**2.3.4 [18F]Florbetapir ([18F]AV-45 or Amyvid)**

[18F]Florbetapir ([18F]AV-45, (E)-2-(2-(2-(2-[18F]fluoroethoxy)ethoxy)ethoxy,)-5-(4 methylaminostyryl)pyridine, Amyvid) was recently developed by Avid Radiopharmaceuticals. As a fluoropegylated stilbene derivative, [18F]Florbetapir is similar in structure to [18F]florbetaben, but the stilbene backbone has been replaced with a styrylpyridine core (Zhang, et al., 2007; Zhang, et al., 2005a). [18F]Florbetapir was chosen from a small number of 18F-labeled styrylpyridine analogs due to its optimum *in vivo* kinetics and high selectivity for Aβ plaques (Zhang, et al., 2007). Pre-clinical characterization of [18F]florbetapir demonstrated that this radiotracer has excellent binding affinity (Kd=3.72±0.30 nM) to Aβ aggregates, moderate lipophilicity, high initial brain uptake (7.33±1.54% injected dose per gram at 2 min post-injection) and rapid washout kinetics (1.88±0.14% injected dose per gram remaining in the brain 60 minutes post injection) in normal mice and primate brain (Choi, et al., 2009). Additionally, as supported by *in vitro* autoradiography of *post-mortem* human brain tissue sections and *ex vivo* autoradiography of transgenic mouse brain, [18F]florbetapir selectively labels fibrillar Aβ plaques, but not tau NFTs (Choi, et al., 2009; Choi, et al., 2011). Non-specific binding is low or non-existent. This spatial distribution of [18F]florbetapir uptake is similar to the pattern observed for [18F]florbetaben (Zhang, et al., 2005b).

Favorably, [18F]florbetapir also exhibits fast brain kinetics comparable to that of [11C]PiB (McNamee, et al., 2009). The signal-to-noise ratio for this radiotracer asymptotes at 50-60

Diagnosis of Dementia Using Nuclear Medicine Imaging Modalities 211

cognitively intact healthy subjects have increased tracer uptake (W. E. Klunk, et al., 2004;

Lin and co-workers presented similar results for [18F]florbetapir in a clinical study, using 6 healthy controls and 3 AD patients (Lin, et al., 2010). Tracer uptake was particularly high in the frontal, parietal, and occipital cortices of AD patients; healthy controls showed substantial non-specific binding in subcortical white matter. Consequently, simple semiquantitative measures (SUVRs with the cerebellum as the reference region) could be used to discriminate between AD patients and healthy controls. Of importance, one AD patient showed little uptake of the radiotracer, similar to the binding pattern of healthy controls. This negative scan may be due to a lack of tracer sensitivity, but more likely is indicative of a

In 2011, Clark *et al.* published the results from the first study of its kind, comparing the efficacy of an Aβ PET imaging agent against the golden standard of neuropathology confirmation at autopsy (Clark, et al., 2011b). This study included individuals near end of life who consented to donating their brain after death. Thirty-six subjects with clinically diagnosed AD were included in the autopsy cohort (but only 29 were included in the primary analysis) while 74 young healthy controls were in the non-autopsy cohort. All 74 young healthy controls were found to have a [18F]florbetapir-negative scan. For the primary analysis autopsy cohort, visual assessment scores of [18F]florbetapir scans and average neocortical and regional SUVRs (cerebellum as reference region) correlated well with *postmortem* amyloid pathology (as measured by immunohistochemistry and silver stain neuritic

Interestingly, only 15 participants met pathological criteria for AD in the primary analysis autopsy cohort. Of these 15 participants, 14 had [18F]florbetapir PET scans visually assessed as positive, giving a sensitivity of 93%. Fourteen participants in the primary analysis autopsy cohort had histologically-confirmed low levels of Aβ aggregation at *post-mortem* and thus did not meet the criteria for AD. All 14 participants had [18F]florbetapir-negative scans, leading to a specificity of 100%. This study also cited good interreader agreement among the three nuclear medicine physicians who visually rated the [18F]florbetapir PET images (0.68≤κ≤0.98). While these Phase III results are very promising, Clark cautioned that this study does not explicitly highlight the specific clinical applications of this imaging agent. Currently, only a [18F]florbetapir-negative scan is considered clinically useful, as it can help rule out the presence of pathologically significant levels of Aβ in the brain and thus AD pathology. [18F]Florbetapir cannot, however, diagnose AD because cerebral amyloid deposition is not specific to this diagnosis. Due to encouraging results from its Phase III clinical study, Avid Radiopharmaceuticals (now a sub-company under Eli Lilly and Company) filed for FDA approval of [18F]florbetapir in late 2010 (Sullivan, 2011). In a vote of 13-3, the Peripheral and Central Nervous System Drugs Advisory Committee did not recommend approval of [18F]florbetapir in January 2011, citing high inter-reader variability and the lack of a single clinically applicable binary reading method as outstanding issues (Sullivan, 2011). The advisory committee did, however, subsequently vote 16-0 in favor of approval if Avid were to implement reader-training programs (Sullivan, 2011). Such

