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Multi-discipline-Integrated Research and Development for the Treatment of Alzheimer’s Dise
| 작성자 | 관리자 | 카테고리 | 전문가 인사이트 |
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| 작성일 | 2016-09-09 | 조회수 | 3,880 |
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Multi-discipline-Integrated Research
and Development for the Treatment of
Alzheimer’s Disease in our Generation
- 글 이희민(Heemin Rhee)
- GPKOL위원
컨설팅 분야
- 당뇨, 지질저하, 호르몬 및 CNS 조절 심장 기능 장애 등의 신진대사 및 심혈관계 질병치료를 위한 신약 및 바이오로직스(biologics) 발굴/개발 천연물 신약 글로벌 마케팅
주요 약력
- 2011-Present: President, Health Research International, North Potomac, MD, U.S.A.
- 2008-2010: Principal Investigator, International Scientific Standard, Inc., Chuncheon, Korea
- 1990-2008: DMEP/OND/CDER, Food and Drug Administration, Silver Spring, MD, U.S.A..
- 1990-1991: Visiting Professor, Howard University Medical School, Washington D.C. , U.S.A.
- 1980-1990: Associate Professor, Oral Robert University Medical School, Tulsa, OK
1. Introduction
Five million Americans and nearly 47 million people worldwide are suffering from Alzheimer’s disease (AD) or a related form of dementia. AD is the sixth leading cause of death in the United States, of which mortality cannot be prevented or cured currently. The disease, irreversibly fatal, and the number of affected patients will be more than triple by 2050. The number of individuals caring for Alzheimer’s patients reached 15.7 million in 2014, providing nearly 18 billion hours of unpaid care valued at more than $217 billion. Fig. 1 shows the estimated healthcare cost of dementia and global distribution of dementia patients.
The brains of Alzheimer’s patients are ridden with tangles and plaques. The tangles are made up of a protein called tau, and the plaques are consisted of amyloid beta (Aβ). However, research scientists do not know exactly what cause the disease because of the complex interactions of the tau tangles, amyloid plaques, and neurotransmitters such as acetylcholine, dopamine and insulin in the central nervous system. Investigators need to develop ways to make an earlier diagnosis and then design trials to test drugs against Aβ and tau buildup. Learning difficulties and memory problems have been reported to occur in affected children, too.
Mild traumatic brain injury accelerates Aβ deposition, tau pathology, and cognitive deficits in transgenic AD mice and further leads to neurodegeneration and cognitive deficits in immature rats. Traumatic brain injury may further lead to AD, as evidenced by elevated production of Aβ in such events. Insulin signaling in human brain also declines with age. This deficiency may be a consequence of decreased insulin uptake into the brain following sustained peripheral hyperinsulinemia. While we currently cannot prevent or cure AD, delaying the onset of symptoms by 10–15 years would make a difference to our patients, to their families and caregivers, and to the global economy.
It has come to the attention of many scientists in recent years that many of these biological perturbations have a link to human microbiome, either directly or indirectly. Microbiome sites vary and exert an enormous influence on the human body. Researchers are now beginning to establish the link between these diverse microbial communities and important pathways such as the immune and nervous systems. Gut microbes, along with the metabolites that are produced from our diets, have a significant impact on the brain such that their effects could play a role in increasing the risk for neurodegenerative disorders such as AD and Parkinson’s Disease (PD) in genetically vulnerable individuals.
Over hundred drug applications, U.S. FDA has approved only five drugs to treat the symptoms of AD, but there is no cure for the AD (Fig. 2). Four drugs are known as cholinesterase inhibitors and are working like Cognex (tacrine). 99.6 % of Alzheimer’s agents tested in the decade between 2002 and 2012 failed in clinical trials and the high failure rate is due to complicated neurochemical and pathological interactive mechanisms that we do not know fully understand at this time. Thus, in this paper, I will briefly review the current epidemiology and neuropathology of AD, the detrimental or beneficial mechanisms of Tau, Aβ, and brain insulin in relation to our systemic microbiome for expedited development of biopharmaceuticals for AD treatment. In particular, the potential role of central insulin for AD pathophysiology will be discussed including several cases studies for AD clinical trials are included as the page spaces are allowed.
