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Alzheimer disease (AD), also known as senile dementia, is a primary degenerative brain disease that occurs in old age and early senility. It refers to a persistent high-grade neurological activity disorder. The disease started insidiously and the course of the disease was chronic progressive. It is mainly manifested as neurocognitive symptoms such as progressive memory impairment, cognitive dysfunction, personality change and language disorder, which seriously affect social, occupational and life functions.
In 1906, Alzheimer used a microscope to study the brain tissue samples of the patient, and found a large number of senile plaques and nerve fiber tangles. In 1910, Krepelin named the disease “Alzheimer's disease” in the eighth edition of “Psychiatry”. Alzheimer is therefore known to the world.
The etiology and pathogenesis of Alzheimer's disease has not yet been elucidated, and it is considered to be a disease caused by a variety of factors including genetic factors and many other risk factors (including biological and psychosocial factors).
From a genetic perspective, Alzheimer's disease is heterogeneous and complex, with no single or simple genetic model. Risk genes for Alzheimer's disease have significant effects on disease susceptibility and age of onset [1]. In general, carrying the Alzheimer's gene gives you a higher chance of developing Alzheimer's disease. So far, scientists have confirmed the correlation between multiple gene mutations and Alzheimer's disease, such as amyloid protein precursor protein gene (APP), Presenilin-1(PS-1), Presenilin-2(PS-2), Apolipoprotein E (ApoE), etc. [2]. The mutation of these genes can lead to the occurrence of nerve plaques or senile plaques formed by the amyloid-β(Aβ) peptide aggregation outside brain nerve cells, abnormal aggregation of tau protein in brain nerve cells, and extensive neuronal deletion.
Figure 1. The influence of genetic factors on Alzheimer's disease
APP: amyloid precursor protein; PS-1: presenilin 1; PS-2: presenilin 2; ApoE: apolipoprotein E; ACE: angiotensin I converting enzyme; CH25H: cholesterol 25hydroxylase; CHRNB2: Nicotinic acetylcholine receptors; PRNP: Prion protein; CST3: cystatin 3; GAB2: scaffolding/adaptor proteins; MAPT: microtubule associated protein tau; TF: Transferrin
Most epidemiological studies suggest that family history is a risk factor for the disease. Family members of some patients have higher rates of the same disease than the general population.
In addition to genetic factors, there are some risk factors associated with Alzheimer's disease that may have an important impact on the formation of the disease.
Figure 2. Effects of modifiable and non-modifiable risk factors on Alzheimer's disease
At the 2017 Alzheimer's Association International Conference (AAIC), a report from the Lancet Commissions [3] caused extensive discussion. The report entitled Dementia Prevention, Intervention and Care presents nine risk factors for dementia. Based on the population attribution score (PAF), the following major risk factors were identified:
In short, the risk factors for Alzheimer's disease are mostly uncontrollable.
Alzheimer's disease is a degenerative neurological degenerative disease that develops insidiously. Clinical features mainly include memory impairment, aphasia, and loss of recognition. Alzheimer's disease has manifestations and symptoms before the onset of the disease. Knowing the early performance is the key to preventing Alzheimer's disease.
Memory disorders, especially near memory disorders, occur in the early stages. The patient's daily life is characterized by repeatedly asking the same thing or repeating the same thing.
The earliest problems in Alzheimer's patients were language barriers, mainly in the absence of suitable words when speaking.
In the early stages of Alzheimer's disease, there are visual spatial disorders, such as the inability to accurately determine the location of the item and getting lost.
Dysgraphia is caused by the difficulty in expression, content is often expressed as unsatisfactory words.
Alzheimer's disease can be divided into three periods based on cognitive ability and deterioration of bodily functions.
The first stage (1 to 3 years) is mild dementia; the second stage (2 to 10 years) is moderate dementia; the third stage (8 to 12 years) is severe dementia. Alzheimer's patients generally die from complications such as infection.
Figure 3. Symptoms of Alzheimer's disease
Alzheimer's disease has early onset and late onset. Early onset (before 65 years old) accounted for only about 5% of all Alzheimer's patients. Alzheimer's patients mostly are late-onset (after 65 years of age), more common in people over 70 years old. Demographic epidemiological statistics indicate that there are very few people with Alzheimer's disease in people under the age of 40 [4]. As early as 2011, the global incidence of dementia has reached about 24 million, and this number is still growing at a high speed. It is expected to double every 20 years by 2040 [5][6].
Data from the World Alzheimer Report 2018 shows that there will be one patient with dementia every 3 seconds in the world. About 20 million people worldwide suffer from dementia in 2018. By 2050, this number will increase to 152 million, which is three times that of the present. It is estimated that the cost of global social dementia in 2018 is $1 trillion, and by 2030 this number will increase to $2 trillion.
Figure 4. Data related to Alzheimer's disease
(Image reference article World Alzheimer Report 2018)
The main pathological features of AD: neuronal plaques or senile plaques formed by aggregation of amyloid peptide (Aβ) outside the brain, neurofibrillary tangles (NFT) formed by abnormal accumulation of tau in cranial nerve cells, and extensive neurons deletion [7]. All factors affecting Aβ, Tau protein and neurons are associated with Alzheimer's disease. The current study found that multiple signal transduction pathways are involved in the pathogenesis of AD.
