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Therapeutic development for Alzheimer’s disease at

AUTHORS lzheimer’s disease (AD) is the most In vitro experiments and current in vivo Michael Hutton1, Michael Irizarry2, common form of dementia, which models are not adequate to fully address 3 2 2 Mark Mintun , Phyllis Ferrell , Eric Siemers , is estimated to affect more than this multitude of complex questions and 2 2 Christer Nordstedt & Ronald DeMattos A 1 46 million people worldwide . This number is inform on the likelihood of therapeutic 1 Eli Lilly and Company, Lilly Research expected to double every 20 years, reaching success; the ultimate test of a hypothesis, Centre, Erl Wood Manor, Sunninghill 131.5 million by the middle of the century. As therefore, comes from large-scale clinical trials. Road, Windlesham, Surrey GU20 6PH, a result, in the absence of effective disease- However, therapeutic development, from United Kingdom. 2 Eli Lilly and Company, Lilly Corporate modifying therapies, AD is projected to have initial hypothesis to non-clinical compound Center, Indianapolis, Indiana 46285, USA. an increasing impact on patients, carers and on development and phase 1, 2 and 3 clinical 3 Avid Radiopharmaceuticals, Inc society, with massive costs incurred by health trials, can take up to 15 years and cost in (a wholly owned subsidiary of Eli Lilly systems throughout the world. excess of a billion dollars5. This expensive and Company), 3711 Market Street In its earliest clinical stages, AD is typically and lengthy development process limits Philadelphia, Pennsylvania 19104, USA. associated with a progressive loss of memory the number of potential therapies that can Address for correspondence: and other cognitive domains. Subsequently, be tested and partly explains why, despite Michael Hutton, Eli Lilly and Company, this leads to functional deficits in activities considerable investment in the academic and Lilly Research Centre, Sunninghill Road, of daily living, neuropsychiatric symptoms in pharmaceutical sectors, there is currently no Windlesham, Surrey GU20 6PH, UK. some patients and ultimately death2. Strong disease-modifying therapy that can slow or e-mail: [email protected] genetic and biochemical evidence highlights halt disease progression. The symptomatic a central role for the amyloid pathway in treatments that are available, cholinesterase the pathogenesis of AD3. The central theme inhibitors and (an NMDA receptor of the ‘amyloid hypothesis’ is that protein antagonist), provide only modest cognitive mis-folding of the amyloid-β (Aβ) benefits and these are rapidly overwhelmed as leads to the extracellular accumulation of toxic the disease progresses2. Aβ aggregates, including β-amyloid plaques, Given the increasing prevalence of AD, which are the causative factor for the initiation addressing this unmet medical need is of of the neurodegenerative cascade that includes primary importance. Lilly is committed to inflammation, gliosis, neuronal damage and improving treatment options for AD and synaptic loss. Furthermore, the injury caused has been working towards this goal for by extracellular Aβ aggregates is thought to 28 years. Here, we outline our extensive trigger the spread of neurofibrillary tangle pipeline of potential therapeutics and (NFT) pathology in the form of misfolded, molecular diagnostics that reflect this aggregated tau proteins beyond the medial longstanding investment. temporal lobe4 — a key step in the onset of clinical symptoms. The combined insults lead Lilly’s Alzheimer’s disease to synapse loss, neuronal cell death and tissue therapeutic portfolio atrophy. Importantly, although significant Lilly’s AD programme is focused on developing progress has been made over the past two disease-modifying therapies that slow or decades, many mechanistic unknowns remain, halt clinical progression by targeting the including what is the exact neurotoxic moiety underlying causes of the disease. We have of Aβ (soluble oligomer or fibril), what is the prioritized targets and pathways that are nature of the interaction between extracellular validated by human genetics. This has led to β-amyloid/Aβ and intracellular tau, what is the our current emphasis on Aβ/β-amyloid and role of inflammation in the neurodegenerative tau. In addition, although our main focus cascade and what ultimately drives is on disease modification, we continue to neuronal death3? look for improved treatments for both the

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disease modification across the full range of people with AD, reflecting the different disease stages and other variables in this population. Moreover, despite recent increases in our knowledge, there is considerable uncertainty about which species of amyloid

and tau are most important for synaptic- and SPONSOR FEATURE neurodegeneration, and by extension which are most important to target for effective treatment. Second, by targeting different points in the pathogenic process we have the opportunity to develop rational combinations that have the potential for enhanced efficacy compared with individual monotherapies.