The committee's decision was partially based on the results presented in the study by Clark and co-workers (Clark, et al., 2011b). Upon independently analyzing the critical individual reader score data, the FDA found substantial inter-reader variability among independent, extensively trained readers of [18F]florbetapir PET scans for individuals in the autopsy

Mintun, et al., 2006; Morris, et al., 2009; Rowe, et al., 2007).

low Aβ load in this clinically diagnosed AD patient.

implementation is currently in progress.

plaque score).

minutes post injection and remains stable until at least 90 minutes post-injection (Wong, et al., 2010); contrastingly, both [18F]flutemetamol and [18F]florbetaben reach maximum effect size at 85-90 minutes post injection (Barthel, et al., 2010; Nelissen, et al., 2009). This property of [18F]florbetapir creates a large time-frame to obtain a 10 minute image and allows for shorter imaging times, if necessary. Moreover, [18F]florbetapir has a good safety profile and biodistribution. The typical administered dose is 382.0±14 MBq (10.3±0.38 mCi), and the effective dose is 6.66±0.38 mSv using an administered dose of 370 MBq (whole-body effective dose conversion factor = 18.0±1.01 μSv/MBq) (Lin, et al., 2010). As expected, [18F]florbetapir delivers a higher radiation burden than [11C]PiB, but still within the normal range for 18F-labeled radiopharmaceuticals (O'Keefe, et al., 2009); and thus it remains suitable for clinical imaging applications.

Clinical studies of [18F]florbetapir have consistently shown its high discriminatory power in being able to differentiate between AD patients, patients with amyloid positive and amyloid negative MCI, and healthy controls (e.g. Figure 2) (Lister-James, et al., 2011). For example, in a study of 15 elderly healthy controls and 11 AD patients, [18F]florbetapir uptake was significantly higher in AD patients than in healthy controls, especially in cortical target areas, such as the frontal and temporal cortices and the precuneus (Wong, et al., 2010). Variable tracer uptake was seen in the occipital cortex, in which Aβ deposition is thought to occur inconsistently. Contrastingly, healthy controls had tracer accumulation predominantly in white matter areas, as non-specific binding. It was noted, however, that two elderly healthy controls presented with increased tracer accumulation, indistinguishable from AD patients, and two other healthy controls had borderline levels of tracer uptake, especially in the precuneus. This finding is consistent with previous [11C]PiB studies, in which 10-30% of

Fig. 2. Florbetapir F-18 PET imaging (coronal, axial, and sagittal views). Top left, healthy control (SUVR = 0.98; visual read score = 0); top right: patient with clinically diagnosed AD and interpreted as Aß+ (SUVR = 1.68; visual read score = 3); bottom left, patient with mild cognitive impairment and interpreted as Aß- (SUVR = 1.03; visual read score = 0); bottom right, patient with mild cognitive impairment and interpreted as Aß+ (SUVR = 1.61; visual read score = 4). *(Reprinted with permission from Lister-James J, Pontecorvo MJ, Clark C, et al. Florbetapir F-18: A histopathologically validated beta-amyloid positron emission tomography imaging agent. Semin. Nucl. Med. 2011;50:300-304)*

minutes post injection and remains stable until at least 90 minutes post-injection (Wong, et al., 2010); contrastingly, both [18F]flutemetamol and [18F]florbetaben reach maximum effect size at 85-90 minutes post injection (Barthel, et al., 2010; Nelissen, et al., 2009). This property of [18F]florbetapir creates a large time-frame to obtain a 10 minute image and allows for shorter imaging times, if necessary. Moreover, [18F]florbetapir has a good safety profile and biodistribution. The typical administered dose is 382.0±14 MBq (10.3±0.38 mCi), and the effective dose is 6.66±0.38 mSv using an administered dose of 370 MBq (whole-body effective dose conversion factor = 18.0±1.01 μSv/MBq) (Lin, et al., 2010). As expected, [18F]florbetapir delivers a higher radiation burden than [11C]PiB, but still within the normal range for 18F-labeled radiopharmaceuticals (O'Keefe, et al., 2009); and thus it remains

