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Author: Camille Jessica Cunanan

Alzheimer’s Disease

What is it?

Alzheimer’s disease is a progressive neurodegenerative disorder that affects 15 million individuals worldwide. In the United States alone, Alzheimer’s disease represents the most common form of dementia and affects more than 5.5 million Americans (1). The number of people living with Alzheimer’s disease in the United States is projected to grow to 13.8 million by the mid-century (1). The average duration of Alzheimer’s disease is 8–10 years, but the pre-symptomatic phases typically occur over two decades before clinical diagnosis (2). Sporadic Alzheimer’s disease is the most common form of the illness and is considered late-onset, occurring at an average of 80 years of age (2). Conversely, a small population (less than 1%) of patients suffer from autosomal dominant inherited Alzheimer’s disease (DIAD). DIAD is inherited and considered early-onset, occurring at an average of 45 years of age (2).

Alzheimer’s disease is characterized by the accumulation of aggregate forms of amyloid-β, which form insoluble plaques in extracellular areas, including in the walls of blood vessels. In the subgroup of early-onset Alzheimer’s, genetic mutations in the genes encoding amyloid precursor proteins, presenilin 1, and presenilin 2 have been found to induce overexpression and aggregate formation of aberrant forms of amyloid-β (2). Amyloid-β forms by the proteolytic cleavage of amyloid precursor proteins by a family of enzymes, specifically β‑secretases and γ‑secretases(2). The production of amyloid-β aggregates has been tightly associated to a polymorphism present in the gene encoding apolipoprotein E (ApoE) (2). ApoE has been found to have a major effect in determining the age of onset of Alzheimer’s disease. AD is also associated with the aggregation of tau proteins of microtubules in the neurofibrillary tangles present in neurons, but the details of such implications are still uncertain.

The study of disease mechanisms of Alzheimer’s disease in humans have been leading to new discoveries and insights into the pathogenesis, diagnosis, and treatment of the disease. Currently, amyloid-β, ApoE, and tau are the elements that show most evidence towards the contribution of disease progression. Neuropathological hallmarks in Alzheimer’s disease by way of amyloid-β, APOE, and tau, include synaptic loss and selective neuronal death, a decrease in specific neurotransmitters, and the presence of abnormal proteinaceous deposits in neurons or neurofibrillary tangles in extracellular space.

Many studies have supported that amyloid-β plaques play an influential pathogenic role in Alzheimer’s disease. Research has shown that amyloid-β is a product of APP metabolism in normal cells and is generated at high levels in neurons throughout a person’s lifespan (2). However, the mutated gene causes a change of conformation of a β-sheet, which results in aberrant activity of amyloid-β and its accumulation (2).

In addition to amyloid-β plaques, ApoE has been associated as a strong genetic risk factor for developing Alzheimer’s disease. Populations studies have shown that polymorphisms in the APOE protein is the highest risk factor and most common allele present in individuals with late-onset Alzheimer’s disease (2). ApoE is located on chromosome 19 and is involved in catabolizing triglyceride-rich lipoproteins (2). Research has shown that polymorphisms in the transcriptional regulatory region of ApoE is closely related to the development of Alzheimer’s disease (2). The amino acid substitutions involved in the disease affects the net charge and overall conformation of ApoE, compromising its binding to cellular receptors and lipoprotein particles (2). Such changes have implications on affecting stability, rate of production, and clearance of amyloid-β.

Tau proteins have also been implicated in the pathological development of Alzheimer’s disease. Researchers that have studied the “Tau Hypothesis” have shown that total tau and phosphorylated tau levels are elevated in both brain and cerebrospinal fluid of patients with Alzheimer’s disease (3). While there have been many studies that have proposed the pathway of tau proteins, the exact mechanistic details of how increased tau aggregates form is still uncertain.

Diagnosis of Alzheimer’s disease is challenging due to variations in the severity of cognitive symptoms, leading to patients being undiagnosed or misdiagnosed with different form of dementia. For example, 35% of patients diagnosed with Alzheimer’s disease were misdiagnosed (2). However, recent advances in amyloid-β PET imaging and diseased cerebrospinal fluid profiles have aided physicians in predicting progression from more cognitive impairment to dementia due to Alzheimer’s disease.

