Novel Treatments for Alzheimer Disease Disorders

Alzheimer disease (AD) is characterized by progressive cognitive and functional decline and emergence of neuropsychiatric symptoms driven biologically by accumulation of amyloid-β protein (Aβ) plaques, neurofibrillary tangles (NFTs), and neuron loss.¹ The canonical features of AD are accompanied by a variety of other disease processes, including inflammation, vascular changes, accumulation of other proteins (eg, transactive response DNA-binding protein 43 [TDP-43] or α-synuclein), mitochondrial dysfunction, and synaptic abnormalities.

AD is a major threat to public health. As the world’s population ages, more individuals enter the age-related risk period of AD and exhibit progressive cognitive decline. There are 5.8 million individuals in the US with AD dementia and this will increase to 14 million by 2060.² Worldwide figures are even more staggering, with a current 40 million with AD dementia increasing to over 130 million by 2030.^3,4

Despite the high frequency and great burden of AD, there has been limited progress in developing new therapies. Since 2003, the Food and Drug Administration has approved only 1 new drug (aducanumab), and only 1 other agent (sodium oligomannate approved in China in 2019) has been approved in any other country. Despite a history of trials that have found no effect of other candidate treatments, there have been enormous learnings in trial design, outcome measures, appropriate populations for trials, biomarkers, and clinical trial conduct.⁵ These lessons provide the foundation for ever more refined hypotheses to be tested in ongoing and planned trials.

The Common Alzheimer Disease Research Ontology (CADRO) developed by the National Institute on Aging and International Funders summarizes therapeutic targets in AD and associated proposed mechanisms of action (MOAs) of drugs in development (Box). This review presents selected examples of drugs from the CADRO categories in current or recent clinical trials. The treatments are divided into biologic therapies such as monoclonal antibodies (MAbs) or small molecule therapeutics. Small molecule refers to drugs of low molecular weight that can penetrate the blood-brain barrier, typical

The clinical trials database clinicaltrials.gov shows 126 agents in clinical trials (accessed January 5, 2021).⁶ Putative disease-modifying therapies (DMTs) account for 82.5% of these agents. Cognitive-enhancing agents account for another 10.3% , and 7.1% of pipeline agents are being developed to address neuropsychiatric symptoms of AD. Drugs with targets related to Aβ, tau, inflammation, bioenergetics, and synaptic plasticity are the CADRO categories with the largest number of agents in trials.

Amyloid-β Protein Targeting Agents

Amyloid-β-Directed MAbs

Observations in animal models showing removal of amyloid plaque by vaccine-induced antibodies provided the groundwork for advancing immunotherapy for AD.^7,8 The first human trial of an Aβ-directed vaccine was suspended when a small number of patients developed an allergic encephalitis.⁹ Autopsy studies of the vaccinated participants documented reduced Aβ plaque burden, that encouraged continued investigation of the promise of immunotherapy for AD.¹⁰

MAbs are the principal immunotherapies for AD in clinical trials and the most common approach to targeting Aβ in the AD drug development pipeline. Table 1 summarizes the 11 Aβ-directed MAbs being assessed. in phase 1, phase 2, and phase 3 clinical trials. Aducanumab had a promising phase 1b trial, after which 2 phase 3 trials were begun but terminated after futility analysis suggested no benefit of treatment.^11,12 Longer-term observations and accrual of additional data, however, indicated 1 of the trials met the primary objective, and the second showed a response among those treated with higher doses for longer periods of time, suggesting that the therapeutic response is time and dose dependent.¹² Although an FDA Advisory Panel recommended against approval¹³; other reviewers found the data to be convincing for a treatment response.¹² Aducanumab has been approved by the FDA, becoming the first DMT for AD, and now enters the armamentarium of AD treatments addressing cognitive decline in those with early AD.

