age 85 or older
Figure: Risk factors of AD a. Age b. Sex
B. Sex: Women are more prone to Alzheimers than men. In Americans, Almost two-thirds of women are suffering with Alzheimers.
C. Genetic modification: APOE- e4 increases ones risk for developing Alzheimers. Black/African Americans have higher possibilities of continuing the e4 allele (at least one copy) than European Americans. Family history shows these variations.
D. Modifiable risk factors:
? Cardiovascular disease risk factors (smoking, obesity, hypertension, high cholesterol and diabetes)
? Traumatic brain injury (TBI)
? Social and cognitive engagement
E. Diet: High in sugar-sweetened beverages can be risk factors.
Current Hypothesis about Alzheimers disease progression:
Lack of knowledge about the etiology and pathogenesis of selective neuronal death is the chief obstacle for understanding Alzheimer’s disease (AD). Until now, Researchers do not fully aware of the underlying pathogenesis of Alzheimers disease. Due to the human brains complexity and many factors involve in disease state, animal models and research tools are not established. Some hypotheses are discussed below as the root cause of the development and progression of AD. These entire hypotheses are interrelated with each others.
Figure: Different pathogenesis of Alzheimers disease hypothesis.
(A) Tau hypothesis; (B) Cholinergic hypothesis; (C) Free radical damage hypothesis; (D) Inflammation hypothesis; (E) Amyloid cascade hypothesis.
1) Gene Mutation hypothesis
Early-onset AD (EOAD) is related to family link, known as Familial Alzheimers disease (FAD). In EOAD 3 types of gene mutation occur:
? APP (Amyloid precursor protein; at chromosome 21)
? PSEN1 (Presenilin 1; at chromosome 14)
? PSEN2 (Presenilin 2; at chromosome 1)
Alzheimers disease related to these genes is referred as Autosomal-Dominant Alzheimers disease (ADAD). Here, mutation in APP facilitated Beta Amyloid plaques formation whereas Presenilin 1 and 2 increases Beta Amyloid plaques production by ?-secratase.
Figure: Schematic representation of Gene Mutation hypothesis (APOE gene)
Late-onset AD (LOAD) is known as Sporadic Alzheimers disease (SAD) which differ in the age and cause of onset. APOE gene (apolipoprotein E polymorphism; at chromosome 19) is recognized as a major risk factor for LOAD by producing astrocytes and microglia in the brain. Isoforms of APOE have been identified as contributing to the disease with the following population prevalence: APOE3 (77%78%) > APOE4 (14%16%) > APOE2 (7%8%)
2) Formation of Beta Amyloid plaques hypothesis
The amyloid hypothesis or amyloid cascade hypothesis shows that the deposition of the amyloid-? peptide in the brain parenchyma, ultimately leads to Alzheimer’s disease. In AD, A? is excised from APP (on chromosome 21) by ?- and ?-secretase and released outside the cell. As the metabolic ability to degraded A? is decreased so A? peptides may be accumulated. In accumulated A? amyloid fibrils, A? 40 and A? 42 are major components. Increased A? 42 (APP C-terminal fragments), develop into plaque, causes neurotoxicity and induction of tau pathology, directed to neuronal cell death and neurodegeneration. Mutations in PS1 /PSEN1 (Presenilin 1; at chromosome 14) and PS2 /PSEN2 (Presenilin 2; at chromosome 1) genes are linked to the early onset forms of AD like APP.
Figure: Schematic representation of Beta Amyloid plaques formation hypothesis in Alzheimers disease
3) Formation of Neurofibrillary Tangle or Tau Protein hypothesis
Tauopathies (Tau pathologies) is based on the observation of NFTs density and its distribution in brain. This hypothesis shows the mutation in Tau gene (on chromosome 17) which causes NFT.
In AD, Hyperphosphorylated Tau spontaneously accumulated into Paired Helical Filaments (PHF), which subsequently prompting its detachment from microtubules, destabilization them and the disrupted the neuronal transport. Thus, form the neurofibrillary tangles (NFTs). Increased Tau oligomers worsen the AD.
Figure: Schematic representation of Tau Protein hypothesis in Alzheimers disease
4) Neuroinflammation induced Alzheimers disease hypothesis
Microglias, Triggering receptor expressed on myeloid cells 2 (TREM2) and complement system are behind synaptic pruning.
Microglia continuously looking for signs or existence of any infection or inflammation into the brain, which are originated by toxic proteins (beta-amyloid and anything else). These may damage in the neurons. Microglia also clear the damaging causes from the brain and secrete numerous pro-inflammatory molecules (cytokines) which activate other microglia.
But in Alzheimers, microglia become overactive. They are not only amplifying cytokines production, but also simultaneously less clearing process. Microglia expresses Major Histocompatibility Complex (MHC) I and II, integrins and Fc receptors. Reactive microglia and astrocytes will surround amyloid plaques and pro-inflammatory cytokines, thus cause AD.