Recent studies have found that the c-jun N-terminal kinase signal transduction pathway was activated in both the brain of the animal model of transgenic Alzheimer's disease and the brain of patients with Alzheimer's disease, and believed that this pathway was related to the deposition of Aβ [8][9]. JNK signal transduction pathway is also closely associated with another pathological change in Alzheimer's disease - abnormal phosphorylation of Tau protein and formation of double-stranded filaments [10]. All three pathways of MAPK - ERK, JNK and p38, are involved in the induction of tau hyperphosphorylation, and are related to factors such as Aβ, oxidative stress, inflammatory factors and protein phosphatase.
Figure 5. MAPK Signaling Pathway
The mTOR pathway is an important regulatory pathway for neuronal development. Its functions include the following aspects:
Figure 6. mTOR signaling pathway
One characteristic of Alzheimer's disease is the large number of neuronal loss in certain areas of the brain, which may be related to abnormalities in the mTOR pathway. There is ample evidence that mTOR can influence the formation of learning and memory through different molecular mechanisms. Activation of the mTOR pathway directly up-regulates proteins involved in synaptic plasticity regulation, affecting learning and memory. Abnormal mTOR pathway in Alzheimer's disease (AD) patients also suggests that regulation of mTOR signaling is an important factor for neurological disease [11].
Insulin receptors are widely distributed in the brain, including the hippocampus and the olfactory bulb and hypothalamus. There are three main insulin signaling pathways in the brain: insulin PI3K/AKT-GSK3 signaling pathway; insulin PI3K/AKT-BAD signaling pathway; insulin PI3K/AKT-mTOR signaling pathway. Insulin in neuronal cells accelerates the production of neurons by means of MAPK and PI3K/AKT. When the insulin signaling pathway fails, the PI3K/AKT and MAPK signaling pathway are inhibited, resulting in apoptosis. Insulin can also regulate N-methyl-D-aspartate (NMDA) expression and 1ong term potent-ation (LTP) excitability, which in turn affects memory and learning ability. A large number of studies have shown that pathological changes in AD are associated with neuronal insulin receptor (IR) signal transduction pathway disorders [12].
Figure 7. Wnt signaling pathway
The wnt signaling pathway is involved in most of the processes of functional intact neurons, and numerous studies have shown that the wnt signaling pathway plays an important role in the development of Alzheimer's disease [13].
When there are some early symptoms of Alzheimer's disease, timely detection and diagnosis should be conducted.
The diagnostic criteria for Alzheimer's disease have been revised several times. The following is about the Alzheimer's association and its proposed diagnostic criteria.
Diagnostic criteria: In 1984, the National Institute of Neurology and Language Disorders and Stroke, the Alzheimer's Disease and Related Diseases Association (NINCDS-ADRDA) pioneered the clinical diagnostic criteria for AD.
In 2007, the international working group (IWG) published a revision of the diagnostic criteria of NINCDS-ADRDA in Lancet Neurology [14], which proposed the use of biomarkers to improve the accuracy of the diagnosis of mild cognitive impairment (MCI).
In 2009, the National Institute of Aging and the Alzheimer's Disease Society divided the pathological process of AD into three distinct stages, namely, asymptomatic phase before dementia, symptomatic phase before dementia, and dementia, and formulate the corresponding diagnostic criteria, which referred to as NIA-AA diagnostic criteria.
The IWG has revised the AD diagnostic criteria again in 2014 (IWG-2) [15].
The 10th revision of the international classification of diseases (icd-10) still has some difficulties in the clinical diagnosis of Alzheimer's diseases. At present, the clinical diagnosis of AD remains dependent on medical history, and there are no definitive laboratory diagnostic biochemical indicators and surrogate criteria. Numerous clinical studies have suggested that abnormal levels of amyloid-β in blood, cerebrospinal fluid, and brain tissue are associated with progression of Alzheimer's disease, and total Tau protein content (T-tau) in patients with AD can be increased by 2 - 3 fold [16]. Amyloid-β and changes in Tau protein content in cerebrospinal fluid can be used as characteristic biochemical indicators of Alzheimer's disease [17].
So far, although there are many drugs that can alleviate the development of symptoms, there is no thorough treatment. Prevention is better than cure, and effective prevention of controllable risk factors is quite effective.
The right lifestyle can effectively prevent Alzheimer's disease. Here are a few ways to prevent AD.
Although Alzheimer's disease is currently unable to cure, drug treatment improves symptoms and delays dysfunction in most patients. The main treatments include:
It is now believed that the decrease in ACh in the synaptic cleft is the main cause of memory and cognitive impairment in AD patients. The addition of the neurotransmitter ACh in the brain is the purpose of treating AD.
Neuroprotection refers to the use of drugs that promote the survival or neurotransmission of cholinergic neurons in the brain.
Senile plaque is a characteristic pathological change of AD, and its core component is caused by deposition of Aβ in the brain. Reducing the production of Aβ or promoting its degradation is the key to AD treatment.