The most promising results in terms of a plausible clinical response were seen with antibodies that reduce plaque amyloid as shown by amyloid positron emission tomography (PET). MAbs that reduced insoluble plaque amyloid include aducanumab, lecanemab, gantenerumab, and donanemab. Removal of plaque may be associated with reduced oligomeric protofibrillar forms of Aβ identified as being more neurotoxic than other species of Aβ.^14,15

MAbs are administered intravenously (aducanumab, lecanemab, donanemab) or subcutaneously (gantenerumab). People administered these agents should have demonstrated presence of brain amyloid on PET or as cerebrospinal fluid (CSF) levels of Aβ_1-42. Individuals may also be required to have repeat brain MRIs, at least in the introductory phases of use, to monitor for amyloid-related imaging abnormalities (ARIA).¹⁶ These agents will make unprecedented demands on health care systems for safe delivery of treatment. Ensuring available appropriate treatment will require collaboration among multiple stakeholders including pharmaceutical companies, clinicians, health care system leaders, advocacy groups, patients and care partners, and policy makers.

Amyloid-Directed Small Molecules

Tramiprosate is a prodrug for homotaurine, a modified amino acid previously tested in clinical trials. The prodrug formulation has a longer half-life and less variability in blood levels than seen with the parent compound. ALZ-801 and its metabolites inhibit formation of toxic Aβ oligomers. Prior trial data suggest that people with 2 copies (homozygotes) of the apolipoprotein E ε4 (ApoE4) allele benefited from treatment with tramiprosate, and a trial in participants who are homozygous for ApoE4 has been initiated.¹⁷

Tau Protein Targeting Agents

Tau-Directed MAbs

NFTs composed of hyperphosphorylated tau are another pathologic hallmark of AD, and tau is a target for MAb therapies. Table 2 shows 7 tau-targeted MAbs in clinical trials. Tau is thought to spread from neuron to neuron in established brain networks, and some MAbs (eg, tilavonemab and somorinemab) target extracellular tau as it passes between neurons. Other MAbs are directed at intracellular tau targets, requiring that they penetrate both the blood-brain barrier and cell membranes (eg, JNJ-63733657). IONIS-MAPTRx is a unique approach using an antisense oligonucleotide (ASO) intended to inhibit the translation of tau RNA into tau protein.

Tau abnormalities correlate more strongly with cognition than Aβ, suggesting successful therapy directed at tau may interrupt cognitive decline.¹⁸ Tau PET using ligands that identify NFTs allows identification of potential clinical trial participants who have specific brain levels of tau.¹⁹ Low tau levels might be required for trials attempting prevention of cognitive decline in individuals with preclinical AD, whereas higher levels of tau might be required for trials that target disease progression in people who are mildly symptomatic.

Tau-Directed Small Molecules

PU-AD has effects on multiple proteins characteristic of neurodegenerative disorders; it is an epichaperome inhibitor of heat shock proteins (eg, Hsp90 and Hsc70) that promote neurodegeneration in animal models. PU-AD has effects in animal models of AD, Parkinson disease (PD), amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington disease.²⁰ Although being studied for tauopathies, PU-AD could be a candidate therapy for multiple proteinopathies. PU-AD stabilizes Hsp90 and decreases phosphorylated tau (p-tau) and tau oligomers in experimental models of AD.²¹ PU-AD has been through phase 1 ascending-dose studies; a phase 2 trial involving participants with AD is anticipated.

ApoE, Lipid, and Lipoprotein Receptors

ApoE4 is the major genetic risk factor for AD and is present in 55% to 65% of people with late-onset AD (LOAD). ApoE2 confers protective effects and lowers the risk of LOAD.²² Experimental approaches targeting this biology and under consideration as potential treatments include agents that reduce ApoE4 levels, increase ApoE2 levels, block ApoE4-enhanced Aβ aggregation, switch isoforms, and block protein transcription as well as ApoE4-directed antibodies, and ApoE4 gene editing.^23,24 Some of these interventions have been shown to affect intended targets in experimental settings.²⁵ Based on nonclinical studies in mouse models, a phase 1 trial using an adeno-associated virus gene transfer vector expressing circular DNA (AAVrh.10-ApoE-2) aims to convert ApoE-ε4 isoforms to ApoE-2 isoforms.²⁶