II. Epidemiology of AD
The World Health Organization’s review in 2000 on the Global Burden of Dementia, which was an integrative analysis of 47 surveys across 17 countries, suggested that approximate rates for dementia from any cause are under 1% in persons aged 60-69 years, rising to about 39% in persons 90-95 years old. The prevalence doubles with every 5 years of age within that range, with few differences taking into account secular changes, age, gender, or place of living.
The most common form of dementia, Alzheimer disease (AD) affects approx. 5.3 million people in the U. S. alone, and that number is projected to reach 13.8 million by the year 2050. A larger number of individuals have decreased cognitive function, which frequently evolves into full-blown dementia. Economically, AD is a major public health problem. In the U. S. in 2015, the cost of health care, long-term care, and hospice services for people aged 65 years and older with AD and other dementias was expected to be $226 billion, and this figure does not include the contributions of unpaid caregivers. By 2050, these costs could rise as high as $1.1 trillion. Currently, an autopsy or brain biopsy is the only way to make a definitive diagnosis of AD.
The prevalence of AD increases with age. AD is prevalent in individuals older than 60 years. Some forms of familial early-onset AD can appear as early as the third decade, but familial cases constitute less than 10% of AD overall. Sex-dependent prevalence of AD is not clear, but almost two thirds of Americans with AD are women. Among AD patients overall, any sexual disparity may simply reflect women’s higher life expectancy. Pertaining to the racial basis of AD development, in individuals 65 years of age and older, 7.8% of whites, 18.8% of African Americans, and 20.8% of Hispanics have AD or other dementias, although more studies are necessary for the accurate statistical data from other worldwide races.
III. Current R&D for Alzheimer’s Disease
IIIa. Amyloid Plaques and Neurofibrillary Tangles (NFTs)
Healthy neurons have an internal support structure partly made up of subcellular microtubules, which act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon. A special kind of protein, tau, binds to the microtubules and stabilizes them. Plaques are dense, mostly insoluble deposits of protein and cellular material outside and around the neurons. Plaques are made of Aβ, a protein fragment snipped from a larger protein called amyloid precursor protein (APP) as shown(Fig. 3). These fragments clump together and are mixed with other molecules, neurons, and non-nerve cell, which is the major component of the plaques that develop in the brains of people with AD and is associated with nerve cell death.
In AD, tau is changed chemically by pairing with other threads of tau, which become tangled together. When this happens, the microtubules disintegrate, collapsing the neuron’s transport system. The formation of these NFTs may result first in malfunctions in communication between neurons and later in the death of the cells. The plaques develop in the hippocampus, and whether Aβ plaques themselves cause AD or whether they are a by-product of the AD process is still debated, although changes in APP structure can cause a rare, inherited form of AD. There are likely to be significant age-related differences in the extent to plaques and NFTs.
Although most cases of AD are not inherited, familial forms of AD do exist. Autosomal dominant AD, which accounts for less than 5% of cases, is almost exclusively early onset AD; cases occur in at least 3 individuals in 2 or more generations, with 2 of the individuals being first-degree relatives. Familial clustering represents approx. 15–25% of late-onset AD cases and most often involves late-onset AD. In familial clustering, at least 2 of the affected individuals are third-degree relatives or closer. Mutations in the following genes unequivocally cause early-onset autosomal dominant AD. The APP gene on chromosome 21, the presenilin-1(PS1) gene on chromosome 14 and the presenilin-2 (PS2) gene on chromosome 1. All the three genes lead to a relative excess in the production of the stickier 42-amino acid form of the Aβ peptide over the less sticky 40-amino-acid form.
IIIb. Recent Debate on NFTs and Aβ for the Cause of AD
A new study was conducted with 36 control participants who were cognitively normal and 10 patients with mild AD. The study has helped establish that the new tau imaging agent, called T807, is an important tool for understanding the timeline of AD's progression and for defining which regions of the brain are involved. The findings were published recently in Science Translational Medicine. Investigators need to develop ways to make an earlier diagnosis and then design trials to test drugs against amyloid and tau buildup. While they currently cannot prevent or cure AD, delaying the onset of symptoms by 10–15 years would make a huge difference to the patients, to their families and caregivers, and to the global economy. The new tool is vital to gathering spatial information about affected brain areas. Elevated tau measured in cerebrospinal fluid has long been a marker of dementia; however, this type of data could not pinpoint which parts of the brain were gathering abnormal proteins.
