Introduction
In the field of Alzheimer’s research, there are currently two contesting debates towards the causation of this hindering disease. The first, also known as the amyloid cascade theory, correlates the onset of Alzheimer’s to the deposition of an abnormal protein called amyloid-beta (Aβ) and stands as the most studied explanation of AD [
1]. Those who support this viewpoint have been known as “baptists.”
The second competing hypothesis, which is slowly gaining more attention, associates the onset of Alzheimer’s disease instead to fibrillary tangles called tau protein. Scientists in support of this theory, the “tauists,” are attempting to target and block tau hyperphosphorylation in Alzheimer’s patients in hopes of relieving the negative consequences of the disease.
New innovations, taking into account both perspectives, are changing the field of Alzheimer’s research. Whereas before scientific endeavors sought to target the disease in its later stages, now a more preventative approach is being undertaken in hopes of stopping the onset of the disease altogether. In support of either theory of AD, there is an overwhelming consensus that Alzheimer’s disease can exist in two distinct forms. These dichotomous variants consist of the more common late-onset Alzheimer’s (LOAD) and a more genetic form called early-onset Alzheimer’s (EOAD). Current research seeks to target either form in its earliest stages, even before the very first symptomatic signs of deterioration appear [
2].
The major risks for developing LOAD are the APOE ε4 gene and aging. Individuals carrying both alleles of this gene, as opposed to those who have the ε3 alleles, have a 50 % greater risk of developing the disease [
3,
4]. Researchers are also aware that individuals carrying both ε2 alleles have a 50 % reduced risk of ever contracting Alzheimer’s [
3,
4]. There are, however, other non-genetic predispositions towards the development of AD. These risk factors include various environmental or epigenetic stimulants like decreased hippocampal volume, being amyloid positive, or having a CSF marker for AD such as low CSF Aβ and increased/phosphorylated tau protein [
2]. We also now recognize that there may be several stages of the disease even before the development of AD is evident. Amyloid plaques may be seen in the brains of 20–30 % of normal older individuals through PET imaging and yet it may take years between an abnormal test and the development of AD [
5]. Evidence such as this confirms the existence of a pre-clinical form of AD called mild cognitive impairment (MCI). Slowly, the analysis of these abnormal CSF levels along with the evolving use of PET imaging scans to detect amyloid plaques are beginning to constitute the bio-markers for the clinical diagnosis of MCI due to AD and thus helping to provide the answers needed to halt the onset of dementia in patients.
Current Research
Although medical treatment will be an important component of AD management in the future, there are several encouraging trends towards early preventative measures to reduce the incidence of AD. Simple lifestyle changes such as 20 min of daily exercise, a Mediterranean diet, and early diagnosis and treatment of diabetes concurrent with low cholesterol levels all help decrease the risk of AD. Keeping the brain mentally active with tasks such as learning new languages, increased social interaction, and other complex learning processes have also been found to be essential remedies, which could aid in the prevention of Alzheimer’s disease.
However, these preemptive strategies are not always enough, especially for individuals who are genetically predisposed to Alzheimer’s. Here, medical innovations must take the lead instead, in hopes of relieving the strain the disease causes to both the patient and their family members. Yet although many drugs are currently in the pipeline for AD, no drugs have been successfully approved in the EU and the USA in almost 15 years. Current treatments available for Alzheimer’s disease in the market consist mostly of cholinesterase inhibitors such as donepezil, galantamine, and rivastigmine as well as the NMDA receptor uncompetitive antagonist memantine [
2]. These drugs, which are commonly referred to as symptomatic treatments, are only helpful for a limited time span in improving the cognitive abilities of patients with AD. Consequently, none of these drugs offer the long-term answers we are currently seeking: finding true disease modifiers. In light of this, the research being done on the formation of amyloid β and/or neurofibrillary tangles of tau protein aggregates is essential for finding a more stable, long-term answer for the longevity as well as mental and functional capabilities of individuals afflicted with Alzheimer’s disease. In the near future, this research will provide the answer to the cure and possible early prevention of Alzheimer’s disease.
The Baptists’ Perspective
Limitations and Future Directions of Amyloid PET in Clinical Practice
Amyloid imaging with PET scans has allowed for more confident diagnosis of AD and is being used much more frequently in clinical trials. The PET imaging scans can easily detect the presence of Aβ in the brain. Currently, most of the studies involving the amyloid cascade theory make strategic use of PET scans in the determination of possible research participants. These amyloid PET scans have thus become a recent commodity in the diagnosis of possible AD onset in research subjects. Following the success of this early diagnosis, tau tracers are also currently under development. However, while amyloid PET scans are becoming an invaluable research and diagnosis tool, several improvements and impediments still exist. While the beneficial outcomes of PET have been a clear-cut distinction in clinical trials, US Medicare does not yet cover its full cost of $3500 for diagnostic practices [
5]. If amyloid PET scans become more common in the diagnosis of AD in patients not participating in clinical trials, then they need to become more cost effective as well. Moreover, the implementation of more quantitative measures would be a strong asset as the PET scans currently only indicate if an individual is amyloid positive or negative. More prognostic data, such as a percentage measurement of an individual’s amyloid plaque burden, can be a helpful tool in future research initiatives. However, the biggest impediment with the success of amyloid PET scans seems to be the lack of effective therapeutic intervention. Even if patients test amyloid positive, we currently lack the instrumentations necessary to implement the appropriate follow-up treatments to stop the neurodegenerative progression of the disease.
The Tauist Outlook
Hyperphosphorylation of a microtubule-associated protein known as tau leads to the formation of neurofibrillary tangles in neurons. Neurofibrillary tangles aggregate, or group, in an insoluble form in neurons affecting normal neuronal functions. Several molecules are involved in the phosphorylation of tau including the kinases namely the glycogen synthase kinases (GSK-3) and cyclin-dependent protein kinase (CDK). While studies involving these molecules are further behind those that target the amyloid cascade theory, there have been some promising starts with compounds aimed at inhibiting the tau pathways in novel ways. Several compounds have been developed such as valproate, lithium, and Methylene blue [
26]. Other innovative efforts have also begun in the development of anti-tau vaccines.
Conclusion
Moving forward, we recognize that, potentially, single agents will not be effective in the treatment of Alzheimer’s disease. Instead, the answers sought in this multifactorial disease involving multiple pathways and pathologies can be found in a combination of clinical methodologies and discoveries. The more we fail at single protein-targeted therapies, the more we lean towards a belief that AD is a heterogenic, complex disorder with deregulation of multiple pathways due to genetic, epigenetic, and environmental reasons. Hence, AD needs to be approached using a systems biology/genomic/transcriptomic/proteomic method to get a more comprehensive picture of the cause, effect, and treatment options. Combinational therapies targeting both Aβ accumulation and tau protein malformation may just be the answer so sought after for AD research. Already, PET imaging has given both researchers and physicians a more viable way towards the diagnosis of Alzheimer’s. As future studies are concluded and more information is gathered, the efficacy of Alzheimer’s treatment will be greatly improved.
The epidemic of AD is near at hand. Unfortunately, to date, no new compounds have achieved FDA or EMA approval in the last decade and a half. The stakes are high for a drug to cross this barrier. Several hundred compounds are now under development and almost 200 trials on the way. The scientific and pharmaceutical industries are aligned with millions of dollars being poured into AD research. The scientific knowledge has made significant progress and we may look forward to breakthroughs in the next decade.
Compliance with Ethics Guidelines
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