The Memory thief - Alzheimer's disease

1. What Is Alzheimer's Disease?

Alzheimer's disease (AD) is the prevailing type of dementia, constituting 60% to 70% of dementia cases globally ^[1]. It is a progressive neurodegenerative disorder that impairs the ability to memory, think, learn, and organize, ultimately severely affecting social, occupational and life functions. It generally occurs in old age and early senility.

Neuropathologically, AD is characterized by significant cortical atrophy and enlargement of ventricular. Pathological hallmarks are the senile plaques formed by the abnormal buildup of amyloid-β (Aβ) protein, and neurofibrillary tangles of hyperphosphorylated tau (t) protein.

2. What Are the Symptoms of Alzheimer's Disease?

Alzheimer's disease started insidiously and the course of the disease was chronic progressive. The symptoms of Alzheimer's disease vary from person to person. However, it shares some common symptoms in the early stage, including progressive memory impairment, cognitive dysfunction, language barrier, movement disorder, and personality and behavior changes, as well as mental disorders ^[2].

These symptoms gradually deteriorate over time. In the advanced stages of the disease, the patients develop serious complications, such as dehydration, malnutrition, or infection, which can eventually lead to death ^[3]. .

3. What Are the Causes of Alzheimer's Disease?

The exact cause of Alzheimer's disease is not fully understood, and it is likely influenced by a combination of genetic, environmental, and lifestyle factors.

3.1 Genetic Factors

Most cases of Alzheimer's disease are not directly inherited, but certain genetic factors can increase the risk. Mutations in specific genes, such as APP (amyloid precursor protein)[4], PSEN1 (presenilin 1), and PSEN2 (presenilin 2), are associated with familial forms of Alzheimer's disease and occur at early-onset AD (EOAD). Individuals with these mutations have a higher likelihood of developing Alzheimer's disease at an earlier age.

The APOE gene is the most well-established genetic risk factor for late-onset AD (LOAD). The majority of LOAD cases occur sporadically, with no reported family history of the condition. A substantial number of genes identified by the genome-wide association study (GWAS) could be associated with the Aβ cascade or tau pathology, and tend to cluster within three distinct pathways.

Figure 1. Major pathways involved in AD and affected genes

This picture is cited from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876682/

The Table information is cited from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876682/

Biological Characteristics of Alzheimer's Disease:

The characteristic feature of Alzheimer's is the accumulation of extracellular amyloid β (Aβ) plaques and the presence of intracellular neurofibrillary tangles (NFTs) containing hyper-phosphorylated tau ^[5]. The aggregation of beta-amyloid proteins can disrupt communication between neurons and contribute to neuronal damage. Tau protein is essential for maintaining the structure of neurons, and abnormal aggregation leads to the formation of tangles, disrupting neural function.

These changes are toxic to neurons, resulting in neural dysfunction and inter-connection loss and death. The resulting lesions initially occur in areas of the brain responsible for memory including the entorhinal cortex and hippocampus causing language, behavior, and logic problems, and then spread to almost the whole brain by the last stage of Alzheimer's, leading to significant brain atrophy.

Figure 2. Pathogenesis of Alzheimer's disease

This picture id cited from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4588032/

3.2 Lifestyle and Environmental Factors

At the 2017 Alzheimer's Association International Conference (AAIC), a report from the Lancet Commissions ^[6] 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:

• Less education: A low level of education that causes cognitive decline is thought to be the cause of cognitive decline.
• Hearing: Hearing loss may increase the cognitive load of a fragile brain, cause changes in the brain, or cause social disengagement or depression, and accelerate atrophy, which may lead to cognitive decline.
• Exercise: Observational experiments found a negative correlation between exercise and risk of dementia. Physical exercise can keep the elderly away from dementia.
• Diabetes, hypertension and obesity: Among vascular risk factors, high blood pressure is the most important. Abnormalities in peripheral blood insulin caused by obesity lead to a decrease in brain insulin secretion, which affects amyloid clearance.
• Depressive symptoms: Studies have shown a link between depressive episodes and the risk of dementia.
• Lack of social contact: Social isolation is a risk factor for dementia, which increases the risk of high blood pressure, coronary heart disease and depression. Social isolation can also lead to cognitive inactivity, which is associated with decreased cognitive ability and low mood.
• Smoking: The link between smoking and cardiovascular disease can lead to cognitive impairment.
• Other: Progressive failure of the immune system, weakening of the body's detoxification function and lentivirus infection, as well as social and psychological factors such as widowed, solitary, economic difficulties, and life bumps can be the cause of the disease.

Figure 3. Effects of modifiable and non-modifiable risk factors on Alzheimer's disease

As of 2020, extensive research has revealed additional risk factors for Alzheimer's disease and dementia, including excessive alcohol intake, brain damage, and air pollution ^[7].

4. Data about Alzheimer's Disease

Alzheimer's disease was officially recognized as the sixth leading cause of death in the United States in 2019. In 2020 and 2021, when COVID-19 became one of the top ten causes of death, it fell to seventh place. About 6.7 million Americans aged 65 and older live with Alzheimer's disease in 2023. This number is expected to rise to 13 million by 2050. It is estimated that 60% to 70% of the approximately 55 million people worldwide with dementia have Alzheimer's disease.

Early onset (before 65 years old) of Alzheimer's disease accounted for only about 5% of all Alzheimer's patients. Alzheimer's patients mostly are late-onset (after 65 years of age), and 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 ^[8]. As early as 2011, the global incidence of dementia reached about 24 million, and this number is still growing at a high speed. It is expected to double every 20 years by 2040 ^[9,10].