IIIc. Central Nerve Cholinergic System and AD
Cholinergic deficiency has been implicated in the cognitive decline and behavioral changes of AD. Activity of the synthetic enzyme choline acetyltransferase (CAT) and the catabolic enzyme acetylcholinesterase are significantly reduced in the cerebral cortex, hippocampus, and amygdala in patients with AD. Loss of cortical CAT and decline in acetylcholine synthesis in biopsy specimens have been found to correlate with cognitive impairment and reaction-time performance. Because cholinergic dysfunction may contribute to the symptoms of patients with AD, enhancing cholinergic neurotransmission constitutes a rational basis for symptomatic treatment. The cholinergic system is involved in memory function, which is well documented enough the FDA has approved four acetylcholine esterase inhibitors (AChEIs) for the AD symptomatic relieve.
IIId. Role of CNS Insulin for AD Development
Brain cells use sugar for energy, but the brain cannot make sufficient amount of insulin that is needed in AD patients. The efficiency of getting energy from the rest of the body to the brain is a critical component of the brain's ability to function. AD reduced brain-insulin signaling as well as lower levels of insulin in the spinal fluid. Restoring normal insulin function to the brain might benefit patients with memory declines. 109 AD patients or mild cognitive impairment were treated with either 20 or 40 IU of intranasal insulin daily or placebo. Over the next four months, most placebo-treated patients showed declines in cognitive functioning, while most insulin-treated patients did not.
AD patients have elevated insulin levels in their cerebrospinal fluid (CSF) under fasting conditions. However, more recent studies demonstrated that CSF insulin levels are decreased in patients with mild AD. A high saturated fat and high glycemic diet was found to lower CSF insulin concentrations in healthy adults, corroborating the possibility that physiological mechanisms result in decreased brain insulin levels following peripheral hyperinsulinemia. Interestingly, impaired insulin sensitivity has been linked to cognitive deficits and structural and functional brain deficits in the elderly. Proteins that influence the development and progression of AD are suppressed by insulin, a new treatment strategies for AD. Rates of AD are nearly twice as high among patients with obesity or type 2 diabetes (T2DM) compared to a general population due to a combination of factors: vascular dementia, impaired insulin metabolism and signaling pathways, and dysfunctional glucose transport to the brain. Several studies have supported a causal link between insulin resistance or impaired insulin response, even early in life, with the development of AD (Fig. 4). Insulin, insulin receptors and their transporters are densely located in areas of the brain that support memory function.
Accumulating evidence indicates a role for metabolic dysfunction in the pathogenesis of AD. T2DM increases the risk of developing AD, and several postmortem analyses have found evidence of insulin resistance in the AD brain. Thus, insulin-based therapies have emerged as potential strategies to slow cognitive decline in AD. The main methods for targeting insulin to date have been intravenous insulin infusion, intranasal insulin administration, and use of insulin sensitizers. These methods have elicited variable results regarding improvement in cognitive function. Targeting insulin signaling to improve cognitive function in AD and what these results mean for future studies of the role of insulin-based therapies for AD are challenging.
A small study also implies that insulin resistance, as evidenced by decreased cerebral glucose metabolic rate measured by a specific type of positron emission tomography (PET) scan, may be useful as an early marker of AD risk, even before the onset of Mild Cognitive Impairment (MCI). The PET scan revealed a qualitatively different activation pattern in patients with prediabetes or T2DM during a memory encoding task, as compared with healthy individuals who were not insulin resistant. A study by Schrijvers et al in a larger population (3,139 subjects) found a similar association between insulin resistance and AD over 3 years, which then disappeared after that time. These researchers used a different measure of insulin resistance, the homeostasis model assessment. Disturbances in insulin metabolism may not cause neurological changes but may influence and accelerate these changes, leading to an earlier onset of AD.
IIIe. Other Potential Problems for AD
Oxidative stress is believed to be a critical factor in normal aging and in neurodegenerative diseases such as Parkinson disease, amyotrophic lateral sclerosis, and AD. Formation of free carbonyls and thiobarbituric acid-reactive products, an index of oxidative damage, are significantly increased in AD brain tissue compared with age-matched controls. Plaques and tangles display immunoreactivity to antioxidant enzymes.