Figure 1 | Lilly’s Alzheimer’s disease portfolio. Therapeutics and diagnostics in clinical and late Aβ/β-amyloid therapeutics preclinical development are shown. The names of individual assets are listed with molecular targets Most of Lilly’s disease-modifying programmes shown in parentheses. The development stage of each asset is indicated in the bar chart. Aβ, in clinical development target Aβ/β-amyloid amyloid-β peptide; BACE, β-secretase; mAb, ; N3pG Aβ; amyloid-β peptide with (Fig. 2). This emphasis on Aβ/β-amyloid pyroglutamate modification at position 3; 1D PAM, D1 dopamine receptor positive allosteric modulator. reflects the robust genetic and pathological evidence that supports an early and causative

role for Aβ (especially the longer form Aβ42) in the development of AD3. In addition, recent evidence from clinical trials of experimental Aβ/β-amyloid therapies has provided further support for this approach3. The current portfolio of programmes target Aβ production and Aβ/β-amyloid clearance with a mixture of small molecules and monoclonal antibodies. To target Aβ production, Lilly has two BACE1 inhibitors in clinical development. These molecules inhibit β-secretase, which is one of two enzymes responsible for the generation of Aβ from the amyloid precursor protein (APP) (Fig. 2). The more advanced of these molecules (AZD3293) is being developed in partnership with Astra Zeneca and is now in Figure 2 | Targeting multiple stages in the amyloid cascade for disease modification.Schematic phase 3 trials, having successfully passed an representation of the amyloid cascade with Lilly’s current disease-modification programmes shown interim phase 2 safety assessment in early 2016. at the pathogenic stages they impact. Targeting multiple stages in the disease cascade as shown This molecule has previously been shown to also enables the development of rational combinations that are expected to have enhanced efficacy reduce Aβ levels in cerebrospinal fluid (CSF) by compared with individual monotherapies. APP, amyloid precursor protein; Aβ, amyloid-β peptide; more than 70% at a dose of 50mg per day in

BACE, β-secretase; mAb, monoclonal antibody; AZ BACEi, AZD3293 BACE inhibitor; N3pG Aβ; healthy volunteers. The current phase 3 trial of amyloid-β peptide with a pyroglutamate modification at position 3. AZD3293 (AMARANTH, NCT02245737) is being conducted in patients who have prodromal and mild amyloid-PET positive AD. A second cognitive and psychiatric symptoms of AD. We (florbetapir), a β-amyloid PET tracer and phase 3 trial (DAYBREAK-ALZ, NCT02783573) recognize that even after disease-modifying flortaucipir, a tau PET tracer in phase 3 trials is being conducted in patients with mild-AD treatments become available there will be a (Figs 1 and 3). only. The second BACE1 inhibitor (LY3202626) continued, or even increased, need for effective The disease-modifying programmes are is a highly potent molecule that entered phase symptomatic therapies. intended to target different points in the 2 trials in 2016 (NAVIGATE-AD, NCT02791191). At present Lilly’s AD therapeutic portfolio hypothesized pathogenic cascade with a LY3202626 has been shown to reduce CSF Aβ includes seven assets that are in clinical major focus on Aβ production, Aβ/β-amyloid levels by more than 90% at a dose of 26mg development (Fig. 1). These include six clearance and tau pathology (Fig. 2). The per day (for 14 days) in healthy volunteers. potential disease-modifying therapies and rationale behind targeting the disease at This BACE inhibitor freely penetrates the a novel approach to improving cognitive multiple stages is that, first, as with other brain, which, combined with its high potency, function. The current portfolio also includes chronic diseases, we anticipate that multiple means that low doses will produce substantial two molecular diagnostics: Amyvid therapies will be required to achieve optimal reductions in CNS Aβ levels. This reduces

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the risk of peripheral off-target effects, including those mediated by BACE2 inhibition. Other BACE inhibitors currently in clinical development are not selective for BACE1 over BACE2. LY3202626 can also be used to explore higher levels of central Aβ reduction (>90%)

