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S. Gauthier1, P.S. Aisen2, J. Cummings3, M.J. Detke5, F.M. Longo6, R. Raman2, M. Sabbagh4, L. Schneider7, R. Tanzi8, P. Tariot9, M. Weiner10, J. Touchon11, B.Vellas12 and the EU/US CTAD Task Force*


* EU/US/CTAD TASK FORCE: Susan Abushakra (Framingham); John Alam (Boston); Sandrine Andrieu (Toulouse); Anu Bansal (Simsbury); Monika Baudler (Basel); Joanne Bell (Wilmington); Mickaël Beraud (Zaventem); Tobias Bittner (Basel); Samantha Budd Haeberlein (Cambridge); Szofia Bullain (Basel); Marc Cantillon (Gilbert); Maria Carrillo (Chicago); Carmen Castrillo-Viguera (Cambridge); Ivan Cheung (Woodcliff Lake); Julia Coelho (San Francisco); Daniel Di Giusto (Basel); Rachelle Doody (South San Francisco); John Dwyer (Washington); Michael Egan (North Wales); Colin Ewen (Slough); Charles Fisher (San Francisco); Michael Gold (North Chicago); Harald Hampel (Woodcliff Lake) ; Ping He (Cambridge) ; Suzanne Hendrix (Salt Lake City) ; David Henley (Titusville) ; Michael Irizarry (Woodcliff Lake); Atsushi Iwata (Tokyo); Takeshi Iwatsubo (Tokyo); Michael Keeley (South San Francisco); Geoffrey Kerchner (South San Francisco); Gene Kinney (San Francisco); Hartmuth Kolb (Titusville); Marie Kosco-Vilbois (Lausanne); Lynn Kramer (Westport); Ricky Kurzman (Woodcliff Lake); Lars Lannfelt (Uppsala); John Lawson (Malvern); Jinhe Li (Gilbert); Mark Mintun (Philadelphia); Vaidrius Navikas (Valby); Gerald Novak (Titusville); Gunilla Osswald (Stockholm); Susanne Ostrowitzki (South San Francisco); Anton Porsteinsson (Rochester); Ivana Rubino (Cambridge); Stephen Salloway (Providence); Rachel Schindler (New York); Hiroshi Sekiya (Malvern); Dennis Selkoe (Boston); Eric Siemers (Zionsville); John Sims (Indianapolis); Lisa Sipe (San Marcos); Olivier Sol (Lausanne); Reisa Sperling (Boston); Andrew Stephens (Berlin); Johannes Streffer (Braine-l’Alleud); Joyce Suhy (Newark); Chad Swanson (Woodcliff Lake); Gilles Tamagnan (New Haven); Edmond Teng (South San Francisco); Martin Tolar (Framingham); Martin Traber (Basel); Andrea Vergallo (Woodcliff Lake); Christian Von Hehn (Cambridge); George Vradenburg (Washington); Judy Walker (Singapore) ; Glen Wunderlich (Ridgefield); Roy Yaari (Indianapolis); Haichen Yang (North Wales); Wagner Zago (San Francisco); Thomas Zoda (Austin)

1. McGill Center for Studies in Aging, Verdun, QC, Canada; 2. Alzheimer’s Therapeutic Research Institute (ATRI), Keck School of Medicine, University of Southern California, San Diego, CA, USA; 3. Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas (UNLV), USA; 4. Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA; 5. Cortexyme, South San Francisco, CA, USA; 6. Stanford University School of Medicine, Stanford CA USA; 7. University of Southern California Keck School of Medicine, Los Angeles, CA USA; 8. Harvard University, Boston, MA USA; 9. Banner Alzheimer’s Institute, Phoenix AZ USA; 10. University of California, San Francisco, CA USA; 11. Montpellier University, INSERM 1061, Montpellier, France; 12. Gerontopole, INSERM U1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France

Corresponding Author: Serge Gauthier, McGill Center for Studies in Aging, Verdun QC, Canada,

J Prev Alz Dis 2020;3(7):152-157
Published online April 6, 2020,



While amyloid-targeting therapies continue to predominate in the Alzheimer’s disease (AD) drug development pipeline, there is increasing recognition that to effectively treat the disease it may be necessary to target other mechanisms and pathways as well. In December 2019, The EU/US CTAD Task Force discussed these alternative approaches to disease modification in AD, focusing on tau-targeting therapies, neurotrophin receptor modulation, anti-microbial strategies, and the innate immune response; as well as vascular approaches, aging, and non-pharmacological approaches such as lifestyle intervention strategies, photobiomodulation and neurostimulation. The Task Force proposed a general strategy to accelerate the development of alternative treatment approaches, which would include increased partnerships and collaborations, improved trial designs, and further exploration of combination therapy strategies.

Key words: Alzheimer’s disease, dementia, tau, tauopathy, neurotrophins, neuroinflammation, lifestyle intervention, photobiomodulation, neurostimulation, geroscience.



Following a discussion on lessons learned from clinical trials of amyloid-based therapies for Alzheimer’s disease (AD) (1), on December 4, 2019, the EU/US CTAD Task Force turned their attention to alternative approaches for disease modification. These strategies do not negate the validity of the amyloid hypothesis; indeed, recently discovered genetic evidence continues to support the centrality of amyloid in the neurodegenerative processes that lead to AD (2–4). However, genetic and other studies point to additional mechanisms and pathways both upstream and downstream of amyloidogenesis, which may provide druggable therapeutic targets with potential for disease modification.
Neuropathological and imaging studies confirm the complexity and heterogeneity of AD (5) Mixed pathologies are evident in most individuals with a clinical diagnosis of AD (6), and in early clinical studies of amyloid-targeting drugs, a significant proportion of trial participants were shown to have no detectable amyloid. Nonetheless, among putative disease-modifying AD drugs in clinical trials, 40% target amyloid either with small molecules or immunotherapies. Another 18% target tau. Other mechanisms targeted for disease modification include neuroprotection, anti-inflammatory effects, growth factor promotion, and/or metabolic effects (7). Additional trials are underway assessing non-pharmacological approaches to treat AD, including lifestyle interventions and neurostimulation.