IIIf. Effects of Microbiome on Amyloid beta(Aβ) & AD
Microbiota that lines the entirety of the human GI tract comprises approx. 1,014 microbes with a collective biomass around two kilograms. The ratio of microbial to eukaryotic cells of the human body is still in contention, with estimates ranging as high as two to ten times. As for the microbiome, the bacteria of the gut alone originate from over 1,000 different species and encode more than three million genes, far exceeding that of the human genome by 150-fold. A range of physical and biochemical barriers exist to differentiate regions of the gut microbiota, with the spatial distribution of microbes increasing in diversity from the stomach through to the colon.
The composition of microbes in the gut could influence the number and size of the amyloid plaques characteristic of AD, possibly by affecting brain inflammation, although the bacterial composition of the gut can influence brain amyloid levels is notable. The gut microbiome has been implicated in immune and brain function so that the newly launched Microbiome Center in the U.S. may pursue further the potential connections between microbes and AD. A recent study demonstrates that Aβ can function as an antimicrobial peptide, and additional data show that bacteria and yeast can seed Aβ deposition into amyloid, which suggests a complex interplay between the normal function of Aβ, its accumulation in the brain, and host immune defense. Microbiome sites vary and exert an enormous influence on the human body. Researchers are now beginning to establish the link between these diverse microbial communities and important pathways such as the immune and nervous systems.
In a study, scientists used a mouse model of AD that carries two human mutations, forms plaques of accumulated Aβ in the brain, and has glia that invade the brain in response to damage. Treating these mice early in life and long-term with broad-spectrum antibiotics changed their gut microbiomes, though not the overall number of bacteria, compared to controls. Antibiotic-treated mice also had fewer and smaller Aβ and more soluble form in their brains compared with untreated AD mice. In addition to having a different profile of inflammatory markers in the blood, the brains of antibiotic-treated mice showed less intense inflammatory responses—less reactive glial cells and fewer astrocytes—compared to untreated animals. Follow-up metagenomics studies will reveal bacterial compositions in the mice that could, in turn, hint at the metabolites they are producing. They identify these bacterial metabolites and reconstitute a germ-free mouse to see whether they have a direct effect on the brain function. Antibiotics represent a means to perturb the microbiome in these mice, not a treatment for AD.
IV. AD Progress, Diagnosis and Biomarkers
The growing number of plaques and tangles first damage areas (Fig. 5) of the brain that control memory, and language. Later in the disease, physical abilities decline. In efforts to improve the accuracy with which AD can be diagnosed in living individuals, several neurodegenerative biomarkers (eg, from structural magnetic resonance imaging [MRI] and fluorodeoxyglucose [FDG]–positron emission tomography [PET]) and pathophysiologic biomarkers (eg, from amyloid PET and cerebrospinal fluid [CSF] analysis) are now increasingly being used in clinical settings.
Clinical guidelines for the diagnosis of AD have been formulated by the National Institutes of Health-Alzheimer’s Disease and Related Disorders Association (NIH-ADRDA), the American Psychiatric Association, in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM5); and the Consortium to Establish a Registry in Alzheimer’s Disease (CERAD). In 2011, the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) workgroup released new research and clinical diagnostic criteria for AD.
Early diagnosis and treatment allows AD patients to maintain the highest levels of cognitive and functional ability possible. Cholinesterase inhibitors (ChEIs) and mental exercises are used in an attempt to prevent or delay the deterioration of cognition in patients with AD. Imaging agents that bind to Aβ plaque may be useful in the diagnosis of early onset dementia. For a few examples, Florbetapir F 18 (AMYViD) is radioactive diagnostic agent for use with PET brain imaging. Binds to Aβ neuritic plaques and the F 18 isotope produces a positron signal that is detected by a PET scanner. Flutemetamol F 18 (Vizamyl) is a radioactive diagnostic agent for use with PET brain imaging that binds to Aβ neuritic plaques, which can be detected by a PET scanner. Lastly, Florbetaben F 18 (Neuraceq) is a radioactive diagnostic agent for use with PET brain imaging, which binds to Aβ neuritic plaques that can be detected the same way.
V. Biopharmaceutical Development for AD Treatment
Five drugs are approved by FDA to treat the symptoms of AD, but there is no cure for the disease. Four drugs are known as cholinesterase inhibitors (ChEIs). Cognex (tacrine), Exelon (rivastigmine), and Razadyne (galantamine) are approved for mild-to-moderate AD. Aricept (donepezil) is approved to treat all degrees of severity of AD from mild to severe. Cholinesterase inhibitors prevent the breakdown of acetylcholine, a chemical that nerves use to communicate with each other. Alzheimer's Disease Neuroimaging Initiative Project at the National Institute on Aging (NIA) of NIH indicated that the drugs may help delay or decrease the severity of symptoms for a limited time in some people. Side effects of cholinesterase inhibitors are gastrointestinal, such as nausea and diarrhea.