Clinical studies of [18F]florbetapir have consistently shown its high discriminatory power in being able to differentiate between AD patients, patients with amyloid positive and amyloid negative MCI, and healthy controls (e.g. Figure 2) (Lister-James, et al., 2011). For example, in a study of 15 elderly healthy controls and 11 AD patients, [18F]florbetapir uptake was significantly higher in AD patients than in healthy controls, especially in cortical target areas, such as the frontal and temporal cortices and the precuneus (Wong, et al., 2010). Variable tracer uptake was seen in the occipital cortex, in which Aβ deposition is thought to occur inconsistently. Contrastingly, healthy controls had tracer accumulation predominantly in white matter areas, as non-specific binding. It was noted, however, that two elderly healthy controls presented with increased tracer accumulation, indistinguishable from AD patients, and two other healthy controls had borderline levels of tracer uptake, especially in the precuneus. This finding is consistent with previous [11C]PiB studies, in which 10-30% of

Fig. 2. Florbetapir F-18 PET imaging (coronal, axial, and sagittal views). Top left, healthy control (SUVR = 0.98; visual read score = 0); top right: patient with clinically diagnosed AD and interpreted as Aß+ (SUVR = 1.68; visual read score = 3); bottom left, patient with mild cognitive impairment and interpreted as Aß- (SUVR = 1.03; visual read score = 0); bottom right, patient with mild cognitive impairment and interpreted as Aß+ (SUVR = 1.61; visual read score = 4). *(Reprinted with permission from Lister-James J, Pontecorvo MJ, Clark C, et al. Florbetapir F-18: A histopathologically validated beta-amyloid positron emission tomography* 

suitable for clinical imaging applications.

*imaging agent. Semin. Nucl. Med. 2011;50:300-304)*

cognitively intact healthy subjects have increased tracer uptake (W. E. Klunk, et al., 2004; Mintun, et al., 2006; Morris, et al., 2009; Rowe, et al., 2007).

Lin and co-workers presented similar results for [18F]florbetapir in a clinical study, using 6 healthy controls and 3 AD patients (Lin, et al., 2010). Tracer uptake was particularly high in the frontal, parietal, and occipital cortices of AD patients; healthy controls showed substantial non-specific binding in subcortical white matter. Consequently, simple semiquantitative measures (SUVRs with the cerebellum as the reference region) could be used to discriminate between AD patients and healthy controls. Of importance, one AD patient showed little uptake of the radiotracer, similar to the binding pattern of healthy controls. This negative scan may be due to a lack of tracer sensitivity, but more likely is indicative of a low Aβ load in this clinically diagnosed AD patient.

In 2011, Clark *et al.* published the results from the first study of its kind, comparing the efficacy of an Aβ PET imaging agent against the golden standard of neuropathology confirmation at autopsy (Clark, et al., 2011b). This study included individuals near end of life who consented to donating their brain after death. Thirty-six subjects with clinically diagnosed AD were included in the autopsy cohort (but only 29 were included in the primary analysis) while 74 young healthy controls were in the non-autopsy cohort. All 74 young healthy controls were found to have a [18F]florbetapir-negative scan. For the primary analysis autopsy cohort, visual assessment scores of [18F]florbetapir scans and average neocortical and regional SUVRs (cerebellum as reference region) correlated well with *postmortem* amyloid pathology (as measured by immunohistochemistry and silver stain neuritic plaque score).