Anti-tau therapies

The microtubule-associated protein tau (MAPT, commonly referred to as tau) is the main constituent of the neurofibrillary tangles that are one of the two primary pathological hallmarks of AD. Its normal function is to stabilize microtubules and thus regulate intracellular trafficking, but in AD and other tauopathies, the protein undergoes post-translational modifications that lead to the development of a variety of oligomeric species, tangles, and neuropil threads that may be deposited as aggregates in specific brain regions, disrupting normal cytoskeletal function and protein degradation pathways (8). In the human brain, six isoforms of tau are present, which are classified as either 3R or 4R tau based on the number of repeat domains. Approximately equal levels of 3R and 4R tau are expressed in the normal brain; however, 3R:4R tau imbalances are seen in brains of individuals with tauopathies. In AD, isoform imbalances vary across brain regions and disease progression.
Unlike levels of amyloid beta protein (Aβ), which correlate poorly with cognition, tau levels are associated with both neurodegeneration and cognitive deficits (9). Tau pathology has been shown to follow a characteristic progression pathway in the brain, starting in areas responsible for learning and memory before spreading to cortical areas involved in other cognitive functions (10).
The complex progression of tau pathological events provides multiple potential opportunities for intervention. Anti-tau drugs in development target tau expression, aggregation, degradation, protein modifications (e.g. phosphatase modifiers, kinase inhibitors), microtubule stabilization, and extracellular tau inter-neuronal spread (8). As of February 2019, clinical trials were underway for 17 tau-targeting drugs – seven small molecules and 10 biologics (7). Only one drug, LMTX (TRx0237) – a reduced form of methylene blue, and a tau protein aggregation inhibitor — is currently being tested in a Phase 3 trial in early AD at 8 – 16 mg/day doses versus placebo (NCT03446001). This trial follows two Phase 3 trials in mild and mild to moderate AD (NCT01689246, NCT01689233) and a trial in behavioral variant FTD (NCT01626378) with higher doses, which showed negative results in the primary analysis of clinical efficacy. Biogen has a Phase 2 study underway of the anti-tau agent BIIB092 (gosuranemab) in participants with MCI due to AD or mild AD (NCT03352557). Phase 2 studies in biologically defined populations are also being conducted. For example, Roche/Genentech is conducting two Phase 2 studies of the anti-tau monoclonal antibody semorinemab in participants with prodromal or probable AD confirmed by amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) testing (NCT03828747). Clinical trials of anti-tau therapeutics have been conducted in other tauopathies, although two recent Phase 2 studies of anti-tau monoclonal antibody therapies (Abbvie’s AABV-8E12 and Biogen’s gosuranemab) in participants with progressive supranuclear palsy (PSP) were recently terminated for lack of efficacy (NCT2985879 and NCT03068468, respectively). Non-clinical studies of innovative anti-tau therapies are underway, such as a study that uses engineered tau-degrading intrabodies to target intracellular tau (11).
It is also theoretically possible that early anti-amyloid intervention may attenuate or even preclude downstream effects on tau. That is, non-tau-based treatments could have implications for tau and tangles.
Several challenges face developers of tau-based therapeutics. For tau reduction approaches, it is not known how much reduction is needed, how quickly and safely it can be accomplished, when different interventions might be effective during the course of the disease, and how long drug levels must be maintained to get an effect. Tau biology is complicated with numerous fragments and post-translational modifications associated with tauopathies, yet it remains unclear which tau species are toxic. Moreover, the targets, mechanisms and cellular locations through which such tau species promote degeneration remain to be identified. These issues make the design of clinical trials especially complicated and highlight the need for better tau biomarkers. Recent progress made in the development of tau ligands for PET may improve the efficiency of clinical trials, since tau-PET enables early diagnosis and tracking of disease progression, identifying individuals at risk for faster cognitive decline, and rapidly assessing pharmacodynamic effects of treatments (12). Plasma levels of total tau (t-tau) and neurofilament light (NfL) have been developed as biomarkers of neurodegeneration (13). Still needed are biomarkers that distinguish 3R from 4R tau and that quantify the many different tau species.


Neurotrophic strategies

The neurodegeneration that occurs in AD results from a complicated molecular and biochemical signaling network, likely triggered by Aβ and eventually leading to synaptic dysfunction, loss of dendritic spines, and neurite degeneration (14). Growth factors called neurotrophins regulate neuronal survival, development, and function by binding to cell surface receptors. The signaling networks regulated by these receptors have extensive overlap with those associated with neurodegeneration and modulation of neurotrophin receptors has thus been proposed as a potential therapeutic strategy (15). The Longo lab and others have zeroed in on the p75 neurotrophin receptor (p75NTR) as a therapeutic target for AD. Their working hypothesis, supported by human genomic and proteomic data, along with animal studies is that the p75NTR modulates the complex AD degenerative signaling network and that downregulating its signaling renders oligomeric Aβ unable to promote degeneration (16, 17).
Longo and colleagues have developed small molecule ligands that bind to p75NTR, activate survival-promoting signaling, and prevent Aβ-induced neurodegeneration and synaptic impairment (18). One molecule in particular, LM11A-31, has been shown to block Aβ-induced tau phosphorylation, misfolding, oligomerization and mislocalization; reverse late-stage spine degeneration; reverse synaptic impairment; prevent microglial dysfunction; and in wildtype mice suppress age-related basal forebrain cholinergic neuron degeneration (18–20). There is evidence that dendritic spine preservation is associated with cognitive resilience (21).
A Phase 2a pilot study sponsored by PharmatrophiX Inc. and funded in part by the National institute on Aging (NIA) and the Alzheimer Drug Discovery Foundation is underway, testing oral LM11A-31 in participants with mild-to-moderate AD and amyloid positivity assessed by CSF Aβ screening (NCT03069014). With an expected completion in the third quarter of 2020, the trial will assess safety and tolerability as well as cognitive, clinical, biomarker, and imaging exploratory endpoints. LM11A-31 may be effective in other disorders such as Huntington’s disease (22), diabetes-induced macular oedema (23), and traumatic brain injury (24).


Anti-microbial and anti-inflammatory strategies

Neuropathological studies of the AD brain show not only amyloid plaques and tau-based tangles but neuroinflammation as well. Indeed, according to the innate immune hypothesis, plaques, tangles, and neuroinflammation orchestrate an innate immune response that has evolved to protect the brain against microbial infection, with Aβ itself acting as an antimicrobial peptide (AMP) in the brain (25, 26). This hypothesis suggests that subclinical microbial infections in the brain rapidly ‘seed’ Aβ to trap microbes, and that this process drives Aβ neurotoxicity and opsonization (i.e, an ‘eat me’ signal for microglia to remove axons and synapses) (25). Tangles form in response to microbe invasion to block neurotropic microbe spread. AD risk genes are implicated in the innate immune protection hypothesis, which posits that AD-associated genetic risk variants were evolutionarily conserved to keep Aβ deposition, tangle formation, and gliosis/neuroinflammation on a ‘hair trigger’ as a means of protecting a subset of the human species in the advent of a major epidemic of brain infection.
The molecular pathways involved in these processes provide multiple potential therapeutic targets, including the use of anti-viral drugs, antibiotics, blockade of toxic microbial products, and immunization for prevention of subclinical infections; secretase inhibitors and immunotherapies to prevent Aβ seeding; kinase or phosphatase inhibitors to prevent the development of pathological forms of tau, and anti-inflammatories to suppress neuroinflammation. Gut microbiota may also play a role in AD pathogenesis by disrupting neuroinflammation and metabolic homeostasis, thus representing another potential intervention target (27).
One example of a bacterial hypothesis and associated strategy is based on the discovery of the bacterium Porphyromonas gingivalis (Pg), most commonly associated with periodontitis, in the brains of AD patients. Toxic virulence factors from the bacterium, proteases called gingipains, have been identified in AD brains, and gingipain levels correlated with tau and ubiquitin pathology. Oral infection of mice with Pg resulted in brain colonization, increased Aβ1-42, and loss of hippocampal neurons, effects that were blocked by COR388, a small-molecule irreversible lysine- gingipain inhibitor. COR388 significantly lowered markers of inflammation in plasma as well as AD-associated APOE fragments in CSF in a small Phase 1b study in mild-moderate AD patients (28), and a large Phase 2/3 study is underway with an interim readout expected in Q4 2020 and topline data in Q4 2021 (NCT03823404).
A retrospective cohort study showed that Herpes simplex virus (HSV)-infected subjects had a nearly 3-fold increased risk of AD but that treatment with anti-viral drugs such as acyclovir brought risk to non-infected levels (29). There is an ongoing phase 2 trial of valacyclovir for patients with mild AD and positive titers for HSV1 and HSV2 (NCT03282916). Trials in AD using doxycycline and minocycline did not show efficacy (30).
Anti-inflammatory strategies are also being pursued. A Phase 2 study underway in participants with late mild cognitive impairment (MCI) or early AD aims to protect neurons against oxidative stress using two small molecule drugs — tauroursodexycholic acid (TUDCA) and sodium phenylbutyrate — repurposed by Amylyx Pharmaceutical as AMX0035 (NCT03533257). Yet another Phase 3 study sponsored by AZTherapies, Inc. aims to reduce neuroinflammation by converting microglia from a proinflammatory to phagocytic state to promote clearance of Aβ by using a combination of two marketed drugs, cromolyn and ibuprofen, known as ALZT-OP1 (NCT02547818) (31).