SPONSOR FEATURE than has been previously possible. To enhance Aβ/β-amyloid clearance, Lilly is developing two types of monoclonal antibody (mAb) therapy (Fig. 2). The first type of antibody binds selectively to monomeric Aβ and does not bind to aggregated β-amyloid deposits. The most advanced example of this type of antibody is solanezumab, which is in phase 3 clinical testing6. Solanezumab binds to monomeric Aβ with high affinity, primarily in Figure 3 | Imaging tau pathology in patients with 18F-flortaucipir.Summary of the images collected the periphery and as a consequence is thought from baseline scans in a phase 2 study of 18F-flortaucipir (adapted from ref 10). Each brain PET scan to reduce the pool of free monomer in the was normalized by the activity in the cerebellum, averaged across the patients in each diagnostic central nervous system (CNS). In turn, this group and displayed as a coronal slice. Cognitively normal subjects without amyloid positivity leads to a shift in CNS Aβ equilibria to favour (18F-florbetapir) show minimal retention of tracer in the cortex, but there is evidence of early tau the dissolution of β-amyloid deposits as well signals on the amyloid-positive cognitively normal subjects in the inferior temporal lobes. In both as smaller oligomeric assemblies, which may these groups, the overall tau signal across the cortex is low. By contrast, in subjects with cognitive represent the most toxic Aβ species. In two impairment and amyloid positivity, there is increased signal in the temporal lobes, and in the presence previous phase 3 trials (EXPEDITION 1 and 2) of dementia tau signals in multiple lobes of the brain. These data suggest that 18F-flortaucipir PET is in mild-moderate AD, solanezumab missed its able to provide important information on the spread of neurofibrillary tangles (NFT) with Alzheimer’s primary endpoints. However, in a pre-specified disease progression. secondary analysis, solanezumab treatment was associated with a 34% slowing in the rate of cognitive decline (measured using antibody of this type, currently in phase 1 β-amyloid was observed in our preclinical

ADAS-Cog14) in patients with mild AD from the trials, is a humanized immunoglobulin (IgG) 1 models, indicating the therapeutic potential of two trials6. As a result, a further phase 3 trial (LY3002813) directed at an Aβ that is this combination. was initiated (EXPEDITION 3, NCT01900665) present only in β-amyloid plaques (Aβ modified

that included only patients with mild AD with with a pyro-glutamate residue, N3PG). The Tau pathology therapeutics

β-amyloid pathology, as evidenced by amyloid murine surrogate of this anti-N3pG Aβ antibody The accumulation and trans-neuronal PET scans or CSF analyses. Initial findings from has previously been shown to robustly spreading of aggregated tau is the second EXPEDITION 3 are expected to be announced clear pre-existing β-amyloid deposits in a area of focus for Lilly’s disease-modifying at the end of 2016. A second immunotherapy transgenic model (PDAPP line)7. Importantly, therapeutic portfolio. Neurofibrillary tau in the portfolio, which targets monomeric Aβ is β-amyloid clearance occurred in the absence pathology has been shown to correlate closely Aβ antibody Fab-PEG, which like solanezumab of microhaemorrhage, suggesting that this with clinical progression both through classical is expected to shift Aβ equilibria in favour antibody may be able to remove β-amyloid in neuropathological studies and in patients of dissolution of Aβ aggregates in the CNS. patients without causing vasogenic oedema using Lilly’s tau PET tracer flortaucipir10. However, this asset, in contrast to solanezumab, — a common safety concern observed in Moreover, genetic evidence from related is the -binding fragment (Fab) of a mAb human studies with previous therapeutic human tauopathies has demonstrated that targets soluble monomeric Aβ linked to antibodies with a similar mechanism7,8. Recent that tau dysfunction is sufficient to cause

a polyethylene glycol molecule. Aβ antibody phase 1 clinical data with the anti-N3pG Aβ neurodegeneration, further supporting Fab–PEG is optimized for subcutaneous dosing, antibody have indicated that 3 to 5 doses the hypothesis that the development and and more rapid clearance of antibody–Aβ of LY3002813 10mg kg-1 intravenously can spread of tau pathology is crucial for disease complexes than solanezumab. It also has an reduce amyloid deposits (amyloid PET) in progression in AD11. It seems increasingly likely extremely high affinity for monomeric Aβ patients with AD by a mean of 40–50% over that Aβ/β-amyloid accumulation predisposes (around 50-fold greater than solanezumab), 7 months, without evidence of vasogenic the spread of tau pathology beyond the medial which may enhance the pharmacodynamic oedema9. Although antibody treatment was temporal lobe into connected neocortical impact on Aβ clearance. Aβ antibody Fab–PEG complicated by immunogenicity, these initial regions (Fig. 3)4,10. The precise mechanism of is currently in phase 1 trials. observations suggest that preclinical findings tau-pathology spread remains unclear, but