Interestingly, only 15 participants met pathological criteria for AD in the primary analysis autopsy cohort. Of these 15 participants, 14 had [18F]florbetapir PET scans visually assessed as positive, giving a sensitivity of 93%. Fourteen participants in the primary analysis autopsy cohort had histologically-confirmed low levels of Aβ aggregation at *post-mortem* and thus did not meet the criteria for AD. All 14 participants had [18F]florbetapir-negative scans, leading to a specificity of 100%. This study also cited good interreader agreement among the three nuclear medicine physicians who visually rated the [18F]florbetapir PET images (0.68≤κ≤0.98). While these Phase III results are very promising, Clark cautioned that this study does not explicitly highlight the specific clinical applications of this imaging agent. Currently, only a [18F]florbetapir-negative scan is considered clinically useful, as it can help rule out the presence of pathologically significant levels of Aβ in the brain and thus AD pathology. [18F]Florbetapir cannot, however, diagnose AD because cerebral amyloid deposition is not specific to this diagnosis. Due to encouraging results from its Phase III clinical study, Avid Radiopharmaceuticals (now a sub-company under Eli Lilly and Company) filed for FDA approval of [18F]florbetapir in late 2010 (Sullivan, 2011). In a vote of 13-3, the Peripheral and Central Nervous System Drugs Advisory Committee did not recommend approval of [18F]florbetapir in January 2011, citing high inter-reader variability and the lack of a single clinically applicable binary reading method as outstanding issues (Sullivan, 2011). The advisory committee did, however, subsequently vote 16-0 in favor of approval if Avid were to implement reader-training programs (Sullivan, 2011). Such implementation is currently in progress.

The committee's decision was partially based on the results presented in the study by Clark and co-workers (Clark, et al., 2011b). Upon independently analyzing the critical individual reader score data, the FDA found substantial inter-reader variability among independent, extensively trained readers of [18F]florbetapir PET scans for individuals in the autopsy

Diagnosis of Dementia Using Nuclear Medicine Imaging Modalities 213

the 3R-tau isoform. The exact mechanism by which tau is regulated in the brain is also largely unknown; however, recent studies suggest that phosphorylation levels of tau play an important role in tau regulation. Increased phosphorylation of tau likely decreases the ability of the protein to bind to microtubules. For this reason, it is believed that protein kinases and phosphatases play a role in tau regulation. The malfunction of this phosphorylation regulation mechanism is thought to be a major cause of tauopathies. In normally functioning brains, tau proteins contain approximately 2-3 moles of phosphate per

In the case of AD, tau proteins are hyperphosphorylated, which causes a decrease in the ability of the tau to bind to microtubules, leading to microtubule dysfunction and neuronal death. Hyperphosphorylated tau is observed in the plaques of AD patients upon *post-mortem* examination. The mechanism by which this hyperphosphorylated tau is converted into a plaque is currently unknown. One theory for this process is that hyperphosphorylation of the tau causes it to lose binding affinity with microtubules, causing the aggregation of tau into insoluble intraneuronal brain deposits. In all neurodegenerative tauopathies, deposits and tangles of tau proteins are observed in the brain. In AD, tau accumulates in the brain in different structures known as neurofibrillary tangles (NFTs). These NFTs are composed of different structures of tau consisting of paired helical filaments (PHFs) and straight filaments. Tau aggregates are very insoluble in neurons and ultimately cause neuronal death by interfering with the essential axoplasmic flow of nutrients to different cell structures. As so little is known about the cause of Alzheimer's disease and other tauopathies, it is important to develop a better

Non-invasive functional molecular imaging techniques such as PET imaging have the potential to become the future diagnostic standard for Alzheimer's disease and related tauopathies as they would allow for earlier and more definitive diagnosis of such diseases, and provide an effective method for monitoring possible treatments. One such approach being aggressively explored is the development of tau specific radiopharmaceuticals that would allow for the non-invasive quantification of tau NFTs in the brain. Developing appropriate biomarkers for detecting tau has proven challenging as they must cross the blood brain barrier (BBB), bind selectively to tau, demonstrate safe biodistribution, and exhibit low non-specific binding. Nevertheless, several tau-targeting radiopharmaceuticals, radiolabeled with fluorine-18 or carbon-11, are in various stages of clinical and pre-clinical development. Experimental radiopharmaceuticals including BF-158, FDDNP and T808 are possible candidates for PET imaging of tau, and are outlined below for proof-of-concept

2-(1-[6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile

([18F]FDDNP) is a recently developed radiopharmaceutical designed to elucidate brain plaques and NFTs (Small, et al., 2006). Unlike [11C]PiB, [18F]FDDNP can bind to both amyloid-ß plaques as well as tau NFTs, and it has been used in this capacity to quantify NFT and plaque build-up in AD (Small, et al., 2006). Currently [18F]FDDNP is the only biomarker of its kind being studied in human clinical trials, and such trials demonstrated the ability of [18F]FDDNP PET to distinguish healthy control patients from patients with mild cognitive

mole of tau protein (Iqbal, et al., 2005).

method for studying tau.

purposes.