Lifestyle intervention strategies and other non-pharmacological approaches

Multiple epidemiological studies in Europe, the United States, and Canada investigating an observed decline in the prevalence of dementia in recent years have suggested that dementia may be preventable by targeting lifestyle risk factors such as diabetes, hypertension, obesity, physical inactivity, smoking, depression, low education, and social isolation (32). Clinical studies are now beginning to support this assertion. The Systolic Blood Pressure Intervention Trial –Memory and Cognition in Decreased Hypertension (SPRINT MIND) study suggested that intensive blood pressure control may reduce the risk of probable dementia and mild cognitive impairment (MCI), although the results were not statistically significant, in part because the SPRINT trial was terminated early based on the significant benefits of blood pressure control on cardiovascular outcomes. The study may have been underpowered for cognitive endpoints (33). Further study is warranted given that a 10-year study in France showed that hypertension was associated with poorer cognition in middle-aged individuals (34).
Multi-domain strategies have focused on lifestyle factors. For example, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) trial demonstrated improved or stabilized cognitive function in participants that adhered to an intervention combining diet, physical exercise, cognitive training, and vascular risk monitoring (35). The Multidomain Alzheimer Prevention Trial (MAPT) tested an intervention combining cognitive and physical intervention along with omega-3 polyunsaturated fatty acid supplementation in frail, non-demented, community dwelling adults (36, 37). While MAPT failed to demonstrate significant slowing of cognitive decline, subgroup analyses suggested that individuals with low plasma levels of docosahexaenoic acid (DHA, an omega-3 fatty acid) have more cognitive decline, which appeared to be normalized with omega-3 supplementation(38). The benefits of omega-3 supplementation appeared to be greater in amyloid-positive individuals and in those with increased cardiovascular risk scores (39, 40). Based on the results from FINGER, MAPT, and other multidomain intervention studies, many additional studies are planned, including worldwide FINGERS studies (WW-FINGERS), a network of studies throughout the world that are adapting the multidomain strategies of the FINGER trial to different populations (41).
In addition to physical and cognitive activity, other non-pharmacological strategies are being investigated for their potential to slow cognitive decline and prevent dementia. For example, photobiomodulation (PBM) has been shown to be neuroprotective. In animal models PBM improved memory and normalized markers of AD, oxidative stress and neuroinflammation (42). A pilot study is now underway in participants with probable AD (NCT03405662).
Non-invasive neurostimulation with techniques such as repetitive transcranial magnetic stimulation (rTMS) has been proposed as a treatment for AD (43). Other technological approaches including assistive technologies, smart technologies, and telemedicine may improve the treatment and care of people with AD.



Given that aging is the major risk factor for AD, therapeutic strategies aimed at the diseases of aging (e.g., frailty) may slow cognitive decline and the development of dementia (44) Considerable research is underway to investigate the relationship between biological aging and neurodegenerative disease. These efforts have coalesced in the emerging field of geroscience (44), which explores whether the physiological hallmarks of aging such as mitochondrial dysfunction, loss of proteostasis, increased cellular senescence, and stem cell exhaustion may contribute to the development of AD pathology and neurodegeneration (45). Identification of biomarkers of aging and elucidation of how the molecular pathways of aging and AD intersect could advance the identification of novel therapeutic targets and next-generation therapies, such as the use of mesenchymal stem cells (46). The links between aging and AD are being explored as one element of the INSPIRE Research Initiative (Barreto JFA in press).


Conclusions/moving forward

While the AD drug development pipeline continues to be dominated by Aβ-targeting therapies, there is increasing recognition that addressing the complexity of AD may require multiple agents and may need to start in early disease stage before pathology becomes irreversible. A “deep biology” view, such as that proposed by advocates of p75NTR modulation, posits that key ‘hub’ targets may enable modulation of multiple mechanisms (e.g. resilience to both Aβ and tau) and that key components of pathology could be reversible (e.g. spines, synaptic function). A single treatment could thus promote synaptic function and slow progression and prevent upstream tau aggregation and oligomer formation.
Given the importance of tau in the development of AD, and reflecting the recently proposed Research Framework (47), CTAD Task Force members advocated assessment of both Aβ and tau levels in all clinical trials. The A-T+N+ AD phenotype is common and should be targeted for anti-tau trials. A suggestion was made to name this phenotype Dementia Associated and Neurofibrillary tangle Neuroimaging Abnormality (DANNA). Tau imaging may provide a biological outcome, at least in Phase 2 studies, although the Task Force recognized that amyloid and/or tau PET imaging adds substantial subject and trial burden and cost. Other suggestions that could accelerate the development of anti-tau therapies include using basket designs that include participants with other tauopathies such as frontotemporal degeneration (FTD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). While such trials would include participants with heterogeneous presentations, an outcome assessment such as Goal Attainment Scaling (GAS) could enable capture of clinically meaningful outcomes from diverse participants. This tool enables patients, caregivers, and clinicians, to set goals for treatment using a standardized guided interview, followed by an assessment of whether those goals have been attained (48, 49).
The Task Force suggested that combination therapy may be required to tackle such a complex disease as AD (50). They also advocated employing other innovative clinical trial methodologies to accelerate development of alternative approaches.
The Task Force proposed a general strategy to accelerate the development of alternative treatment approaches, which would include:
• Increased partnerships in the pre-competitive space with increased sharing of granular level data, shared biomarkers, statistical approaches, information on site performance
• Innovative trial design
• More collaborative approaches to recruitment and retention of participants for clinical trials with a focus on participation of representative populations.


Acknowledgements: The authors thank Lisa J. Bain for assistance in the preparation of this manuscript.