The epidemiology of Alzheimer’s disease has been extensively studied for many years, but findings are of limited value due to factors such as co-morbidity and mortality of patients. However, due to contemporary technical advancements, such as PET imaging, Alzheimer’s disease and the formation of plaques and tangles are more easily observed in living patients (as opposed to post-mortem studies). Figure 1 (below) depicts the pathological development of Alzheimer’s disease ascertained by molecular imaging techniques (2). Figure 1A shows the apparent formation of amyloid-β plaques and neurofibrillary tangles that spread throughout neurons in the brain as the disease progresses. Figure 1B illustrates the severity of amyloid-β plaques and neurofibrillary tangles depending on the stage progression of the disease. In the more typical cases of Alzheimer’s disease, amyloid‑β deposition occurs before neurofibrillary and neurotic changes with an apparent origin in the frontal and temporal lobes, hippocampus and limbic system (top row). The neurofibrillary tangles and neurotic degeneration start in the medial temporal lobes and hippocampus, and progressively spread to other areas of the neocortex (bottom row).

Treatment of Alzheimer’s disease involves non-pharmacological and pharmacological management. Non-pharmacological management involves caregiver education or use of behavioral techniques (2). Conversely, pharmacological management includes cognition-enhancing agents, treatment of behavioral abnormalities, and medical management of commonly encountered systemic disorders or complications of Alzheimer’s disease to optimize patient–caregiver interactions and minimize behavioral disturbances (2).

Figure 1. The pathological development of Alzheimer’s disease ascertained by molecular imaging techniques

Who are the Culprits?

Extensive research has pointed towards amyloid-β as the causative agent against Alzheimer’s disease pathology and results in astroglyosis, nerve cell atrophy and neuronal loss. Amyloid-β is a peptide consisting of about 40 amino acids, formed by the sequential cleavage of amyloid-β precursor protein, APP (4). According to a piece written by Kametani et al., in normal cell models, amyloid-β is cleaved from APP by β‑secretases or γ‑secretases and released outside of the cell, where it is then degraded or removed (5). However, in diseased conditions, specifically in Alzheimer’s disease, the metabolic ability to break down amyloid-β is decreased, initiating accumulation and the formation of aggregates or plaques (5). Amyloid-β 40 and amyloid-β 42 are the major components of the accumulated proteins. An increase in amyloid-β 40 and 42 induces amyloid fibril formation, which develop into plaques, causing neurotoxicity and induction of tau pathology (5).

The APP gene on chromosome 21 and the discovery of genetic mutations in early-onset familial Alzheimer’s disease has shown to support the amyloid hypothesis. Such mutations on APP are clustered near β‑secretase or γ‑secretase cleavage sites and are associated with elevation of amyloid-β 42 production and formation (5). Other inheritable Alzheimer’s mutations have been identified in presenilin, an element of g-secretase (5). Such polymorphisms in APP and presenilin are closely linked to aggregation of amyloid-β.

Apolipoprotien E or ApoE, is one of the major apoliproteins in the central nervous system. ApoE is produced and secreted by astrocytes and microglia (3). It then binds to lipoproteins and is absorbed by nerve cells through the ApoE receptor during the developmental stages of the central nervous system and during rapid repair of neuronal damage (3). ApoE has many isoforms including ApoE4, which is a common genetic risk factor for sporadic Alzheimer’s disease (3). As the number of ApoE4 genes increases, the age of onset of Alzheimer’s disease declines and the incidence increases (3). Studies have shown that impaired ApoE4 function impairs the clearance process of amyloid-β and controls amyloid-β-induced effects on inflammatory receptor signaling, including stimulation of detrimental processes and suppression of beneficial pathways (3).

Considering the highly significant association between the ApoE4 allele and late-onset familial Alzheimer’s disease, many studies have been conducted to determine the frequency of the gene in populations of Alzheimer’s patients. In a study conducted by Srittmatter et al., the allele frequency of the ApoE4 in 30 random affected patients, each from a different Alzheimer’s disease family, was 0.50 t 0.06 (6). The allele frequency of ApoE4 in 91 age-matched unrelated controls was determined to be 0.16 ± 0.03 (Z = 2.44, P = 0.014) (6). Such results suggests a  functional role of the apolipoprotein E isoform in the pathogenesis of late-onset familial Alzheimer’s disease. While many studies have linked ApoE to disease progression, the exact mechanism of how ApoE obstructs amyloid-β clearance is still undetermined.