Epidemiological data indicates that in the United States, one out of every three individuals aged over 85 is projected to develop Alzheimer's disease. Furthermore, by the year 2050, the population of Americans aged over 85 years is expected to triple. According to the Global Burden of Disease Study, approximately 57.4 million people globally were living with dementia in 2019. This number is expected to reach 152.8 million people by 2050, which is three times that of the present.

5. Alzheimer's Disease Related Signal Pathways

Alzheimer's disease is a complex neurodegenerative disorder with multiple underlying molecular mechanisms. Several signal pathways are implicated in the pathogenesis of Alzheimer's disease.

5.1 MAPK Signaling Pathway

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 ^[11,12]. 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 ^[13]. 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 4. MAPK Signaling Pathway

5.2 mTOR Signaling Pathway

The mTOR pathway is an important regulatory pathway for neuronal development. Its functions include the following aspects:

• Axon formation and directional growth.
• Dendritic occurrence and branching, external signal molecules such as BDNF, PI3K, Akt, etc. can promote dendritic growth and branch expansion by stimulating mTOR activation.
• mTOR regulates synapse formation by affecting the number and morphology of dendritic spines.

Figure 5. 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. The abnormal mTOR pathway in Alzheimer's disease (AD) patients also suggests that the regulation of mTOR signaling is an important factor for neurological disease ^[14].

5.3 Insulin Receptor (IR) Signal Transduction Pathway

Insulin receptors are widely distributed in the brain, including the hippocampus, 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, and insulin PI3K/AKT-mTOR signaling pathway. Insulin in neuronal cells accelerates the production of neurons through 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 long-term potent action (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 ^[15].

5.4 Wnt Signaling Pathway

• Wnt signaling pathway and amyloid-β: The continued loss of Wnt signaling function is associated with neurodegenerative changes induced by amyloid-β in Alzheimer's disease patients. Amyloid-β can affect the expression of target genes by inhibiting the function of the Wnt signaling pathway, thereby producing neurotoxicity, which ultimately leads to the loss of a large number of neurons.
• Wnt signaling pathway and tau protein: Glycogen synthase kinase 3β, a negative regulator of the Wnt signaling pathway, can disrupt neurons by over-phosphorylation of tau protein, resulting in cognitive dysfunction.
• Wnt signaling pathway and neural stem cells: Activation of Wnt signaling pathway regulates the proliferation and differentiation of various stem cells and neural progenitor cells, and the loss of Wnt signal function leads to the decline of neural formation ability directly related to Alzheimer's disease .

Figure 6. 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 ^[16].

6. Current Hot Research Fields of Alzheimer's Disease

Although there is currently no cure for Alzheimer's disease, numerous promising research areas are being investigated in the hopes of finding new treatments and prevention strategies. Immunotherapy and biomarker development stand out among these current hot research fields of Alzheimer's disease.

6.1 Immunotherapy of Alzheimer's Disease

Immunotherapies for AD primarily focus on targeting beta-amyloid. Toxic extracellular deposition of misfolded beta-amyloid protein aggregate is a hallmark of AD. The Aβ-based immunotherapy primarily aims to reduce Aβ aggregate formation, spread, and deposition in the human brain. The two main anti-Aβ therapy concepts are active and passive immunization. Passive vaccination directly introduces exogenous monoclonal antibodies (mAbs), while active vaccination directs the immune system to produce an immunological response using an anti-Aβ agent. Anti-Aβ agents have so far focused on lowering Aβ generation, suppressing Aβ aggregation, and accelerating Aβ clearance.

6.2 Biomarker Development of Alzheimer's Disease

Conventional Alzheimer's disease (AD) biomarkers play a crucial role in aiding clinicians in the diagnosis of Alzheimer's disease, assessing disease progression, and monitoring the effects of potential therapeutic interventions.

Here are some of the commonly used biomarkers:

However, the invasiveness of CSF-based measurements and the high costs of PET imaging render these tests less appealing and time-consuming. Consequently, it is critically important to explore non-invasive and precise biomarkers that can indicate the risk of developing AD and classify its various stages.

Leveraging recent technological advancements, the scientific community has explored/ put forward various biomarkers in blood, plasma, serum, urine, and saliva to detect AD early before LOAD ^{[17, 18]}. The omics technologies are capable of profiling multiple molecules simultaneously, which can avoid the disadvantage of heterogeneity among patients. The combination of molecular patterns and computational power, including artificial intelligence (AI) and machine-learning (ML) tools, holds promise for addressing these challenges ^[19].

Researchers are investigating AI-based methods for diagnosing AD using diverse modalities such as biofluid biomarkers, retinal and iris readings, electroencephalogram (EEG) brain wave measurements ^[20], and online language skills and memory tests ^[21,22]. These advancements could potentially facilitate mass screening for AD, provided they demonstrate high accuracy in real clinical settings.

miRNAs have also been detected in plasma, serum, and CSF as markers for various diseases, including cardiovascular diseases, cancer, and neurodegenerative disorders ^[23]. Studies indicate that nearly 50% of known miRNAs are expressed in the nervous system, playing a significant role in regulating normal brain physiology, aging, and mental health. In Alzheimer's disease, miRNAs target crucial disease-related genes, demonstrating either neurodegenerative or neuroprotective effects ^[24].

These solutions represent significant advancements, but there is ongoing debate and exploration regarding their effectiveness, long-term outcomes, and potential side effects.