Numerous lines of evidence suggest that cholinergic systems that modulate information processing in the hippocampus and neocortex are impaired early in the course of AD. These observations have suggested that some of the clinical manifestations of AD are due to loss of cholinergic innervation to the cerebral cortex. Centrally acting ChEIs prevent the breakdown of acetylcholine. All ChEIs have shown modest benefit on measures of cognitive function and activities of daily living. Patients on ChEIs have shown slower declines on cognitive and functional measures than patients on placebo. However, ChEIs do not address the underlying cause of the degeneration of cholinergic neurons, which continues during the disease. The ChEIs may also alleviate the noncognitive manifestations of AD, such as agitation, wandering, and socially inappropriate behavior.
The fifth drug that the FDA approved is Namenda (memantine) for moderate-to-severe AD. The mechanism of action of Namenda is believed to block the action of glutamate, a brain chemical that may be overactive in people with AD. Namenda may help some patients maintain certain daily functions a little longer. Namenda can be used in combination with ChEIs. A few new AD drugs are: LMTX of TauRx company is supposed to block the activity of a bodily protein that many neuroscientists believe contributes to the brain-destroying effects of Alzheimer’s. The treatment is still being tested in a second study, involving about 700 people, with final data expected later this year. Annexon is to make antibodies that inhibit a protein called C1q, which is a part of the innate immune system. C1q helps identify the ones needed for removal, and helps trigger certain cellular processes that inactivate harmful elements. As we age, the problem is that C1q accumulates on synapses and removes ones we need for normal neuronal function, which might be useful for a host of neurodegenerative diseases.
The FDA designates Phase 3-stage AZD3293 for Fast Track review lately for the treatment of early AD, which inhibits beta secretase cleaving enzyme (BASE) and plays a key role in the formation of myelin sheaths in peripheral nerve cells. Inhibiting BACE will prevent the accumulation of Aβ and slow the progression of AD. An exciting finding was presented in recent Alzheimer’s conference in Toronto. Researchers showed that when healthy older adults played a specific computer brain-training game, they cut their risk for dementia. But treatments that arrest the disease’s progression have been elusive because scientists can’t even understand the pathotoxicological mechanism(s) of AD.
VI. Summary and Conclusions
The exact cause(s) of AD and its progress in human brain are unknown. That is the fundamental reason why the U.S. FDA has approved only five AD agents out of 126 commercial applications. Several investigators now believe that converging environmental and genetic risk factors trigger a pathophysiologic cascade that, over decades, leads to Alzheimer pathology. Risk factors for Alzheimer-type dementia are: advancing age, family history APOE 4 genotype, obesity, insulin resistance, vascular factors, dyslipidemia, hypertension, inflammatory markers, down syndrome, and traumatic brain injury, as we reviewed partially and briefly.
Mid life hypertension is an established risk factor for late-life dementia, of which AD is the most common type. A brain autopsy study evaluating the link between hypertension and AD found that patients using beta-blockers to control blood pressure had fewer Alzheimer's-type brain lesions on autopsy compared to patients taking no drug therapy or those taking other medications. We need not only basic and clinical research on AD, but also need badly for accurate biomarkers for AD. The new tool is vital to gathering spatial information about affected brain areas. Elevated tau measured in cerebrospinal fluid has long been a marker of dementia, although this type of data could not pinpoint which parts of the brain were gathering abnormal proteins. The new agent is approved for use in the context of clinical trials and likely will prove to be important in imaging the brain for other types of disorders that also involve excess tau buildup, including traumatic brain injury.
It is well known that the composition of microbes in the gut could influence the number and size of the amyloid plaques characteristic of AD. The gut microbiome has been implicated in immune and brain function so that scientists investigated the effects of broad-spectrum antibiotics in animals to find that antibiotic-treated mice had fewer and smaller Aβ and more soluble form in their brains compared with untreated AD mice, which indicated gut microbiota can influence on the central neurotransmitters’ biometabolism and subsequent actions or reactions with the CNS pathophysiology of AD.