Recent studies have pointed towards disease progression driven by the neurological damage to be induced by the aggregation of tau proteins. Inconsistencies in the amyloid-β hypothesis, such as the impact of plaques on neuronal death and plaque distribution have led researchers to believe that tau proteins are the primary instigators of neuron damage. Tau pathology more closely correlates to neuronal loss, both spatially and temporally, than amyloid plaques. According to Kametani et al., fibrillary amyloid-β accumulation occurs first and more severely in regions such as the precuneus and frontal lobes of the brain, while neuronal death begins in the entorhinal cortex and the hippocampus, regions with generally few amyloid-β plaques (3). It has been previously discovered that amyloid-β pathology begins in the cortex and spreads inwards, while tau pathology progresses oppositely, suggesting that amyloid-β may be a product of Alzheimer’s disease rather than a causative agent (3).

Tau are microtubule-associated proteins that regulate tubulin assembly stability. There are six tau isoforms, but aggregates of isoforms 3R and 4R tau are predominantly found in brains of patients with Alzheimer’s disease (3). Inclusions of tau are twisted fibrils with ~80 nms periodicity as paired helical filaments or straight filaments (3). Tau inclusions are also termed neurofibrillary tangles when they are formed in neuronal cell bodies (3) . Disease-causing mutations (which are currently not yet known) cluster near the C-terminal microtubule binding repeat and impact tau binding to microtubules, suggesting impairment of the regulation of microtubules.

While there have been many propositions on the pathway of how tau proteins lead to disease progression of Alzheimer’s, there is no clear understanding of the mechanism. In a study conducted by de Calignon et al., a mouse model of an early stage of neurofibrillary pathology was created to understand the sequence of events of how tau leads to the disease progression (7). The formation of tau tangles causes spreading to downstream connected neurons despite restriction of transgene expression (7). In addition, de Calignon et al. found that accumulation of misfolded tau favors severely slowed synaptic, axonal, and somatic degeneration sequentially (7).

Furthermore, certain studies have suggested that amyloid-β and tau proteins are associated and impact Alzheimer’s severity cooperatively. Figure 2 (below) by Musiek et al. demonstrate an amyloid-β and tau protein driven model for Alzheimer’s disease pathogenesis. Factors such as increased synaptic activity, sleep disruption, psychological stress, and genotype of proteins involving metabolism can disturb amyloid-β levels and induce aggregation (4). As aggregates accumulate, plaques develop – providing the preliminary biomarker of Alzheimer’s disease. Proceeding years of amyloid-β aggregation then causes acceleration of tau pathology, as neurofibrillary tangles that being to spread outside the limbic system into the neocortex, inducing more severe neurodegeneration (4). Such events may be facilitated by the production of toxic amyloid-β species, the activation of signaling processes or kinase cascade, or changes in the innate immune system (4).

Figure 2. Amyloid-β and tau protein driven model for Alzheimer’s disease pathogenesis

What are the solutions?

The rapid development of non-invasive tools and techniques for imaging human brains has enhanced the ability to further investigate and understand brain function. Structural and functional brain imaging, such as MRI, CT, and PET scanning, have profoundly influenced the understanding of early changes and symptoms of Alzheimer’s disease. Direct imaging of amyloid plaques in the brains of patients with Alzheimer’s disease has aided in early diagnosis and more effective and streamlined treatment.

According to Nordberg et al., studies in families with AD caused by mutations in APP and presenilin genes have displayed indications of structural changes and impairment of brain glucose metabolism at pre-symptomatic stages that are displayed years before clinical symptoms (8). PET imaging has permitted physicians to follow the progressive impairment of cerebral glucose metabolism in individuals with the mutation. Individuals with polymorphic ApoE allele display low rates of cerebral glucose metabolism in their brains decades before the onset of Alzheimer’s disease (9).

Figure 3 (below) displays a PET scan of an individual with the ApoE mutation with a tracer dose of 8F-fluorodeoxyglucose (8). PET studies were conducted before cognitive symptom (top row) were displayed and 40 months later (bottom row) when cognitive symptoms were expressed. The color scale indicates regional cerebral glucose metabolism. Red colors represent high levels of glucose metabolism and blue colors represent low levels. The top row displays high red color, correlating to the asymptomatic behavior of the patient (8). Conversely, the bottom row displays obvious decreases in red color and therefore decreased levels of glucose metabolism, suggesting the progression of the disease (8).