Neurotransmitter Receptors

Drugs developed to reduce behavioral symptoms of AD or to produce cognitive enhancement both target neurotransmitter receptors. Of drugs being developed to reduce agitation, brexpiprazole is an atypical antipsychotic with a multireceptor binding profile that includes dopamine-2 receptors. AV786 and AX-05 engage the N-methyl-D-aspartate (NMDA) receptor; nabilone targets cannabinoid pathways; and prazosin is an α-adrenergic receptor antagonist.^27-30 Cognitive-enhancing agents target several neurotransmitter receptors including muscarinic and nicotinic acetylcholine receptors.³¹

Neurogenesis

Allopregnanolone is a neurosteroid with cell-regenerative potential being studied in people with early AD. The agent activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons.³² In animal models of AD, allopregnanolone increased neurogenesis and reduced inflammation and Aβ levels.³³ Pharmacokinetic characteristics of allopregnanolone have been defined in preparation for later stage trials.³⁴

Inflammation

Inflammation is increasingly recognized as having a major role in AD and other neurodegenerative disorders. The anticancer drug lenalidomide modulates innate and adaptive immune responses and is an example of an anti-inflammatory agent being studied for potential benefit in AD. Lenalidomide is a pleiotropic agent that lowers expression of proinflammatory factors tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-8, and increases the expression of anti-inflammatory cytokines (eg, IL-10). In animal models of AD, lenalidomide treatment decreased brain levels of TNF-α messenger RNA (mRNA), β-site amyloid precursor protein cleaving enzyme 1 (BACE1) mRNA and protein levels, and Aβ plaque loads. Improved cognitive performance was observed.³⁵ Lenalidomide will be assessed in a phase 2 trial in participants with mild cognitive impairment (MCI) caused by AD.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is associated with increased microglial activation, reduced brain amyloid, and improved memory in transgenic mouse models of AD. In a phase 2 double-blind, randomized, placebo-controlled trial, sargramostim, a recombinant human GM-CSF was administered to 40 participants with mild-to-moderate AD dementia 5 days/week for 3 weeks with follow-up visits on day 45 and 90. A statistically significant benefit was seen on the Mini-Mental State Exam (MMSE) but not the Alzheimer Disease Assessment Scale-cognitive (ADAS-cog) subscale or the Alzheimer Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scale. Biomarker changes were consistent with an immunomodulatory effect of sargramostim.³⁶

Masitinib is a tyrosine kinase inhibitor that inhibits mast-cell activity and migration and decreases survival of mast cells involved in the neuroinflammation present in AD. A 24-week phase 2 trial of masitinib found a response on cognitive measures but not functional outcomes.³⁷ Further trials are planned.

Triggering receptor expressed on myeloid cell 2 (TREM2) is a lipid receptor expressed in microglia. Impaired TREM2 function enhances microglial reactivity and increases inflammatory response to Aβ plaque formation. TREM2 overexpression in mouse models of AD has the reverse effect of less microglial activation and reduced reaction to plaque formation. Treatment of 5 Aβ transgenic mice expressing TREM2 with AL002, a MAb that has TREM2 agonist activity, reduced plaques, dystrophic neurites, and inflammation and improved behavioral symptoms. AL002, is being assessed in 2 phase 1 trials in volunteers without cognitive impairment or AD and participants with mild-to-moderate AD dementia.

Oxidative Stress

Plasma exchange with albumin replacement has been evaluated in a clinical trial for AD.³⁹ This approach may sequester Aβ from the peripheral blood, reducing brain Aβ levels. Albumin has antioxidant effects that may contribute to the observed effects. Further trials are planned.

Cell Death

Neuroprotection is the goal of all disease-modifying therapy. Deposition of Aβ and hyperphosphorylated tau are intermediate processes leading to cell death; sufficient intervention in these processes has the goal of neuroprotection and disease modification.⁴⁰

Bryostatin, a protein kinase C-ε (PKC-ε) activator, reduces apoptosis and cell death, enhances synaptogenesis, and reduces Aβ oligomers and hyperphosphorylated tau in nonclinical studies of cellular models relevant to AD.⁴¹ A phase 2 clinical trial in moderately severe and severe AD failed to meet primary outcomes;⁴² further studies are planned.