Study of Nasal Insulin to Fight Forgetfulness (SNIFF) clinical trial (Phase II/III) will examine whether a type of insulin, when administered as a nasal spray, improves memory in adults with a mild cognitive impairment or AD. The study may also provide evidence about how intranasal insulin works in the body. Normal insulin regulation is essential for healthy cognitive functioning, and impaired insulin regulation leads to cognitive and memory deficits seen in AD. Also, insulin regulates proteins such as APP involved in the pathophysiology of AD, which is associated with the formation of the hallmark plaques in the brains of AD patients. And insulin moderates the metabolism of the protein tau, the building block of neurofibrillary tangles, another distinctive finding in AD. The plaques and tangles lead to neurodegeneration and loss of cognitive function in AD and demensia.
Few side effects other than runny nose and occasional feelings of lightheadedness were reported in the insulin-treated patients. The researchers also conducted lumbar punctures on 23 patients at the beginning of the study and following treatment to look for abnormal proteins associated with AD in the spinal fluid. They found lower levels of some of these proteins in the fluid of insulin-treated patients who also had improved memory and functional status scores. A connection between impaired insulin use and regulation, such as obesity and T2DM, and AD, but the mechanism of association has not been well-defined.
We have discussed briefly neuropathology of AD and current research on Aβ plaques and tau neurofibrillary tangles. Particularly, the roles of central insulin and gut microbiome are notable in relation to AD progress, its alleviation and/or aggravation. Considering the fact that brain insulin has to cross the blood brain barrier and brain may synthesize insulin, more research is justified to its specific central action for the prevention or/and treatment of AD. At the same time, human gut microbiome produces neurotransmitters, hormones and proteins, which may affect numerous human physiology as well as pathological processes such as AD.
To minimize our current failure rate of AD drugs, quality of preclinical studies are absolutely required by focusing the AD pathological progress that is essential for the prediction of valid target agents. The preclinical studies would be expedited if sensitive suitable animal models of human AD. Selective long-term clinical studies with statistically valid data collections should be designed to confirm the safety and efficacy of the AD drug products, which requires sensitive analysis biomarkers to provide stages of AD in different ages and races. All these studies are complicated that a single drug company or institute alone cannot carry out the AD R&D, which requires multi-disciplinary collaboration from various countries. Sharing integrated knowledge and data to speed up the identification and validation of promising neurobiological targets to foster development of treatments for AD is highly recommended.
VII. References
- Alzheimer’s Association. Alzheimers Dement. 2015 Mar. 11 (3):332-84. [Medline]
- Plassman BL, et al. Neuroepidemiology. 2007. 29(1-2):125-32
- Genin E, et al. Mol Psychiatry. 2011 Sep. 16(9):903-7. [Medline]
- Szekely CA, and Zandi PP. CNS Neurol Disord Drug Targets. 2010 Apr. 9(2):132-9. [Medline]
- Goldman JS, et al. Genet Med. 2011 Jun. 13(6):597-605. [Medline]
- Baker LD, et al. Arch Neurol. 2011 Jan. 68(1):51-7. [Medline]
- Schrijvers JCM, et al. The Rotterdam Study. Neurology. 2010;75:1982-1987
- Salomone S, et al.. Br J Clin Pharmacol. 2011 Oct 28. [Medline]
- Kavanagh S, et al. Acta Neurol Scand. 2011 Nov. 124(5):302-8. [Medline]
- Kumar DK, et al.: Sci Transl Med. 2016 May 25;8(340)
- Minter MR et al. Scientific Reports 6: 30028 (2016)
- Knopman DS, et al. Guideline. Neurology. 2001 May 8. 56(9):1143-53. [Medline]
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Ⅷ. Abbreviations
- Alzheimer’s disease (AD)
- Parkinson’s Disease (PD)
- Amyloid beta (Aβ)
- Neurofibrillary Tangles (NFTs)
- Choline acetyltransferase (CAT)
- Acetylcholine esterase inhibitors (AChEIs)
- Presenilin-1(PS1)
- Presenilin-1(PS2)
- Cerebrospinal fluid (CSF)
- Type 2 diabetes (T2DM)
- Mild Cognitive Impairment (MCI)
- Positron emission tomography (PET)
- Beta secretase cleaving enzyme (BASE)
- Study of Nasal Insulin to Fight Forgetfulness (SNIFF)
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