Matt Hoffman

A little more than a century ago, a German psychiatrist and neuropathologist by the name of Aloysius Alzheimer, MD, first described the pathology and symptoms of a disease known as presenile dementia at a 1906 meeting of the Southwest German Psychiatrists.

Nearly 4 years later, his colleague and fellow psychiatrist Emil Kraepelin, MBBS, coined the name 

 in the publication of his eighth edition of the 

Since then, the disease has captivated those who treat the elderly and cognitively impaired, though serious and modern attempts to develop treatments for the disease did not begin until much later in the twenty-first century. Despite that delay, the understanding of Alzheimer disease pathology has become clearer over these last hundred years, though its etiology remains clouded.

Similarly, even with the advances of modern medicine and rigorous trials, the attempts to develop disease-modifying therapies have resulted in what Gregory Day, MD, MSc, once described to 

as a “graveyard of past studies” filled to the brim with the headstones of agents that have failed to produce a viable candidate drug.

While COVID-19 has maintained its grips on the attention of the public in 2020, in the circles of physicians treating Alzheimer disease, another topic has ensnared the conversation: the investigational agent aducanumab.

The challenge of solving this disease has proven in all this time to be as complex and frustrating as the disease itself. 

For this reason, it came as no surprise in 

 when Biogen and Eisai announced that they were discontinuing a pair of phase 3 clinical trials, EMERGE and ENGAGE as well as a phase 2 safety study, EVOLVE, after the independent data monitoring committee determined that the candidate therapy would not achieve the primary end point. 

At the time, it appeared as though aducanumab would be just another addition on the growing list of failures. The amyloid-clearing agent seemed to be positioned to fall into the obscurity that accompanies that futility, and some viewed this as the proverbial nail in the coffin for theamyloid-beta (Aβ) hypothesis.

But, in October, the pair of pharmaceutical giants announced they were changing course to seek FDA approval for aducanumab, and by December, new data from 

 and post hoc analysis of a subset of high-dose treatment in 

 were presented at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) meeting, December 4–7, 2019 in San Diego, California. 

The data suggest that there were statistically significant changes on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores, with 

 values of .010 or .031 based on cutoff dates.

Suddenly, it seemed that aducanumab had legs to stand on, and in January 2020, the FDA gave the go-ahead for Biogen to re-administer aducanumab to patients who were previously enrolled in the trials in a phase 3b redosing study as it prepared to submit for approval. 

Almost as immediately, a fissure of opinions split the medical community. On one side stands those who believe the therapy is poised to become the first-in-class treatment that patients with Alzheimer disease and their families have been waiting on for decades. On the other side stood those skeptical of such an unanticipated 

This division has bubbled over the course of 2020, coming to somewhat of a head in early November, when the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted not to recommend regulatory approval of 

, in possibly the most anticipated advisory committee decision of the year. 

 suggested this division was clear and present, with 40.5% (n = 53) noting their disagreement with the committee, 37.4% (n = 48) stating their agreement, and another 22.1% (n = 30) declaring their uncertainty overall.

It’s no secret that the 2 sides of this aducanumab-engraved coin emerged as a result of the October 2019 data announcement. 

The analyses, even by admission of those involved in the process, as investigator Marwan Sabbagh, MD, director, Cleveland Clinic Lou Ruvo Center for Brain Health, told 

, are extremely complex and can be equally challenging to understand. Ultimately, those who stand with aducanumab have clung to these additional data as the anchor of their favorable view of the drug.

Sabbagh, along with co-investigator Jeffrey L. Cummings, MD, ScD, director emeritus, Cleveland Clinic Lou Ruvo Center for Brain Health and vice-chair, department of brain health, University of Nevada–Las Vegas, also noted in an editorial published days before the Advisory Committee meeting that “the results of the aducanumab studies have not been published in peer‐reviewed form” suggesting that until those data are available to the public, these “discussions must be seen as tentative.” 

Though the point made by Sabbagh and Cummings is a salient one, the lack of access to these data outside of what was presented a full year prior at 

“[The data are] contextually driven, in that it's not like the EMERGE data is by itself. It comes built on the on the shoulders of PRIME, [the phase 1b trial,] and there is clearly a dose-related effect and it is clearly driven at the highest dose,” Sabbagh said. “Every time you see the FDA come out with a position statement, it keeps lowering the bar. At the last iteration, a year ago, EMERGE data hit the target of what the FDA has said is the threshold it will consider [for approval]. I think it hits that, so I disagree with the negative voices.”