Conflicts of interest: The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work. Dr. Gauthier is a member of scientific advisory boards for Biogen, Boehringer-Ingelheim, and TauRx; and a member of the DSMB for ADCS, ATRI, and Banner Health; Dr. Aisen reports grants from Janssen, grants from NIA, grants from FNIH, grants from Alzheimer’s Association, grants from Eisai, personal fees from Merck, personal fees from Biogen, personal fees from Roche, personal fees from Lundbeck, personal fees from Proclara, personal fees from Immunobrain Checkpoint, outside the submitted work; Dr. Cummings is a consultant for Acadia, Actinogen, AgeneBio, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, Cassava, Cerecin, Cerevel, Cognoptix, Cortexyme, EIP Pharma, Eisai, Foresight, Gemvax, Green Valley, Grifols, Karuna, Nutricia, Orion, Otsuka, Probiodrug, ReMYND, Resverlogix, Roche, Samumed, Samus Therapeutics, Third Rock, Signant Health, Sunovion, Suven, United Neuroscience pharmaceutical and assessment companies, and the Alzheimer Drug Discovery Foundation; and owns stock in ADAMAS, BioAsis, MedAvante, QR Pharma, and United Neuroscience. Dr. Detke reports personal fees, non-financial support and other from Cortexyme, during the conduct of the study; personal fees and other from Embera, personal fees and other from Evecxia, personal fees from NIH, outside the submitted work; Dr Kramer is an employee of Eisai Company, Ltd; Dr Longo has equity in and consults for PharmatrophiX, a company focused on the development of small molecule modulators for neurotrophin receptors. He is also a co-inventor on related patent applications. Dr. Raman reports grants from NIH, grants from Eli Lilly, grants from Eisai, outside the submitted work; Dr Sabbagh reports personal fees from Allergan, personal fees from Biogen, personnal fees from Grifols, personal fees from vTV Therapeutics, personal fees from Sanofi, personal fees from Neurotrope, personal fees from Cortexyme, other from Neurotrope, other from uMethod, other from Brain Health Inc, other from Versanum Inc, other from Optimal Cognitive Health Company, outside the submitted work; Dr. Schneider reports grants and personal fees from Eli Lilly, personal fees from Avraham, Ltd, personal fees from Boehringer Ingelheim, grants and personal fees from Merck, personal fees from Neurim, Ltd, personal fees from Neuronix, Ltd, personal fees from Cognition, personal fees from Eisai, personal fees from Takeda, personal fees from vTv, grants and personal fees from Roche/Genentech, grants from Biogen, grants from Novartis, personal fees from Abbott, grants from Biohaven, grants from Washington Univ/ NIA DIAN-TU, personal fees from Samus, outside the submitted work; Dr. Tanzi is a consultant and shareholder in AZTherapies, Amylyx, Promis, Neurogenetic Pharmaceuticals, Cerevance, and DRADS Capital; Dr. Tariot reports personal fees from Acadia , personal fees from AC Immune, personal fees from Axsome, personal fees from BioXcel, personal fees from Boehringer-Ingelheim, personal fees from Brain Test Inc., personal fees from Eisai, personal fees from eNOVA, personal fees from Gerontological Society of America, personal fees from Otuska & Astex, personal fees from Syneos, grants and personal fees from Abbvie, grants and personal fees from Avanir, grants and personal fees from Biogen, grants and personal fees from Cortexyme, grants and personal fees from Genentech, grants and personal fees from Lilly, grants and personal fees from Merck & Co, grants and personal fees from Roche, grants from Novartis, grants from Arizona Department of Health Services, grants from National Institute on Aging, other from Adamas, outside the submitted work; In addition, Dr. Tariot has a patent U.S. Patent # 11/632,747, “Biomarkers of Neurodegenerative disease.” issued; Dr. Weiner is the PI of The Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Brain Health Registry. I am a Professor at University of California San Francisco; Dr. Touchon has received personnal fees from Regenlife and is JPAD associated Editor and part of the CTAD organizing committee; Dr. Vellas reports grants from Lilly, Merck, Roche, Lundbeck, Biogen, grants from Alzheimer’s Association, European Commission, personal fees from Lilly, Merck, Roche, Biogen, outside the submitted work

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H.-Y.Wang1,2, Z. Pei1, K.-C. Lee1, E. Lopez-Brignoni3, B. Nikolov3, C.A. Crowley4, M.R. Marsman4, R. Barbier4, N. Friedmann4, L.H. Burns4

1. Department of Molecular, Cellular and Biomedical Sciences, City University of New York School of Medicine, New York, NY, USA; 2. Department of Biology and Neuroscience, Graduate School of the City University of New York, New York, NY, USA; 3. IMIC, Inc., Palmetto Bay, FL, USA; 4. Cassava Sciences, Inc., Austin, TX, USA

Corresponding Author: Lindsay H. Burns, PhD, Cassava Sciences, Inc., 7801 N. Capital of Texas Hwy, Ste. 260, Austin, TX 78746, Phone: 512-501-2484, Email:    

J Prev Alz Dis 2020;4(7):256-264
Published online February 7, 2020,


BACKGROUND: The most common dementia worldwide, Alzheimer’s disease is often diagnosed via biomarkers in cerebrospinal fluid, including reduced levels of Aβ1–42, and increases in total tau and phosphorylated tau-181.  Here we describe results of a Phase 2a study of a promising new drug candidate that significantly reversed all measured biomarkers of Alzheimer’s disease, neurodegeneration and neuroinflammation. PTI-125 is an oral small molecule drug candidate that binds and reverses an altered conformation of the scaffolding protein filamin A found in Alzheimer’s disease brain. Altered filamin A links to the α7-nicotinic acetylcholine receptor to allow Aβ42’s toxic signaling through this receptor to hyperphosphorylate tau. Altered filamin A also links to toll-like receptor 4 to enable Aβ-induced persistent activation of this receptor and inflammatory cytokine release. Restoring the native shape of filamin A prevents or reverses filamin A’s linkages to the α7-nicotinic acetylcholine receptor and toll-like receptor 4, thereby blocking Aβ42’s activation of these receptors. The result is reduced tau hyperphosphorylation and neuroinflammation, with multiple functional improvements demonstrated in transgenic mice and postmortem Alzheimer’s disease brain.
OBJECTIVES: Safety, pharmacokinetics, and cerebrospinal fluid and plasma biomarkers were assessed following treatment with PTI-125 for 28 days. Target engagement and mechanism of action were assessed in patient lymphocytes by measuring 1) the reversal of filamin A’s altered conformation, 2) linkages of filamin A with α7-nicotinic acetylcholine receptor or toll-like receptor 4, and 3) levels of Aβ42 bound to α7-nicotinic acetylcholine receptor or CD14, the co-receptor for toll-like receptor 4.
DESIGN: This was a first-in-patient, open-label Phase 2a safety, pharmacokinetics and biomarker study.
SETTING: Five clinical trial sites in the U.S. under an Investigational New Drug application.
PARTICIPANTS: This study included 13 mild-to-moderate Alzheimer’s disease patients, age 50-85, Mini Mental State Exam ≥16 and ≤24 with a cerebrospinal fluid total tau/Aβ42 ratio ≥0.30.
INTERVENTION: PTI-125 oral tablets (100 mg) were administered twice daily for 28 consecutive days.
MEASUREMENTS: Safety was assessed by electrocardiograms, clinical laboratory analyses and adverse event monitoring. Plasma levels of PTI-125 were measured in blood samples taken over 12 h after the first and last doses; cerebrospinal fluid levels were measured after the last dose. Commercial enzyme linked immunosorbent assays assessed levels of biomarkers of Alzheimer’s disease in cerebrospinal fluid and plasma before and after treatment with PTI-125. The study measured biomarkers of pathology (pT181 tau, total tau and Aβ42), neurodegeneration (neurofilament light chain and neurogranin) and neuroinflammation (YKL-40, interleukin-6, interleukin-1β and tumor necrosis factor α). Plasma levels of phosphorylated and nitrated tau were assessed by immunoprecipitation of tau followed by immunoblotting of three different phospho-epitopes elevated in AD (pT181-tau, pS202-tau and pT231-tau) and nY29-tau. Changes in conformation of filamin A in lymphocytes were measured by isoelectric focusing point. Filamin A linkages to α7-nicotinic acetylcholine receptor and toll-like receptor 4 were assessed by immunoblot detection of α7-nicotinic acetylcholine receptor and toll-like receptor 4 in anti-filamin A immunoprecipitates from lymphocytes. Aβ42 complexed with α7-nicotinic acetylcholine receptor or CD14 in lymphocytes was also measured by co-immunoprecipitation. The trial did not measure cognition.
RESULTS: Consistent with the drug’s mechanism of action and preclinical data, PTI-125 reduced cerebrospinal fluid biomarkers of Alzheimer’s disease pathology, neurodegeneration and neuroinflammation from baseline to Day 28. All patients showed a biomarker response to PTI-125.  Total tau, neurogranin, and neurofilament light chain decreased by 20%, 32% and 22%, respectively. Phospho-tau (pT181) decreased 34%, evidence that PTI-125 suppresses tau hyperphosphorylation induced by Aβ42’s signaling through α7-nicotinic acetylcholine receptor. Cerebrospinal fluid biomarkers of neuroinflammation (YKL-40 and inflammatory cytokines) decreased by 5-14%. Biomarker effects were similar in plasma. Aβ42 increased slightly – a desirable result because low Aβ42 indicates Alzheimer’s disease. This increase is consistent with PTI-125’s 1,000-fold reduction of Aβ42’s femtomolar binding affinity to α7-nicotinic acetylcholine receptor. Biomarker reductions were at least p ≤ 0.001 by paired t test. Target engagement was shown in lymphocytes by a shift in filamin A’s conformation from aberrant to native: 93% was aberrant on Day 1 vs. 40% on Day 28. As a result, filamin A linkages with α7-nicotinic acetylcholine receptor and toll-like receptor 4, and Aβ42 complexes with α7-nicotinic acetylcholine receptor and CD14, were all significantly reduced by PTI-125. PTI-125 was safe and well-tolerated in all patients. Plasma half-life was 4.5 h and approximately 30% drug accumulation was observed on Day 28 vs. Day 1.
CONCLUSIONS:  PTI-125 significantly reduced biomarkers of Alzheimer’s disease pathology, neurodegeneration, and neuroinflammation in both cerebrospinal fluid and plasma. All patients responded to treatment. The magnitude and consistency of reductions in established, objective biomarkers imply that PTI-125 treatment counteracted disease processes and reduced the rate of neurodegeneration. Based on encouraging biomarker data and safety profile, approximately 60 patients with mild-to-moderate AD are currently being enrolled in a Phase 2b randomized, placebo-controlled confirmatory study to assess the safety, tolerability and efficacy of PTI-125.