GV1001 is a 16-amino-acid protein fragment corresponding to the catalytic site of human telomerase reverse transcriptase. Telomere shortening has been proposed as a promoter of age-related disease, and induction of telomerase may protect against neurodegeneration.⁴³ In nonclinical studies, GV1001 was neuroprotective, reducing reactive oxygen species (ROS), oxidative stress, apoptosis and inflammation, and stabilizing mitochondria. In a phase 2 trial of GV1001 given subcutaneously every 4 weeks for 24 weeks to participants with moderate-to-severe AD, there was less decline on Severe Impairment Battery (SIB) scores with the higher of 2 doses. No other significant differences between GV1001 and placebo were seen, however.⁴⁴ Additional studies related to telomerase reverse transcriptase and telomere shortening are planned.

Proteostasis/Proteinopathy

Posiphen exemplifies targeting proteostasis/proteinopathies. This oral agent is a protein translation inhibitor that decreases the levels of amyloid precursor protein (APP) and Aβ in transgenic models of AD and lowers α-synuclein in cell models of PD.^45,46 Posiphen is in a dose-finding study for AD and PD and in a treatment trial of participants with early AD.

Nilotinib is a tyrosine kinase inhibitor approved for treatment of Philadelphia chromosome-positive chronic myeloid leukemia. Nilotinib also targets discoidin domain receptors and effectively reduces protein misfolding, including Aβ and tau proteinopathies in animal models of neurodegeneration. A 1-month phase 2 study of nilotinib included 37 participants with mild-to-moderate AD dementia. There was a significant drug-placebo difference on amyloid PET in the frontal lobe with decrease in the active treatment group vs an increase in the placebo group, although there was no significant difference between drug and placebo groups for whole brain amyloid. Comparing nilotinib vs placebo, CSF Aβ₄₂ levels were reduced at 12 months, p-tau-181 was reduced at 6 and 12 months, and hippocampal volume loss was attenuated by 27% at 12 months.⁴⁷

Metabolism and Bioenergetics

There are many bioenergetic agents in the AD pipeline, most of which are repurposed antidiabetic agents, including glucagon-like peptide-1 (GLP-1) agonists (eg, semaglutide and liraglutide) and a biguanide (metformin). In AD models, GLP-1 agonists have reduced neurodegeneration, enhanced synaptic plasticity, and improved learning and memory.⁴⁸ Epidemiologic studies support a decreased risk of AD among people taking these agents for treatment of their diabetes.⁴⁹ Liraglutide was associated with preserved brain metabolism on fluorodeoxyglucose (FDG)-PET compared with placebo in a double-blind study involving participants with AD.⁵⁰

Vasculature

Vascular factors are linked to increased risk of AD and identified in the CADRO system as targets for AD treatment. Angiotensin receptor blockers (ARBs) used for treating hypertension have been associated with reduced risk of progression from MCI to AD.⁵¹ Several antihypertensive agents alone or in combination with other agents with potential vascular effects are in clinical trials. Nilvadipine, a calcium channel blocking agent, with nonclinical observations suggesting a potential benefit in AD, was tested in an 18-month, phase 3 randomized controlled trial involving 511 participants with mild-to-moderate AD dementia; no benefit was observed.⁵²

Growth Factors and Hormones

Hormones and growth factors are identified as potential targets in the CADRO system for AD drug development. ATH-1017 (NDX-1017) increases expression of the hepatocyte growth factor (HGF)/MET receptor system. HGF enhances neuron survival and proliferation, increases hippocampal synaptic plasticity, and improves learning and memory in mice overexpressing HGF.⁵³ MET receptors are reduced in postmortem studies of the hippocampus of patients with AD.⁵⁴ ATH-017 is in a phase 2 AD clinical trial.