**2.4.2.1 [18F]FDDNP** 

**2.4.2 PET imaging of tau neurofibrillary tangle burden** 

cohort (Carome and Wolfe, 2011); in particular, sensitivities ranged from 55% to 90%, while specificities were between 80% and 100%. The FDA determined that the readers probably had different thresholds for positive and negative scans on their visual assessment scale; and thus, education initiatives are needed to introduce a consistent binary reading method (Clark, et al., 2011a). In March 2011 the FDA echoed the advisory committee's recommendation in their official response on [18F]florbetapir, requesting that Avid Radiopharmaceuticals work to implement a reader-training program that will lead to better inter-reader reliability. When this issue has been adequately addressed, it is expected that FDA approval will be gained for [18F]florbetapir.

#### **2.4 Imaging tau neurofibrillary tangle burden in Alzheimer's disease 2.4.1 Introduction to tauopathies**

Besides amyloid-β, tau is the other hallmark protein that plays a primary role in the pathogenesis of Alzheimer's disease. Tau microtubule-associated protein is essential for maintaining proper neuronal function, but in some individuals this protein can accumulate intraneuronally due to abnormal changes in the regulation of the protein. This process is believed to be the cause of a wide spectrum of different types of dementias known collectively as neurodegenerative tauopathies. In addition to Alzheimer's disease, other common tauopathies in humans include Frontotemporal dementia (FTD), Pick's disease, progressive Supranuclear Palsy (PSP), and Parkinson's disease (Ludolph, et al., 2009), and, unfortunately, many of these diseases are currently not curable.

As addressed above, there is currently no effective way to definitively diagnose AD (or other tauopathy) patients before the disease has done irreversible damage. As is the case with amyloid-β plaques, risky brain biopsies can be used to determine the presence of tau, but *post-mortem* examination of the brain is needed to definitively diagnose these types of disease. While many clinical diagnostic techniques can be used, they require patients to be in moderate to late stages of the disease, a time when treatment is much less effective. New diagnostic techniques, however, are being explored to enable earlier and more definitive diagnosis of AD with PET imaging. While numerous probes have targeted amyloid-β plaques, the most promising possibility is to develop a tau-specific PET biomarker that would improve diagnostic confidence, enable detection of early stages of AD, and allow doctors to monitor the progress of future treatments.

Microtubules are the cytoskeletal components that allow nutrients to be transported far distances along the length of axons. Axoplasmic transport in neurons is an essential process, necessary to maintain proper neuron function. Microtubules however are somewhat unstable and must be stabilized by tau proteins in order to function properly. In normally functioning human brains, tau binds to microtubules to promote stability and polymerization in order to enable axoplasmic flow and preserve overall neuronal functioning. Six tau isoforms exist in the adult human brain, each with an alternative exon splicing sequence. Three of these isoforms, known as 3R-tau are made up of three carboxyterminal tandem repeat sequences and the other three isoforms, known as 4R-tau consist of four carboxy-terminal tandem repeat sequences. In adult humans the ratio of 3R-tau to 4Rtau is approximately 1:1 (V. M. Y. Lee, et al., 2001). The purpose of these different isoforms is not completely understood. It is known, however, that only the shortest form of 3R-tau is expressed in the fetus, while all six isoforms are expressed in adult brains. One study suggests that the 4R-tau isoform is more effective in promoting microtubule binding than

cohort (Carome and Wolfe, 2011); in particular, sensitivities ranged from 55% to 90%, while specificities were between 80% and 100%. The FDA determined that the readers probably had different thresholds for positive and negative scans on their visual assessment scale; and thus, education initiatives are needed to introduce a consistent binary reading method (Clark, et al., 2011a). In March 2011 the FDA echoed the advisory committee's recommendation in their official response on [18F]florbetapir, requesting that Avid Radiopharmaceuticals work to implement a reader-training program that will lead to better inter-reader reliability. When this issue has been adequately addressed, it is expected that