Key words: tau, neurofilament light chain, neurogranin, YKL40, neuroinflammation.



Alzheimer’s disease (AD) is the most common dementia, afflicting fifty million people worldwide (1). PTI-125 is a new small molecule drug candidate for AD with a novel mechanism of action: it binds and restores to normal an altered conformation of the scaffolding protein filamin A (FLNA) (2-4). PTI-125’s target, an altered conformation of FLNA, is a known proteopathy in AD brain (2, 3). FLNA is a large, 280-KDa intracellular scaffolding protein best known for cross-linking actin to regulate cell structure and motility and is highly expressed in brain. FLNA dimerizes by a domain in its membrane-bound C terminal, protruding into the cytoplasm as an inverse V shape to interact with at least 90 different proteins (5), indicating potential involvement in numerous intracellular processes. In the cell membrane, FLNA constitutively associates with certain receptors such as the insulin receptor and the mu opioid receptor, and FLNA regulates insulin receptor signaling and mu opioid receptor – G-protein coupling (6). FLNA does not normally link to α7-nicotinic acetylcholine receptor (α7nAChR) or toll-like receptor 4 (TLR4); however, in AD brain, the altered conformation of FLNA enables FLNA’s association with both (3). Importantly, the aberrant FLNA linkages of altered FLNA to α7nAChR and TLR4 promote toxic signaling of soluble Aβ42 via each receptor, contributing to AD pathology (3, 4).
The extremely tight binding (high femtomolar affinity) of Aβ42 to α7nAChR, first demonstrated two decades ago (7), is reinforced by altered FLNA’s linkage to this receptor (3). Aβ42 signals via α7nAChR to hyperphosphorylate tau protein by activating kinases ERK and JNK1 (8). Tau hyperphosphorylation is a hallmark of AD pathology and disrupts tau’s function of stabilizing microtubules, promoting degeneration. Hyperphosphorylated tau also initiates neurofibrillary lesions and tau protofibril formation, leading to eventual fibrillar tau-rich tangles. This toxic signaling pathway of Aβ42 via α7nAChR has been confirmed by multiple laboratories under conditions that maintain Aβ42 as soluble monomers or small oligomers (9-11).
Aβ42 activates TLR4 by binding the TLR4 co-receptor CD14 (12). Aβ42 binding to CD14 promotes a sustained activation of TLR4 and persistent release of inflammatory cytokines such as IL-6, IL-1β and TNFα (13). Like Aβ42 signaling through α7nAChR, this Aβ42-induced TLR4 activation requires the linkage of altered FLNA to TLR4 (4). The chronic activation of TLR4 by amyloid in AD leads to neuroinflammation and exacerbates neurodegeneration.
By preferentially binding the altered conformation of FLNA and restoring its native shape, PTI-125 releases FLNA from α7nAChR and TLR4, reducing Aβ42-driven tau hyperphosphorylation and neuroinflammation, thereby attenuating neurodegeneration (2). In triple transgenic AD mice, PTI-125 restored α7nAChR, NMDAR and insulin receptor signaling, improved synaptic plasticity, reduced amyloid deposits and neurofibrillary lesions, robustly attenuated inflammatory cytokine levels, and improved cognition (3). In vitro PTI-125 incubation of postmortem human AD brain (or age-matched control brain treated with exogenous Aβ42) also reduced FLNA linked to α7nAChR or TLR4, decreased Aβ42 – α7nAChR complex levels, decreased Aβ42-induced tau hyperphosphorylation, and again improved synaptic plasticity and receptor function. IC50s for these effects were nanomolar, and significant effects were seen at concentrations as low as 1 picomolar (3, 4).
This Phase 2a clinical trial follows favorable safety and tolerability data from a Phase 1 study of 50, 100, or 200 mg of PTI-125 in healthy volunteers. In this first-in-patient, Phase 2a clinical trial, thirteen mild-to-moderate AD patients received 100 mg oral PTI-125 b.i.d. for 28 days. Patients were age 50-85, MMSE ≥ 16 and ≤ 24, with a CSF T-tau/Aβ42 ratio ≥ 0.30. The 100 mg dose was selected because it is equivalent by body surface area conversion (the accepted method of determining equivalent doses between species) to effective daily doses of PTI-125 in AD mouse models (3, 4). The T-tau/Aβ42 ratio was selected as a low cutoff to confirm AD diagnosis based on biomarker determinations from samples obtained from the Swedish bioFINDER and ADNI (Alzheimer’s Disease Neuroimaging Initiative) cohorts (14), recognizing that we used commercial enzyme-linked immunosorbent assays (ELISAs) and that study used ElectroChemiLuminescence Immunoassays (ECLIAs).  Although these assays are not directly comparable, values from each are reported in pg/mL. Safety was monitored by electrocardiograms, clinical labs, adverse event monitoring and physical examinations. Change from baseline was measured for CSF and plasma biomarkers of AD pathology (T-tau, P-tau and Aβ42), neurodegeneration (neurofilament light (NfL) chain and neurogranin) and neuroinflammation (YKL-40 and inflammatory cytokines IL-6, IL-1β and TNFα). Pre-dose and Day 28 samples were tested in triplicate in a single ELISA plate according to manufacturers’ instructions.
A recent meta-analysis showed that in CSF of AD patients vs. age-matched controls, T-tau and P-tau are increased respectively by 2.5- and 1.9-fold and Aβ42 is reduced by half (15). NfL, expressed predominantly in large caliber axons and indicating axonal damage, is increased by 2.3-fold in CSF of AD patients relative to controls (15). NfL may track disease progression and is emerging as a plasma AD biomarker (16). Neurogranin, a post-synaptic protein in dendritic spines, is elevated in AD and represents synaptic/dendritic destruction (17-19). The secreted glycoprotein YKL-40, an inflammation mediator, is thought to accompany microglial activation and extracellular tissue remodeling and is also elevated in AD (18, 20, 21).




Of 19 patients screened, 13 enrolled. All 13 were mild-to-moderate AD patients, age 50-85, MMSE ≥ 16 and ≤ 24, with a CSF T-tau/Aβ42 ratio ≥ 0.30. Although the protocol stated 12 patients would be enrolled, 13 were enrolled due to multiple patients in screening near the end of the study.

Lymphocyte and plasma preparation

To prepare lymphocytes, 8 ml venous blood collected in EDTA-containing tubes was layered onto 8 ml Histopaque-1077 at 25°C and centrifuged (400 g, 30 min, 25°C) to yield plasma (top layer) and lymphocytes (opaque interface). Plasma fractions were aliquoted into Eppendorf centrifuge tubes and stored at -80°C until assay. The obtained lymphocytes were washed twice by mixing with 10 ml phosphate-buffered saline (PBS) followed by centrifugation at 250 g for 10 min. The final lymphocyte pellet was resuspended in 600 µl cell freezing medium (DMEM, 5% DMSO, 10% fetal bovine serum), aliquoted and held at -80°C until assay.