Synaptic Plasticity and Neuroprotection

Several programs are targeting synaptic protection. CT1812 is a brain penetrant small molecule antagonist of the σ-2 calcium receptor complex. In several animal models of AD, CT1812 displaced Aβ oligomers bound to synaptic receptors, facilitated oligomer clearance into the CSF, increased synaptic number, and improved cognitive performance. In human participants with AD, CT1812 significantly increased CSF concentrations of Aβ oligomers, reduced concentrations of proteins indicating of synaptic injury (ie, neurogranin and synaptotagmin), decreased p-tau fragments, and reversed CSF expression of proteins implicated in synaptic structure and function.⁵⁵

The enzyme glutaminyl cyclase promotes formation of synaptotoxic pyroglutamate-Aβ oligomers, and inhibition of glutaminyl cyclase in AD is promising.⁵⁶ In a 12-week phase 2 study of participants with biomarker-proven early AD (MCI and mild AD dementia), varoglutamstat significantly reduced glutaminyl cyclase activity, with an average target occupancy in the CSF over 90%. There was a significant reduction of theta power in the EEG frequency analysis and a significant improvement in the One Back test of the Neuropsychological Test Battery (NTB). YKL-40, a marker of inflammation, was significantly reduced. No significant drug-placebo differences were observed in Aβ, total tau, p-tau, or neurogranin levels.⁵⁷

Neflamapimod is an inhibitor of the intracellular enzyme p38 mitogen activated protein kinase α (MAPK p38). Nonclinical mechanistic studies show that p38 mediates impaired synaptic plasticity associated with Aβ, inflammation, and p-tau.⁵⁸ The adverse effects on synaptic function may reflect defective synaptic endocytosis mechanisms regulated by Rab5 which in turn is under the control of MAPK p38. Neflamapimod was tested in 16 participants in an open-label study to determine the effects on brain amyloid and neurocognitive function.⁵⁹ Variable effects were seen on amyloid PET and improvement was observed on memory performance. More studies are anticipated.

The Gut-Brain Axis

Sodium oligomannate is one of the few agents in the AD drug development pipeline targeting the gut-brain axis.^60,61 This agent was approved in China in 2019 for treatment of cognitive impairment in mild-to-moderate AD. In animal models of AD, this marine-derived oligosaccharide changed the microbiome from a species composition unique to the models toward the wild-type microbiota. There was an accompanying reduction in peripheral inflammation and concomitant decrease in neuroinflammation, brain Aβ, and brain levels of tau. A phase 3 trial conducted in China demonstrated a sustained, statistically significant improvement on the ADAS-cog in those treated with sodium oligomannate compared with those treated with placebo; there was a trend toward benefit on the Clinician’s Interview-Based Impression of Change with Caregiver Input (CIBIC+).⁵³ No drug-placebo difference was observed on functional or behavior measures. No biomarkers were included in the Chinese phase 3 trial to confirm the microbiome-based mechanism in humans. A global phase 3 trial with clinical and biomarker outcomes is in progress.

Circadian Rhythm and Sleep

Lemborexant is a dual orexin antagonist (DORA) being investigated for treatment of irregular sleep wake rhythm disorder (ISWRD) and restoring circadian rhythm parameters including nighttime sleep and daytime wakefulness in patients with AD. A phase 2 dose-finding study showed benefits for participants with AD dementia on a measure of the least-active 5 hours daily, rest-activity rhythms, and mean duration of sleep.⁶² Further studies are anticipated.⁴ Another DORA, suvorexant, was assessed for treatment of insomnia in participants with mild-to-moderate AD dementia. There was a significant increase in total sleep time, reduction in awakenings after sleep onset, and improved sleep efficiency as demonstrated by polysomnography.⁶³ Suvorexant labeling was adjusted to include efficacy and safety information for use in individuals with AD.

Environmental Factors

Trials addressing environmental factors most often involve lifestyle interventions. In a 2-year, randomized, double-blind trial involving participants with vascular risk factors and mild changes in cognition, participants received either a multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring or were assigned to a control group that received general health advice. After 2 years in the study, individuals who received the structured intervention performed significantly better on the NTB compared with those who had received general health advice.⁶⁴ Global replication of the study is in progress and other lifestyle intervention trials are planned or on-going.