The second class of anti-amyloid mAb with the anti-N3pG Aβ antibody will translate attention has increasingly focused on the in the Lilly portfolio binds exclusively to to patients with AD. In addition, when the trans-neuronal transmission of aggregated

β-amyloid deposits and is thought to remove N3pG murine surrogate antibody was used in tau seeds that are capable of templating pre-existing β-amyloid through microglial- combination with a BACE inhibitor, a synergistic their structure onto endogenous tau within mediated phagocytosis. The most advanced and near complete removal of pre-existing connected neurons12.

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This ‘prion-like’ transmission of tau develop when a threshold level of preclinical and early AD, we aim to identify pathology is the basis of Lilly’s leading tau neurodegeneration occurs in the hippocampus potential surrogate markers of progression and therapeutic (Figs 1 and 2) — a humanized and entorhinal cortex. Further deterioration treatment effects. mAb (tau mAb) designed to bind and to dementia (CDR 1–3) is associated with neutralize extracellular tau seeds, preventing NFT pathology spread, progressive synaptic Molecular diagnostics: an their transmission to other synaptically loss and neuronal loss on a background established amyloid PET tracer connected neurons. The murine surrogate of of peak amyloid deposition. Based on this and the advent of tau imaging SPONSOR FEATURE the therapeutic tau mAb has previously been formulation, AD pathophysiology occurs in the In addition, to delivering therapeutics, shown to efficiently inhibit tau pathogenesis hippocampus, entorhinal cortex and neocortex Lilly is committed to the development of in multiple transgenic models of human at different times and rates, accounting for the innovative molecular diagnostics, exemplified tauopathy. This tau mAb is currently in phase 1 clinical features of the disease. by amyloid and tau PET tracers that are trials and is Lilly’s first tau therapeutic to Accordingly, the greatest impact of being used to identify patients with AD enter clinical development. A second small- disease-modifying therapeutics is likely to pathology, track progression and demonstrate molecule tau therapy, designed to block the be earlier in the disease, prior to irreversible treatment response. Lilly’s amyloid PET intra-neuronal formation of tau aggregates, neuronal loss. However, the disease tracer, 18F-florbetapir, has been extensively is currently in late preclinical development process is slow and variable, especially in investigated, including the first study to (Figs 1 and 2). preclinical and prodromal stages, so that compare PET images to histopathology at clinical trials require large sample sizes autopsy. This led to 18F-florbetapir being the Improved therapies for and a long duration to identify treatment first imaging agent to gain regulatory approval symptom relief effects (in the current absence of a surrogate to estimate β-amyloid neuritic plaque density16. The major focus of Lilly’s AD programme is the biomarker). The Lilly clinical development In addition to the potential clinical utility, development of disease-modifying therapies, programmes for solanezumab and two multiple applications of 18F-florbetapir as a however, we are also committed to the BACE inhibitors (AZD3292 and LY3202626) biomarker for the presence and progression delivery of improved treatments for the relief highlight several approaches to address of amyloid plaques in AD research have been of both the cognitive and neuropsychiatric these challenges: initiating treatment explored. One recent focus, has been on symptoms of AD. This recognizes that earlier in the disease, enriching for AD the use of amyloid imaging to provide early improved symptomatic treatments will still pathology based on confirmation of amyloid detection of AD pathology, prior to symptoms. be needed even after disease-modifying status, and incorporation of biomarkers of This is being tested by using 18F-florbetapir therapies become available. The most neurodegeneration as potential surrogate PET to screen for preclinical AD in the first advanced symptomatic treatment within markers of progression and treatment effect. major therapeutic trial for an at-risk, but 17 the Lilly portfolio is a D1 receptor positive The original solanezumab EXPEDITION 1 asymptomatic population . allosteric modulator (D1 PAM), which is mainly and 2 phase 3 clinical trials involved people In contrast to amyloid plaque tracers, a treatment for cognitive decline in Alzheimer’s with mild-moderate AD without confirmation the discovery of tracers for the visualization and Parkinson’s disease (Fig. 1). Dopamine’s of amyloid status. Treatment benefit in of neurofibrillary tau pathology has been action on D1 receptors in the prefrontal cognition and function was observed in very recent. Lilly’s most advanced tau tracer, cortex has long been shown to be crucial patients with mild AD pooled from the 18F-flortaucipir (previously AV1451 and T807) for memory and central executive function two studies, but a significant proportion of was described in 2013 (ref. 18) as having a high 13 in both primates and humans . D1 PAMs, patients in the study were found to be amyloid affinity for filamentous tau lesions and selectivity therefore, offer the potential to alleviate negative15. To replicate and expand on the compared with other β-pleated pathological cognitive dysfunction by restoring dynamic EXPEDITION 1 and 2 results, subsequent deposits. The first in-human study of healthy dopaminergic modulation in prefrontal cortex solanezumab studies are focusing on control subjects and subjects diagnosed impaired by neurodegenerative disease. Lilly’s earlier stages of disease, including mild AD with AD demonstrated good brain uptake leading D1 PAM is currently in a phase 1 trial. (EXPEDITION 3, NCT01900665); prodromal AD and, in those with AD, subsequent cortical (ExpeditionPRO, NCT02760602); preclinical AD retention of tracer in areas consistent with the Clinical development strategy for (A4, NCT02008357); and presymptomatic AD pathological distribution of neurofibrillary disease-modifying therapies in autosomal dominant AD mutation carriers tau19. As neurofibrillary tau pathology tracks Current models of AD pathogenesis and its (DIAN, NCT01760005). These studies, as well as with neurodegeneration and the clinical relationship to clinical symptoms are based the clinical trials of BACE inhibitors AZD3293 progression of the disease4, 18F-flortaucipir is on neuropathology, basic science, clinical (AMARANTH (NCT02245737), DAYBREAK–ALZ being developed as a potential biomarker of research and biomarkers14. An asymptomatic (NCT02783573) and LY3202626 (NAVIGATE– neurodegeneration. To this end, Lilly has made preclinical stage (clinical dementia rating AD (NCT02791191)) require confirmation of 18F-flortaucipir widely available for academic