Treatment of CSF and plasma for biomarkers

CSF and plasma were thawed on ice and immediately treated with 20X protease inhibitor cocktail (Complete mini EDTA-free protease inhibitors, Roche, 04693159001) and protein phosphatase inhibitor cocktail (Phosphostop phosphatase inhibitors, Roche, 04906837001).

Determination of CSF and plasma biomarkers

Levels of biomarkers in protease and protein phosphatase inhibitor treated CSF and plasma were measured by enzyme-linked immunosorbent assays (ELISA) in triplicate against standards, according to manufacturer’s instruction.  The ELISA kits (Table 1) from Invitrogen or Lifespan were solid phase sandwich ELISAs (except neurogranin, a solid phase indirect ELISA) that detect endogenous levels of biomarkers with a specific detecting antibody followed by an anti-species IgG, horseradish peroxidase (HRP)-linked antibody to recognize the bound detection antibody. HRP substrate tetramethylbenzidine was added to develop color. Absorbance for the developed color is proportional to the quantity of protein. Absorbances were analyzed against standards by linear regression using GraphPad Prism.

Table 1. ELISA kits used to measure CSF and plasma biomarkers

Table 1. ELISA kits used to measure CSF and plasma biomarkers


Measurement of FLNA – α7nAChR/TLR4 linkages and Aβ42 –α7nAChR/CD14 complexes in lymphocytes and ex vivo Aβ42 treatment

Levels of FLNA – α7nAChR/TLR4 and Aβ42 – α7nAChR/CD14 interactions were assessed in patient lymphocytes.  Lymphocytes (200 μg) from patients at the indicated dosing days were incubated at 37°C with oxygenated protease inhibitors containing Kreb’s Ringer (K-R) or 0.1 μM Aβ42 for 30 min (250 μl total incubation volume). The assay mixtures were aerated with 95%O2/5%CO2 for 1 min every 10 min. Reactions were terminated by adding ice-cold Ca2+-free K-R containing protease and protein phosphatase inhibitors (Roche) and centrifuging. The obtained lymphocytes were homogenized in 250 μl ice-cold immunoprecipitation buffer (25 mM HEPES, pH 7.5, 200 mM NaCl, 1 mM EDTA, 0.2% 2-mercaptoethanol with protease and protein phosphatase inhibitors) by sonication for 10 s on ice, and solubilized by nonionic detergents (0.5% NP-40/0.2% Na cholate/0.5% digitonin) for 60 min (4°C) with end-to-end rotation. The obtained lysate was centrifuged at 20,000 g for 30 min (4°C) and the resultant supernatant (0.25 ml) was diluted 4x with 0.75 ml immunoprecipitation buffer. Aβ42 – α7nAChR complexes were immunoprecipitated with immobilized anti-FLNA (SC-58764 + SC-17749, Santa Cruz) or anti-Aβ42 (AB5078P, Millipore Sigma) + anti-actin (SC-8432+ SC-376421) antibodies onto protein A/G-conjugated agarose beads (#20421, Thermo). Resultant immunocomplexes were pelleted by centrifugation (4°C), washed 3x with ice-cold PBS, pH 7.2, containing 0.1% NP-40, and centrifuged. Immunocomplexes were solubilized by boiling 5 min in 100 μl SDS-PAGE sample preparation buffer (62.5 mM Tris-HCl, pH 6.8; 10% glycerol, 2% SDS; 5% 2mercaptoethanol, 0.1% bromophenol blue) and centrifuged to remove antibody-protein A/G agarose beads. Levels of α7nAChRs (SC-58607) and β-actin (SC-47778) were determined by immunoblotting, with FLNA and β-actin levels serving as the indicators of immunoprecipitation efficiency and gel loading (3, 4, 22). Blots were then stripped and re-probed with specific antibodies against TLR4 (SC-302972) and CD14 (SC-1182) to assess levels of FLNA – TLR4 and Aβ42 – CD14 associations, respectively. Blots of anti-Aβ42 immunoprecipitates size-fractionated on 20% SDS-PAGE were used to survey the molecular mass of Aβ42 using anti-Aβ42 (AB5078P, Millipore Sigma).

Measurement of phosphorylated and nitrated tau in plasma

Phosphorylated and nitrated tau in plasma were assessed using an established method (3, 8, 23). Total tau proteins were immunoprecipitated by 1 µg immobilized anti-tau (SC-65865 and SC-166060), which does not discriminate between phosphorylation states. Levels of phosphorylated tau (pS202tau, pT231tau and pT181tau), nitrated tau (nY29tau) and total tau precipitated (loading control) were assessed by immunoblotting with antibodies specific to each phosphoepitope (pS202tau: AT8 [MN1020], pT231tau: AT180 [MN1040] and pT181tau: AT270 [MN1050], all from Thermo Invitrogen), anti-nY29tau (SC-66177), and anti-tau (SC-32274).

Isoelectric point assessment

Lymphocyte FLNA was isolated using a procedure established for brain tissues (3) with slight modification. Lymphocytes (200 µg) were sonicated for 10 s on ice in 200 µl modified hypotonic solution (50 mM Tris HCl, pH 8.0, 11.8 mM NaCl, 0.48 mM KCl, 0.13 mM CaCl2, 0.13 mM Mg2SO4, 2.5 mM NaHCO3) with a cocktail of protease and protein phosphatase inhibitors. The treated lymphocytes were solubilized using 0.5% digitonin/0.2% sodium cholate/0.5% NP-40 (4°C) with end-over-end rotation for 1 h. Following centrifugation to remove insoluble debris, the lysate was treated with 1% sodium dodecyl sulfate (SDS) for 1 min to dissociate FLNA-associated proteins, diluted 10x with immunoprecipitation buffer, and immunopurified with immobilized anti-FLNA (SC-58764 + SC-17749). Resultant FLNA was eluted using 200 µl antigen-elution buffer (#21004, Thermo), neutralized immediately with 100 mM Tris HCl (pH 9.0), diluted to 500 µl with 50 mM Tris HCl, pH 7.5, and passed through a 100-kD cut-off filter to remove low-molecular weight FLNA fragments. Once purified, FLNA was suspended in 100 µl isoelectric focusing sample buffer. Samples (50 µl) were loaded onto pH 3-10 isoelectric focusing gels and proteins fractionated (100 V for 1 h, 200 V for 1 h, and 500 V for 30 min). Separated proteins were then electrophoretically transferred to nitrocellulose membranes. FLNA was identified by immunoblotting with anti-FLNA (SC-57864) antibodies.

Pharmacokinetic methods

Blood samples (4 mL) were drawn into a Vacutainer® tube containing K2EDTA, placed on ice, and centrifuged 1000 xg for 15 min. Plasma was split into two aliquots, transferred to polypropylene tubes and stored at -20°C or below until analysis.
Plasma PK parameters for PTI-125 were calculated using non-compartmental methods in WinNonlin. The peak drug concentration (Cmax), the time to peak drug concentration (Tmax), Tlast and Clast, the time to the last quantifiable drug concentration, were obtained directly from the data without interpolation. The following parameters were calculated: the elimination rate constant (λz), the terminal elimination half-life (T1/2), the AUC from time zero to the time of the last quantifiable concentration (AUClast), the AUC from time zero extrapolated to infinity (AUCinf), and the percentage of AUCinf based on extrapolation (AUCextrap(%)), Cl/F, the apparent oral clearance, and Vz/F, apparent volume of distribution. Accumulation was estimated by the ratios of the AUC on the last day of dosing to the corresponding AUC the first day of dosing.
Below limit of quantitation (BLQ) concentrations were treated as zero from time-zero up to the time at which the first quantifiable concentration was observed; embedded and/or terminal BLQ concentrations were treated as “missing.” Full precision concentration data and actual sample times were used for all pharmacokinetic and statistical analyses.