Imperial College's research team demonstrated that PGC-1α blocks Aβ formation at the cellular level [22]. This experiment was extended to a mouse model, and PGC-1α also prevented the formation of Aβ [23].
A promising drug strategy that blocks tau transmission has been reported. The researchers found that a small molecule called cambinol blocks the transfer of tau aggregates from cell to cell. What is cambinol? It is a small molecule that can subvert the"transfer" step by blocking an enzyme called nSMase2, which is essential for catalyzing production of the exosome carriers. If the approach is successful in animals, it could be tested in clinical trials.
References
[1] Gatz M, Reynolds C A, Fratiglioni L, et al. Role of Genes and Environments for Explaining Alzheimer Disease [J]. Arch Gen Psychiatry, 2006, 63(2):168-174.
[2] Bertram L, Lill C M, Tanzi R E. The genetics of Alzheimer disease: back to the future [J]. Neuron, 2010, 68(2):270-281.
[3] Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care [J]. Lancet, 2017, 390(10113).
[4] Harvey R, Skelton-Robinson M, Rossor M. The prevalence and causes of dementia in people under the age of 65 years [J]. Journal of Neurology Neurosurgery & Psychiatry, 2003, 74(9):1206.
[5] Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease [J]. Nature Reviews Neurology, 2011, 7(3):137-152.
[6] Chan K Y, Wang W, Wu J J, et al. Epidemiology of Alzheimer's disease and other forms of dementia in China, 1990–2010: a systematic review and analysis [J]. The Lancet,2013, 381(9882): 2016-2023.
[7] Querfurth H W, Laferla F M. Alzheimer's disease [J]. N Engl J Med, 2010, 362(4):329-344.
[8] Savage M J, Lin Y G, Ciallella J R, et al. Activation of c-Jun N-terminal kinase and p38 in an Alzheimer's disease model is associated with amyloid deposition [J]. Journal of Neuroscience the Official Journal of the Society for Neuroscience, 2002, 22(9):3376.
[9] Shoji M, Iwakami N, Takeuchi S, et al. JNK activation is associated with intracellular beta-amyloid accumulation [J]. Molecular Brain Research, 2000, 85(1-2):221-233.
[10] CristianaAtzori, BernardinoGhetti, RobertoPiva, et al. Activation of the JNK/p38 Pathway Occurs in Diseases Characterized by Tau Protein Pathology and Is Related to Tau Phosphorylation But Not to Apoptosis [J]. J Neuropathol Exp Neurol, 2001, 60(12):1190-1197.
[11] Lafay-Chebassier C, Paccalin M, Page G, et al. mTOR/p70S6k signalling alteration by A-beta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer's disease [J]. Journal of Neurochemistry, 2005, 94(1):215-225.
[12] Grimm MO1, Hundsdörfer B, Grösgen S, et al. PS dependent APP cleavage regulates glucosylceramide synthase and is affected in Alzheimer's disease [J] . Cell Physiol Biochem, 2014, 34: 92-110.
[13] Boonen R A, Van T P, Zivkovic D. Wnt signaling in Alzheimer's disease: up or down, that is the question [J]. Ageing Research Reviews, 2009, 8(2):71-82.
[14] Dubois B, Feldman H H, Jacova C, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria [J]. Lancet Neurology, 2007, 6(8):734-746.
[15] Dubois B, Feldman H H, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria [J]. Lancet Neurology, 2014, 13(6):614-629.
[16] Maccioni RB, Lavados M, Guillón M, et al. Anomalously phosphorylated tau and Aβ fragments in the CSF correlates with cognitive impairment in MCI subjects [J].Neurobiology of Aging, 2006, 27(2):237-244.
[17] Hansson O, Zetterberg H, Buchhave P, et al. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study.[J]. Lancet Neurology, 2006, 5(3):228.
[18] Shal B, Ding W, Ali H, et al. Anti-neuroinflammatory Potential of Natural Products in Attenuation of Alzheimer's Disease [J]. Frontiers in Pharmacology, 2018, 9:548.
[19] Tan M S, Yu J T, Tan C C, et al. Efficacy and adverse effects of ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis [J]. Journal of Alzheimers Disease Jad, 2015, 43(2):589-603.
[20] Henderson V W. Three Midlife Strategies to Prevent Cognitive Impairment Due to Alzheimer's Disease [J]. Climacteric, 2014, 17(2):38.
[21] Larsson S C, Markus H S. Does Treating Vascular Risk Factors Prevent Dementia and Alzheimer's Disease? A Systematic Review and Meta-Analysis [J]. Journal of Alzheimers Disease, 2018, 64(2):1-12.
[22] Katsouri L, Parr C, Bogdanovic N, et al. PPARγ co-activator-1α (PGC-1α) reduces amyloid-β generation through a PPARγ-dependent mechanism.[J]. Journal of Alzheimers Disease Jad, 2011, 25(1):151-62.
[23] Katsouri L, Lim Y M, Blondrath K, et al. PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer's disease model [J]. Proc Natl Acad Sci USA, 2016, 113(43):12292-12297.
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