Epigenetic Factors

Accumulation of epigenetic changes with aging results in DNA methylation, histone modification, and chromatin remodeling. Overexpression of the enzyme histone deacetylase (HDAC) promotes tau hyperphosphorylation and inhibits tau degradation.⁶⁵ Targeting HDAC in clinical trials is an attractive therapeutic approach, and clinical trials of HDAC inhibitors nicotinamide and vorinostat are in progress.

Multiple Targets

Many drugs have multiple targets. In some cases, these are intended, whereas in others the unintended target engagement results in “off-target” effects or side effects. Drugs are typically classified according to the principal effect for which they have been optimized.

Rasagiline was discovered and developed as a monoamine oxidase inhibitor (MAO-I) and then found to improve mitochondrial function and reduce amyloid accumulation, tau hyperphosphorylation, NFT formation, and neuron loss.^66,67 The Figure shows the scope of biologic effects of rasagiline and its major metabolite on processes relevant to AD. Rasagiline was assessed in a 6-month phase 2 proof-of-concept trial with changes in the biomarker, FDG PET as the primary outcome. The study met its primary end point, demonstrating significantly less decline in FDG-PET in middle frontal, anterior cingulate, and striatal regions in participants receiving rasagiline compared to those given placebo. Clinical measures showed benefit in quality of life, digit span, and verbal fluency. No drug-placebo differences were observed on the ADAS-cog or measures of activities of daily living.⁶⁸ This study shows that this class of agents may slow metabolic changes related to the biologic effects of rasagiline and that trials with larger sample sizes may demonstrate treatment benefits on clinical outcomes.

Porphyromonas gingivalis is a bacteria species associated with chronic periodontitis. At autopsy, these pathogens have been identified in the brain of people with AD along with toxic proteases produced by the bacteria, termed gingipains. Administration of gingipains to mice causes AD-like brain changes including AΒproduction. Atuzaginstat is a gingipain inhibitor that, in infected mice, reduced the bacterial load of the P. gingivalis brain infection, blocked Aβ production, reduced neuroinflammation, and rescued hippocampal neurons in the hippocampus.^69,70 Effects on Aβ production, inflammation, and neuron survival provide the basis for classifying atuzaginstat as having multiple target effects. A phase 3 trial of atuzaginstat in people with AD is ongoing.

Filamen A is needed for interaction of α-7 nicotinic receptors with Aβ₄₂. In nonclinical studies, blocking binding of Aβ to filamen A by sumafilam, reduced Aβ aggregates, tau hyperphosphorylation, and inflammatory cytokine release.⁷¹ A phase 2 open label study of 13 people with mild-to-moderate AD dementia, found significant changes in CSF and plasma biomarkers consistent with the proposed mechanism.⁶⁰ Total tau, neurogranin, and neurofilament light (NfL) chain levels decreased by 20%, 32% and 22%, respectively, and p-tau181 level decreased 34%. Neuroinflammation biomarkers (ie, YKL-40 and inflammatory cytokines) decreased by 5% to 14%. Biomarker effects were similar in CSF and plasma when both were available. Further studies of sumafilam are anticipated.

Discussion

This review describes select agents in trials and demonstrates how the CADRO classification is applied in drug development. Many agents have more than 1 biologic effect and might be classified in several groups or as compounds exhibiting multiple effects. Studies are needed to determine when an agent interacts with multiple targets, as described by the CADRO system, and when drug-related changes are consequences of an upstream effect with multiple measurable downstream changes. This review identifies compounds with principal intended targets. A wide variety of targets and interventions are discussed, and their nonclinical backgrounds described where available.

The success of AD drug development is low,⁷² but the recent approval of aducanumab changes the treatment and drug development landscapes. Combination therapies can be anticipated as mechanistic information on AD biology and its treatment-related manipulation grows. In addition, refinement of biomarkers, populations, and trial conduct make successful drug development more likely.⁷³

Acknowledgement

Dr Cummings is supported by NIGMS grant P20GM109025; NINDS grant U01NS093334; NIA grant R01AG053798; NIA grant P20AG068053; and NIA grant R35AG7147.