Statistics and blinding

All CSF and plasma ELISA biomarker data were analyzed by two-sided paired t test by an independent statistician. Plasma tau phosphorylation and lymphocyte data including FLNA conformation were analyzed by one-way ANOVA with post-hoc two-sided t test (unpaired) on all 13 patients, with one missing (baseline) value. All biomarker assessments were performed blind to treatment day; samples were coded prior to testing.




This first-in-patient Phase 2a trial enrolled 13 patients: 9 females, 4 males; 3 black, 10 white; 6 Hispanic, 7 non-Hispanic. Both CSF and plasma/lymphocyte data were n=12 (or n=13 with one missing value) because one patient declined the second CSF draw, and the baseline plasma/lymphocyte sample was missing for another patient. Additionally, one patient stopped dosing on Day 21, was tested positive for cocaine on that day, did not resume dosing, but returned for the CSF draw and whole blood sample on Day 28. This patient’s CSF and plasma biomarker data are included.

Safety and pharmacokinetics

In this Phase 2a trial, PTI-125 was safe and well tolerated with no drug-related adverse events. Half-life was 4.5 h, and approximately 30% accumulation was observed on Day 28 compared to Day 1 exposure. PK parameters are shown in Table 2.  The CSF to plasma ratio of the PTI-125 analyte used plasma levels from the nearest PK time point to the time of CSF draw on Day 28, or the average of two if in the middle. Ratios ranged from 0.09 to 1.2, with CSF draw times ranging from 1.15 to 7.75 h post-dose, with higher ratios trending to later time points.

Table 2. Mean PK parameters of PTI-125 100 mg b.i.d. in AD patients (± SD)

Table 2. Mean PK parameters of PTI-125 100 mg b.i.d. in AD patients (± SD)


CSF and plasma biomarkers

Consistent with PTI-125’s mechanism of action and preclinical data, PTI-125 treatment reduced CSF biomarkers of neurodegeneration and AD pathology from baseline to Day 28 (Fig. 1). T-tau decreased 20%, neurogranin decreased 32%, and NfL decreased 22%. P-tau (pT181) decreased 34%, evidence that PTI-125 suppresses tau hyperphosphorylation induced by Aβ42’s signaling through α7nAChR. CSF biomarkers of neuroinflammation were also reduced: YKL-40, IL-6, IL-1β and TNFα decreased by 9%, 14%, 11% and 5%, respectively. Plasma NfL, neurogranin, T-tau and YKL-40 levels were similarly reduced (Fig. 1). All reductions were of slightly lower magnitude in plasma except for neurogranin, which was reduced 40.7% in plasma. In contrast to the consistent and highly significant reductions of all other biomarkers, Aβ42 increased slightly in both CSF and plasma – a desirable result because low Aβ42 in CSF and plasma indicates AD. This increase, significant only in plasma due to variability in CSF, is consistent with PTI-125’s mechanism: Aβ42 bound to α7nAChR is released due to a profound reduction in Aβ42’s affinity for α7nAChR when PTI-125 binds altered FLNA and restores its native shape (2-4).

Figure 1. PTI-125 treatment reduces CSF and plasma biomarkers

Figure 1. PTI-125 treatment reduces CSF and plasma biomarkers

All CSF biomarkers elevated in AD were significantly reduced in CSF after PTI-125 treatment. T-tau, NfL, neurogranin (Nrgrn) and YKL-40 were also significantly reduced in plasma. The slight increase in Aβ42 was significant in plasma but not in CSF due to variability. Inflammatory cytokines and P-tau in plasma were not assessed. *p < 0.0001, +p < 0.001, # p < 0.01 in paired t test comparing Day 28 to pre-dose baseline. N=12. Error bars are SEM.


Spaghetti plots of individual CSF biomarker values (pg/mL) show that each patient responded to PTI-125 treatment on virtually all biomarkers (Fig. 2). Interestingly, the two patients with high Aβ42 levels showed a decrease in this biomarker post-treatment. Familial AD mutations were not assessed but may have contributed. Although cytokines can be difficult to measure, the lower limits of quantitation (2x background) were 3.9 pg/mL for IL-6 (R2 value 0.8864) and 7.8 pg/mL for both IL-1β and TNFα (R2 values 0.9374 and 0.8767, respectively).

Figure 2. Individual patient changes in CSF biomarkers

Figure 2. Individual patient changes in CSF biomarkers

Each spaghetti plot shows reductions from baseline for each patient in one of nine biomarkers of Alzheimer’s disease, neurodegeneration or neuroinflammation. Levels of Aβ42, usually low in AD patients, increased after treatment with PTI-125, except for two patients with high baseline Aβ42.  Data are plotted as pg/mL.

Because levels of phosphorylated tau defined by individual phospho-epitopes are low in CSF and even lower in plasma (as reflected in total tau levels), plasma levels of phosphorylated tau were assessed by immunoprecipitation of tau with anti-tau followed by immunoblotting of three different phospho-epitopes known to be elevated in AD. Tau phosphorylation at these sites (pT181-tau, pS202-tau and pT231-tau) was significantly reduced in plasma by 12.5%, 14.0% and 16.3%, respectively, following PTI-125 treatment (Fig. 3), corroborating pT181-tau results in CSF. Because tau is immunoprecipitated with a tau-specific antibody, tau levels serve as the control for phospho-tau and nitrated tau levels. The ratios for each P-tau epitope and nY to total tau were adjusted by the average reduction in total tau reduction (0.955 for Day 14 and 0.887 for Day 28; loading could not be adjusted in the experiment due to blinding). The higher than expected molecular weight for tau may be due to additional phosphorylation in blood; the anti-tau antibody used to detect tau is commonly used. The reduction in phosphorylated tau, together with 20.4% lower nitrated tau (nY29-tau; Fig. 3), suggests that PTI-125 can reduce tau hyperphosphorylation and oxidative stress to stabilize mitochondria and attenuate neurofibrillary lesions and neurodegeneration.

Figure 3. PTI-125 treatment reduces phosphorylated and nitrated tau in plasma

Figure 3. PTI-125 treatment reduces phosphorylated and nitrated tau in plasma

a, b, Reductions in tau phosphorylation and tau nitration found in plasma following PTI-125 treatment.  Reductions were evident by 14 days and stronger by 28 days of dosing, demonstrated by anti-tau antibody immunoprecipitation and immunoblotting with antibodies specific for each phosphorylation or nitration site. Blots (a) were evaluated by densitometric quantitation (b). *p < 0.001 vs. dosing day 0, +p < 0.01 vs. dosing day 14. N=13 with one missing value. Error bars are SEM


Mechanism and target engagement in patient lymphocytes

Patient lymphocytes, which express FLNA (24), α7nAChR and TLR4, were used to demonstrate target engagement and mechanism of action of PTI-125. Confirming the altered and acidic FLNA in AD brain (3), FLNA in patients’ lymphocytes had an isoelectric focusing point (pI) of 5.3 prior to treatment. PTI-125 treatment reverted FLNA’s pI from almost exclusively 5.3 on Day 0 to mostly 5.9 on Day 28 (Fig. 4a,b), indicating the reversal of pathological to physiological, native conformation (3).
The benefit of this shift in FLNA conformation is shown by reduced FLNA linkages to α7nAChR and TLR4 in patient lymphocytes (by 45.4% for each, Fig. 4c,d) assessed by immunoblot detection of α7nAChR and TLR4 in anti-FLNA immunoprecipitates, as previously described for assessments in AD mouse models and AD postmortem human brain (3, 4).  Finally, PTI-125 treatment benefit is also corroborated by reduced binding of Aβ42 to both α7nAChR and CD14, the co-receptor for TLR4, by 54.6% and 40.1%, respectively, demonstrated by immunoprecipitation with a specific anti-Aβ42 antibody and subsequent immunoblot detection of α7nAChR or CD14 in the immunoprecipitate  (Fig. 5a, b). Immunoblot detection of Aβ42 itself in the immunoprecipitate showed a <10 KDa species that increases following treatment, indicating small oligomers or monomers, as well as a band of 57 KDa, representing Aβ42 monomers tightly bound to α7nAChR or CD14 (7, 25), which decreased with treatment (Fig. 5c, d). The reduction in Aβ42 bound to α7nAChR is consistent with PTI-125’s 1000-10,000-fold reduction in binding affinity of Aβ42 to α7nAChR (4).