Besides amyloid-β, tau is the other hallmark protein that plays a primary role in the pathogenesis of Alzheimer's disease. Tau microtubule-associated protein is essential for maintaining proper neuronal function, but in some individuals this protein can accumulate intraneuronally due to abnormal changes in the regulation of the protein. This process is believed to be the cause of a wide spectrum of different types of dementias known collectively as neurodegenerative tauopathies. In addition to Alzheimer's disease, other common tauopathies in humans include Frontotemporal dementia (FTD), Pick's disease, progressive Supranuclear Palsy (PSP), and Parkinson's disease (Ludolph, et al., 2009), and,

As addressed above, there is currently no effective way to definitively diagnose AD (or other tauopathy) patients before the disease has done irreversible damage. As is the case with amyloid-β plaques, risky brain biopsies can be used to determine the presence of tau, but *post-mortem* examination of the brain is needed to definitively diagnose these types of disease. While many clinical diagnostic techniques can be used, they require patients to be in moderate to late stages of the disease, a time when treatment is much less effective. New diagnostic techniques, however, are being explored to enable earlier and more definitive diagnosis of AD with PET imaging. While numerous probes have targeted amyloid-β plaques, the most promising possibility is to develop a tau-specific PET biomarker that would improve diagnostic confidence, enable detection of early stages of AD, and allow

Microtubules are the cytoskeletal components that allow nutrients to be transported far distances along the length of axons. Axoplasmic transport in neurons is an essential process, necessary to maintain proper neuron function. Microtubules however are somewhat unstable and must be stabilized by tau proteins in order to function properly. In normally functioning human brains, tau binds to microtubules to promote stability and polymerization in order to enable axoplasmic flow and preserve overall neuronal functioning. Six tau isoforms exist in the adult human brain, each with an alternative exon splicing sequence. Three of these isoforms, known as 3R-tau are made up of three carboxyterminal tandem repeat sequences and the other three isoforms, known as 4R-tau consist of four carboxy-terminal tandem repeat sequences. In adult humans the ratio of 3R-tau to 4Rtau is approximately 1:1 (V. M. Y. Lee, et al., 2001). The purpose of these different isoforms is not completely understood. It is known, however, that only the shortest form of 3R-tau is expressed in the fetus, while all six isoforms are expressed in adult brains. One study suggests that the 4R-tau isoform is more effective in promoting microtubule binding than

FDA approval will be gained for [18F]florbetapir.

**2.4.1 Introduction to tauopathies** 

**2.4 Imaging tau neurofibrillary tangle burden in Alzheimer's disease** 

unfortunately, many of these diseases are currently not curable.

doctors to monitor the progress of future treatments.

the 3R-tau isoform. The exact mechanism by which tau is regulated in the brain is also largely unknown; however, recent studies suggest that phosphorylation levels of tau play an important role in tau regulation. Increased phosphorylation of tau likely decreases the ability of the protein to bind to microtubules. For this reason, it is believed that protein kinases and phosphatases play a role in tau regulation. The malfunction of this phosphorylation regulation mechanism is thought to be a major cause of tauopathies. In normally functioning brains, tau proteins contain approximately 2-3 moles of phosphate per mole of tau protein (Iqbal, et al., 2005).

In the case of AD, tau proteins are hyperphosphorylated, which causes a decrease in the ability of the tau to bind to microtubules, leading to microtubule dysfunction and neuronal death. Hyperphosphorylated tau is observed in the plaques of AD patients upon *post-mortem* examination. The mechanism by which this hyperphosphorylated tau is converted into a plaque is currently unknown. One theory for this process is that hyperphosphorylation of the tau causes it to lose binding affinity with microtubules, causing the aggregation of tau into insoluble intraneuronal brain deposits. In all neurodegenerative tauopathies, deposits and tangles of tau proteins are observed in the brain. In AD, tau accumulates in the brain in different structures known as neurofibrillary tangles (NFTs). These NFTs are composed of different structures of tau consisting of paired helical filaments (PHFs) and straight filaments. Tau aggregates are very insoluble in neurons and ultimately cause neuronal death by interfering with the essential axoplasmic flow of nutrients to different cell structures. As so little is known about the cause of Alzheimer's disease and other tauopathies, it is important to develop a better method for studying tau.