Figure: Schematic representation of Neuroinflammation induced Alzheimers disease hypothesis
5) Calcium hypothesis
The calcium ion (Ca2+) is essential second messenger in the brain for provide the functional and structural activity to nerve cell circuits. Ca2+ signaling regulates several neuronal functions, like- neuronal growth, exocytosis, synaptic plasticity and cognitive function. So Ca2+ homeostasis can affect the neuron normal structure (amyloid formation and accumulation, neuronal cell apoptosis) and function (memory loss, cognitive dysfunction) by disruption of intracellular Ca2+ homeostasis.
The calcium hypothesis attempts to explain how Amyloid metabolism influences the synaptic plasticity and neuronal apoptosis by remodeling the neuronal Ca2+ signaling pathway. This occurs through two main pathways.
a. Firstly, The A? oligomers formation and amyloid ? (A?) release can increase Ca2+ entry. The cellular prion protein (PrPC) is a cell surface protein which can be a receptor for the A? oligomers, thus facilities up regulation of Ca2+ signaling.
b. Secondly, Release of the APP intracellular domain (AICD) may remodel the Ca2+ signaling system by altering the expression of components for example up regulation of the Ryanodine Receptor (RYR) and down regulation of the Calbindin.
c. Mutations of presenilin also boost up signaling by- reduction in the leak pathway, activation of the SERCA pump and sensitization of the InsP3 receptor. Bcl-2 may diminish rhe sensitization by reducing the activity of the InsP3 receptor.
Figure: Schematic representation of Calcium hypothesis
Ultimately, remodeled Ca2+ signaling system disrupts the synaptic mechanisms and excessive Ca2+ stimulated mitochondria to discharge Cytochrome C for apoptosis.
6) Cholinergic hypothesis:
Cholinergic hypothesis was state that a loss of cholinergic function in the CNS contributes extensively to the cognitive impairment connected with advanced age and AD. In the advanced aged and early AD brain, alterations occurs in high-affinity choline uptake, reduction in cortical cholinergic innervations, impaired acetylcholine & glutamatergic release, deficits in the expression of nicotinic and muscarinic(M1AChR & M2AChR) receptors, dysfunctional neurotrophin support (i.e., NGF receptors), and deficits in axonal transport . Also causes reduced soluble APP secretion, increased amyloid protein formation. These condition shows, neuron either by a reduced number of symbols exists or by reduced color intensity.
Figure: Schematic representation of Cholinergic hypothesis
7) Ion channel hypothesis
The ion channel hypothesis is also known as the channel hypothesis or the amyloid beta ion channel hypothesis. This ion channel hypothesis of Alzheimer’s disease (AD) identify that the beta-amyloid (A?) peptides accumulate in plaques in the brain, actually damage and/or kill neurons by forming ion channels & causes neurotoxicity.
A? peptides can form ion channels at neurons, lipid bilayers, liposomes, oocyctes, and endothelial cells which possess distinct physiologic characteristics toxic properties. A? channels are heterogeneous in size, selectivity, blockade, gating and it is also voltage-independent, and relatively poorly selective amongst physiologic ions, Ca2+, Na+, K+, Cs+, Li+, and possibly Cl-. A? channels are reversibly blocked by Zn2+, and tromethamine (tris), and irreversibly by Al3+. Thus causes neurotoxicity.
Figure: Schematic representation of Ion channel hypothesis
8) Oxidative stress hypothesis:
Increased oxidative stress has a role in the pathogenesis of neuron degeneration and death in AD.
Several numbers of conditions (Normal aging process, Head trauma, Ischemia, Hypoperfusion, A?, APP & PS1 gene mutation and Increased Fe, Al, and Hg etc.) can cause free radical generation which ultimately leads to peroxidation of membrane polyunsaturated fatty acids.
? This leads to formation of other oxy-radicals and generates aldehydes (4-hydroxynonenal (HNE)) by lipid peroxidation. 4-HNE is capable of altering membrane ATPases leading to increased intracellular calcium, which initiates a cascade of events leading to further free radical generation and neuron death.
? Oxidized proteins such as Hydradize-reactive protein carbonyl moieties amplify the protein oxidation.
? 8-hydroxy-2-deoxyguanosine is a marker of DNA oxidation causes oxidative damage in nuclear and mitochondrial DNA in brain with increasing age.
Figure: Schematic representation of Oxidative stress hypothesis
? Energy metabolism deficient and decreased Cytochrome C oxidase
? Advanced glycation end products (AGE), Malondialdehyde, Carbonyls, Peroxynitrite, Heme oxygenase-1 and SOD-1 are capable of generating free radicals.
Thus, neuron death occurs for free radical generation.