New strategies are now being developed to generate new compounds capable for in vivo imaging of amyloid-β plaques in human brains with Alzheimer’s disease. For example, radiolabeled amyloid-β antibodies and peptide fragments have been used to detect plaques; however, such techniques have displayed limited uptake by diseased brains (10). The most successful amyloid imaging has been seen using a small molecular approach. The binding of different derivatives of Congo red and thioflavin has been studied to be effective in human autopsy brain tissue and in transgenic mice (8).

In addition to technological advancements in brain imaging for more effective diagnosis procedures, non-pharmacological interventions for adults with mild cognitive impairment due to Alzheimer’s disease has been shown to improve brain function. According to a study conducted by Rodakowski et al., data has suggested that cognitive training concentrated on remediation and physical exercise may encourage improvements in cognitive abilities (11). Some patients with Alzheimer’s disease, especially older adults, have preferred non-pharmacological methods rather than pharmacological treatments to maintain cognitive function and independence (11). Additionally, pharmacological treatments can also impose adverse side-effects and can be more dangerous and hazardous to the overall health of the patient (11).

Cognitive remediation involves improving cognitive function through focused training and practice. For example, patients are trained to maintain independence, safety, or engagement in daily activities through the use of outside aids (11). In order to understand the impact of such techniques on the mental abilities of patients, assessments of memory after memorization training were conducted (11). In addition to memory training, verbal fluency, verbal learning, immediate and delayed memory, attention, information processing speed, and psychomotor speed are exercised and evaluated (11). Widespread studies of populations of patients of Alzheimer’s disease indicates that cognitive training concentrated on remediation has displayed significantly greater improvements in cognitive abilities (11). However, even though non-pharmacological measures have proven to be influential, there is not much evidence for the long-term maintenance and improvement on the effects of brain function of individuals suffering from the disease.

Although the prevalence of Alzheimer’s disease has increased greatly, there are only five approved drugs that have been shown to control symptoms, instead of amend the course of the disease. Because of pre-symptomatic effects of Alzheimer’s disease present themselves earlier than visible and diagnosable symptoms, pharmacological design and effectiveness has been challenging (12). As a result, drug treatments have focused on maintenance of comfort rather than preventative or curative measures (12).

Among the approved drug treatments for Alzheimer’s disease are Tacrine, Donepezil, Rivastigmine and Galantamine, all cholinesterase inhibitors (12). Each drug possesses faintly different pharmacological properties, but all inhibit the breakdown of acetylcholine, an important neurotransmitter involved with memory, by blocking the enzyme acetylcholinesterase (13). On average, effects of cholinesterase inhibitors on cognition and function are fairly slight and response rates are inconsistent. About one-third of patients display no benefit from the drug and a smaller proportion (one-fifth) showed more improvement (12). Additionally, about one-third of patients cannot tolerate a cholinesterase inhibitor because of its adverse side effects (12). It is believed that down-regulation of cholinergic transmission occurs too far downstream in the pathological process for disease treatments, such as cholinesterase inhibitors, to induce profound effects (12).

As an alternative to cholinesterase inhibitors, inhibitors of the NMDA receptor, such as Memantine, have been used to treat patients with Alzheimer’s disease. Memantine works by uncompetitively blocking the NMDA receptor. Such activity has implications of being neuroprotective by preventing neuron loss and improving symptoms of the disease by restoring the function of damaged neurons (12). Typically, Memantine has been used by physicians to treat patients with moderate to severe forms of the disease, with little evidence showing its efficiency on individuals with milder cases (12). Furthermore, Memantine is frequently prescribed concurrently with cholinesterase inhibitors, like Donepezil, for patients of mid-stage Alzheimer’s disease who display cognitive deterioration (12).

Although such drugs are the most effective and currently available pharmacologic treatments for the disease, they display very slight improvements and do not alter the rate of neuronal death and the neurodegenerative process. Potential future drug options are in the process of being developed and focus influencing more upstream factors in the pathological process. For example, anti-amyloid therapy targets neuronal damage by modifying the amyloid cascade (12). Additionally, monoclonal antibodies of amyloid-β have been shown to reduce the rate of amyloid accumulation in ApoE4 mutation carriers (12).