(CDR) of 0) is defined by amyloid accumulation amyloid status by CSF Aβ42 or amyloid PET research, and there are currently more than throughout the cortex, beginning years imaging. The solanezumab, AZD3293 and 40 studies underway using this imaging tool. before clinical symptoms. Amyloid deposition LY3202626 clinical trials also have sub-studies Recent human data have demonstrated that predisposes people to NFT pathology and assessing effects of treatment on imaging PET imaging with 18F-flortaucipir can reproduce neurodegenerative changes in vulnerable markers of neurodegeneration such as tau PET the Braak staging of neurofibrillary tangles in brain regions. The initial symptoms of mild and volumetric MRI. By incorporating a range patients and have provided insights into the cognitive impairment (prodromal AD; CDR 0.5) of biomarkers across multiple clinical trials in role of β-amyloid in driving the spread of tau

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pathology10 (Fig. 3). It is therefore hoped that tau 5.5 million by 2050 (ref. 20). Lilly is working benefit, disease-modifying treatments need imaging can shed new light on AD pathobiology to meet this challenge by delivering a to be given early in the course — ideally before and, potentially, accelerate the development of comprehensive portfolio of disease-modifying symptoms occur — when there is the greatest new therapeutics. therapeutics and diagnostics that are designed opportunity to preserve brain function. to increase our ability to successfully identify, Solving this problem will involve patient and Concluding remarks treat and prevent AD. doctor education, in particular removing the