Figure 4. PTI-125 restores FLNA’s native shape and reduces FLNA linkages to α7nAChR and TLR4

Figure 4. PTI-125 restores FLNA’s native shape and reduces FLNA linkages to α7nAChR and TLR4

a, b Restoration of FLNA’s native shape. Isoelectric focusing gel (a) and its quantitation (b) show that 93% of FLNA isolated from lymphocytes prior to treatment is in the altered conformation (pI 5.3), with just 7% in the native shape (pI 5.9).  PTI-125 treatment for 28 days shifts this distribution to 40% in the altered and 60% in the native conformation. *p < 0.0001 comparing 5.9 to 5.3, #p < 0.0001 vs. dosing day 0, +p < 0.0001 vs. dosing day 14. c,d, Reductions in FLNA linkages to TLR4 and α7nAChR found in lymphocytes. Reductions are illustrated by TLR4 or α7nAChR levels detected using immunoblotting with specific antibodies in solubilized anti-FLNA antibody immunoprecipitates of lymphocytes. Additionally, exogenous Aβ42 added in vitro to lymphocytes reversed these reductions in FLNA associations, returning levels to pre-treatment baseline. Blots (c) were assessed by densitometric quantitation (d). *p < 0.001 vs. dosing day 0, +p < 0.01 and ++p < 0.05 vs. dosing day 14. N=13 with one missing value. Error bars are SEM.

The fact that reduced FLNA linkages and Aβ42 binding to α7nAChR/CD14 can be reversed by adding exogenous Aβ42 (0.1 µM) illustrates the dynamic nature of this Aβ42-mediated pathogenesis in AD. Because CSF biomarkers were notably reduced, these findings in lymphocytes of PTI-125-treated patients can be inferred also to occur in brain. In support, reductions in FLNA linkages to α7nAChR and TLR4 in lymphocytes (unpublished data) of transgenic AD mice treated with PTI-125 tracked similar reductions we reported in brains of these mice (3).

Figure 5. PTI-125 treatment reduces levels of Aβ42 bound to α7nAChR and CD14

Figure 5. PTI-125 treatment reduces levels of Aβ42 bound to α7nAChR and CD14

a, b, Reductions in levels of complexes of Aβ42 with α7nAChR and CD14 found in lymphocytes. Reductions are illustrated by α7nAChR and CD14 levels detected using immunoblotting with specific antibodies in anti-Aβ42 antibody immunoprecipitates of lymphocytes. c, d, The 57-KDa band representing Aβ42 tightly bound to CD14 or α7nAChR is progressively reduced over dosing days. Aβ42 in lymphocytes (endogenous or exogenously added) is predominantly monomeric, illustrated by size < 10 KDa (c). As with FLNA linkages, exogenous Aβ42 added in vitro to lymphocytes reversed these reductions in Aβ42 – α7nAChR/CD14 complexes, returning levels to pre-treatment baseline. Actin simultaneously immunoprecipitated by anti-actin antibodies was used as a loading control for both blots. Blots (a, c) were assessed by densitometric quantitation (b, d). *p < 0.001 vs. dosing day 0, +p < 0.01 and ++p < 0.05 vs. dosing day 14. N=13 with one missing value. Error bars are SEM


Discussion/Future development plans

In a first-in-patient clinical trial of PTI-125, CSF and plasma biomarkers of AD pathology, neurodegeneration and neuroinflammation were markedly improved following 28-day oral treatment with PTI-125. All patients showed a biomarker response to PTI-125.  The drug was well tolerated, with no observable drug-related adverse events. PTI-125’s effects in patients are consistent with its mechanism of action and published preclinical data. Target engagement and mechanism of action of PTI-125 were demonstrated in patient lymphocytes by reduced associations of FLNA with α7nAChR and TLR4, reduced binding of Aβ42 to α7nAChR or CD14 and a shift back to FLNA’s native shape, visible by isoelectric focusing point. The magnitude and consistency of reductions in several established, objective biomarkers following treatment with PTI-125 at 100 mg twice daily for 28 days imply a slower rate of neurodegeneration or a suppression of disease processes in AD.
Cognition and function were not assessed in this small study. However, elevated CSF biomarkers of P-tau and total tau/Aβ42 ratio have previously been correlated with worse performance on a wide range of memory and sustained attention assessments (26) and define the disease state if not also progression. We therefore hypothesize that decreasing these markers will favorably impact patient cognition and function or their rates of decline. Additionally, other research has shown that 11-13% decreases in CSF neurogranin and P-tau and a slower increase in CSF NfL compared to placebo over 18 months is associated with a slower rate of cognitive decline in prodromal AD patients (27).
Based on these encouraging safety and biomarker data, patients are currently being enrolled in a Phase 2b study to assess the safety, tolerability and effects of PTI-125 in patients with mild-to-moderate AD. This blinded, randomized, placebo-controlled, clinical trial will enroll approximately 60 patients with mild-to-moderate Alzheimer’s disease.  In the Phase 2b study, patients are administered PTI-125 100 mg, 50 mg or matching placebo, twice daily, for 28 continuous days. The primary endpoint is improvement in biomarkers of Alzheimer’s disease from baseline to Day 28. Although Phase 2b is too small (N=60) to generate statistically meaningful data in cognition, a cognition scale (beyond MMSE) is being utilized to guide statistical considerations for future, large-scale clinical investigations with PTI-125. Unambiguous improvements in cognition and function is a key efficacy criterion for FDA approval of a new drug in AD (28), a hurdle which, to date, no drug candidate for AD has met with clear and compelling clinical data. Ultimately, to demonstrate disease modification in AD, future investigations must correlate improvements in biomarkers by PTI-125 with beneficial effects on cognition and function.


Funding:  This trial was funded by grant award AG060878 from the National Institute on Aging at NIH.

Acknowledgements: We sincerely thank NIA for their support of our work in Alzheimer’s disease. We thank the clinical investigators and patients who have participated in the clinical program for PTI-125. We thank consultants Chuck Davis for statistics on ELISA biomarkers and Jeff Stark for PK analyses.

Conflict of interest: LHB, CAC, RB and NF are employees of Cassava Sciences, Inc. HYW and MRM are science advisors to Cassava Sciences, Inc. ELB and BN are employees of IMIC, Inc., an independent clinical site that participated in this study.

Role of the sponsor: Cassava Sciences, Inc. provided all drug supply and material support for this clinical research, designed the study in consultation with its advisors and monitored the conduct of the study and data collection. Biomarker assays were conducted blind to treatment day by HWY and his lab at CUNY Medical school. LHB assisted in the interpretation of the data and wrote the manuscript together with RB and HWY.

Ethical standards: All participants and their caregivers provided written informed consent. The protocol, informed consent forms and clinical sites were all approved by Advarra IRB.



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