Figure 3. PET scan of an individual with the ApoE mutation with a tracer dose of 8F-fluorodeoxyglucose

 

 

Sources:

  1. “2017 Alzheimer’s Disease Facts and Figures.” 2017. Alzheimer’s & Dementia 13 (4): 325–73. https://doi.org/10.1016/j.jalz.2017.02.001.
  2. Masters, Colin L., Randall Bateman, Kaj Blennow, Christopher C. Rowe, Reisa A. Sperling, and Jeffrey L. Cummings. 2015. “Alzheimer’s Disease.” Nature Reviews. Disease Primers 1: 15056. https://doi.org/10.1038/nrdp.2015.56.
  3. Kametani, Fuyuki, and Masato Hasegawa. 2018. “Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer’s Disease.” Frontiers in Neuroscience 12. https://doi.org/10.3389/fnins.2018.00025.
  4. “Three Dimensions of the Amyloid Hypothesis: Time, Space and ‘wingmen’ | Nature Neuroscience.” n.d. Accessed April 11, 2018. https://www.nature.com/articles/nn.4018.
  5. Kametani, Fuyuki, and Masato Hasegawa. 2018. “Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer’s Disease.” Frontiers in Neuroscience 12. https://doi.org/10.3389/fnins.2018.00025.
  6. Strittmatter, W. J., A. M. Saunders, D. Schmechel, M. Pericak-Vance, J. Enghild, G. S. Salvesen, and A. D. Roses. 1993. “Apolipoprotein E: High-Avidity Binding to Beta-Amyloid and Increased Frequency of Type 4 Allele in Late-Onset Familial Alzheimer Disease.” Proceedings of the National Academy of Sciences 90 (5): 1977–81. https://doi.org/10.1073/pnas.90.5.1977.
  7. de Calignon, Alix, Manuela Polydoro, Marc Suárez-Calvet, Christopher William, David H. Adamowicz, Kathy J. Kopeikina, Rose Pitstick, et al. 2012. “Propagation of Tau Pathology in a Model of Early Alzheimer’s Disease.” Neuron 73 (4): 685–97. https://doi.org/10.1016/j.neuron.2011.11.033.
  8. Nordberg, Agneta. 2004. “PET Imaging of Amyloid in Alzheimer’s Disease.” The Lancet Neurology 3 (9): 519–27. https://doi.org/10.1016/S1474-4422(04)00853-1.
  9. Small, G. W., L. M. Ercoli, D. H. Silverman, S. C. Huang, S. Komo, S. Y. Bookheimer, H. Lavretsky, et al. 2000. “Cerebral Metabolic and Cognitive Decline in Persons at Genetic Risk for Alzheimer’s Disease.” Proceedings of the National Academy of Sciences of the United States of America 97 (11): 6037–42. https://doi.org/10.1073/pnas.090106797.
  10. Esler, W. P., E. R. Stimson, J. R. Ghilardi, H. V. Vinters, J. P. Lee, P. W. Mantyh, and J. E. Maggio. 1996. “In Vitro Growth of Alzheimer’s Disease Beta-Amyloid Plaques Displays First-Order Kinetics.” Biochemistry 35 (3): 749–57. https://doi.org/10.1021/bi951685w.
  11. Rodakowski, Juleen, Ester Saghafi, Meryl A. Butters, and Elizabeth R. Skidmore. 2015. “Non-Pharmacological Interventions for Adults with Mild Cognitive Impairment and Early Stage Dementia: An Updated Scoping Review.” Molecular Aspects of Medicine, Towards prevention and therapy of Alzheimer’s disease, 43–44 (June): 38–53. https://doi.org/10.1016/j.mam.2015.06.003.
  12. Briggs, Robert, Sean P. Kennelly, and Desmond O’Neill. 2016. “Drug Treatments in Alzheimer’s Disease.” Clinical Medicine 16 (3): 247–53. https://doi.org/10.7861/clinmedicine.16-3-247.
  13. Birks, Jacqueline S. 2006. “Cholinesterase Inhibitors for Alzheimer's Disease.” In The Cochrane Library. John Wiley & Sons, Ltd. https://doi.org/10.1002/14651858.CD005593.

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