SPONSOR FEATURE AD and other forms of dementia represent It is important, however, to recognize stigma associated with the disease, which one of the most significant health-care crises that the development of effective disease- delays many people seeking help. It will affecting modern society. The projected modifying treatments will be just the start also require increased access to molecular increase in the number of patients over the of the process to address the developing diagnostics that can identify the patients next 50 years, if not addressed, will have an AD crisis. Currently, health-care systems are who will respond to these therapies early in enormous impact on the lives of patients, designed for the symptomatic treatment their disease. carers and worldwide healthcare systems1. As a paradigm and change is necessary to reach the At Lilly, we recognize that one company result the development of disease-modifying patients that will benefit most from disease- alone cannot be successful. Therefore, therapies that can slow the progression, or modifying therapies. In particular, health-care in addition to the development of new delay the onset, of dementia is becoming systems will need to adapt their approach medicines, Lilly is committed to working with increasingly important. It is estimated that a to detection and diagnosis. At present, most health-care systems around the world and, treatment that delays the onset of dementia patients either never receive a diagnosis or where appropriate, to have a role in ensuring by just 5 years would reduce the number are diagnosed at a relatively late stage of that the right patients, get the right drug, at of patients in the United States alone by the disease (US data20). But to have greatest the right time.

REFERENCES 1. Prince, M. et al. World Alzheimer Report 2015. 9. Irizarry, M. C. et al. Safety, pharmacokinetics 16. Yang, L. et al. Brain amyloid imaging: FDA The Global Impact of Dementia (Alzheimer’s (PK), and florbetapir F-18 positron emission approval of florbetapir F18 injection. N. Engl. Disease International, 2015). tomography (PET) after multiple dose J. Med. 367, 885–887 (2012). 2. Kelley, B. J. & Petersen, R.C. Alzheimer’s administration of LY3002813, a β-amyloid 17. Sperling, R. A. et al. The A4 study: stopping disease and mild cognitive impairment. plaque-specific antibody, in Alzheimer’s AD before symptoms begin? Sci. Transl. Med. Neurol. Clin. 25, 577–609 (2007). disease (AD). In Proc. Alzheimer’s Assoc. Int. 6, 228 (2014). 3. Scheltens, P. et al. Alzheimer’s disease. Lancet Conf. (AAIC, 2016). 18. Xia, C. F. et al. Early clinical PET imaging 388, 505–517 (2016). 10. Schwarz, A. et al. Regional profiles results with the novel PHF-tau radioligand 4. Crary, J. F. et al. Primary age-related tauopathy of the candidate tau PET ligand [F18]-T808. J. Alzheimers Dis. 38, 171–184 (PART): A common pathology associated 18F-AV-1451 recapitulate key features (2014). with human aging. Acta Neuropathol. 128, of Braak histopathological stages. Brain 19. Chien, D. T. et al. Early clinical PET imaging 755–766 (2014). 139, 1539–1550 (2016). results with the novel PHF-tau radioligand 5. Paul, S. M. et al. How to improve R&D 11. Hutton, M. et al. Association of missense [F-18]-T807. J. Alzheimers Dis. 34, 457–468 productivity: the pharmaceutical industry’s and 5’-splice-site mutations in tau with the (2013). grand challenge. Nature Rev. Drug Discov. 9, inherited dementia FTDP-17. Nature 393, 20. Alzheimer’s Association. 2015 Alzheimer’s 203–214 (2010). 702–705 (1998). disease facts and figures. Alzheimer’s 6. Siemers, E. R. et al. Phase 3 solanezumab trials: 12. Jackson S. J. et al. Short fibrils constitute the Dementia 11, 332–415 (2015). Secondary outcomes in mild Alzheimer’s major species of seed-competent tau in the disease patients. Alzheimer’s Dement. 12, brains of mice transgenic for human P301S 110–120 (2016). tau. J. Neurosci. 36, 762–772 (2016). 7. DeMattos, R. et al. A plaque-specific 13. Goldman-Rakic, P. S. The cortical dopamine antibody clears existing β-amyloid plaques system: role in memory and cognition. Adv. in Alzheimer’s disease mice. Neuron. 76, Pharmacol. 42, 707–711 (1998). 908–920 (2012). 14. Perrin, R. J. et al. Multimodal techniques 8. Racke, M. M. et al. Exacerbation of for diagnosis and prognosis of Alzheimer’s cerebral amyloid angiopathy-associated disease. Nature 461, 916–922 (2009). microhemorrhage in APP transgenic mice 15. Doody, R. S. et al. Phase 3 trials of immunotherapy is dependent on antibody solanezumab for mild-to-moderate recognition of deposited forms of amyloid-β. Alzheimer’s disease. N. Engl. J. Med. J. Neurosci. 25, 629–636 (2005). 370, 311–321 (2014).

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