Additionally, the data shows a consistent reduction of clinical decline as measured by the pre-specified secondary end points: The Mini Mental State Exam (MMSE; 18% versus placebo; 

= .05), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13; 27% versus placebo; 

 = .01) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI; 40% versus placebo; 

As well, imaging of amyloid plaque deposits showed that both low- and high-dose aducanumab were associated with reduced burden compared with placebo at 26 and 78 weeks (

Alongside that belief in the data stands an undeniable desire to bring a long-lost hope back to the forefront of the Alzheimer community—one shared by both sides. After Biogen’s biologics license application was filed in July 2020, FDA set a decision date for aducanumab for March 7, 2021.10 Although an approval would not bring a cure for the disease or the end of a decades-long fight, it would potentially usher in a new and modern era of treatment for 

“It would just be the beginning; a steppingstone. Rather than the final breakthrough, it would be the first,” principal investigator Stephen Salloway, MD, MS, director, Neurology and the Memory and Aging Program, Butler Hospital, told 

. “To quote a colleague of mine, ‘in order to get the best-in-class drug, we must have the first-in-class drug.’ That's how I see this.”

The context of this present moment, as Sabbagh put it, is rooted in the last 17 years of failure. In that time, at least 40 phase 3 studies have failed, equating to more than $8 billion in investments with nothing to show for the efforts. 

As a result, several companies have left the space altogether, deeming the effort not worth the cost. It would not be out of the question to assume this has led to a bit of cynicism piling on top of healthy skepticism. But many still believe in the therapy’s chances at approval.

The need for an approval in Alzheimer has never been greater, and in part, this prerequisite has motivated the scientific community to ensure the upkeep of rigorous and well-executed clinical trials. As such, the other side of the aducanumab coin has pointed to the need for further analysis when it comes to the investigational treatment.

The pushback on the excitement about aducanumab is perhaps best summarized by a commentary from a trio of authors: David S. Knopman, MD, professor of neurology, Mayo Clinic; David T. Jones, MD, assistant professor of neurology and radiology, Mayo Clinic; and Michael D. Greicius, MD, MPH, associate professor of neurology and neurological sciences, Stanford Hospital and Clinics. Published in 

 in early November, it pointed to the lack of evidence presented to correlate the observed biomarker changes in treated patients to actual cognitive benefits.

Acknowledging that cognitive benefits are a possible offering of the therapy, Knopman, who was a site investigator in the aducanumab trials, and colleagues proposed that the existing data are “clearly insufficient to support a claim of efficacy,” even when looking past the distortions brought on by the premature termination of the trials. Most notably, they surmised that the finding of 1 positive (EMERGE) and 1 negative (ENGAGE) result from the 2 trials “is a statement of inconclusiveness.”

As well, they pointed to the differing performances of placebo groups in the 2 trials. “The larger decline in the placebo group in EMERGE is an alternative explanation for statistically significant benefits for high‐dose aducanumab in that trial,” they wrote.

For many, the issue is rooted in the point raised by Knopman and colleagues about pairing a positive and negative trial together and calling the result definitive. 

Lon Schneider, MD, MS, professor of Psychiatry and the Behavioral Sciences, and Della Martin Chair in Psychiatry and Neuroscience, University of Southern California Keck School of Medicine, told 

 that for him, the challenge for aducanumab all started with Biogen’s reversal, and because of the trial results, the controversy shouldn’t exist to begin with.

“The studies weren't completed. The studies were stopped. They were stopped for futility, and now you have incomplete studies,” Schneider said. “That's the beginning of it. If these studies had actually been completed and showed something like they're showing now, we would have controversy, but we would not have controversy over whether the positive study was a positive study. We would have some controversy over whether it was adequate and well-controlled, certainly.”

He explained that the majority of the discussions surrounding aducanumab are based on the notion that the studies, particularly EMERGE, were completed. One particular conversation that did not operate on this perception, he noted, is the Advisory Committee meeting—the results of which speak for themselves.

“What should have happened is that they should have done 2 studies and completed those 2 studies. Both could have been positive, adequate, and well controlled, and the drug would have been approved,” Schneider said. “Or 1 would have been positive and the other would have had data that could be interpreted as confirming. Here, they don’t have the data that could be interpreted as confirming.”

Those in the camp with Schneider and Knopman ultimately do not oppose the approval of a first-in-class therapy. In fact, they have not even given up hope that aducanumab could be that therapy—really, they just want to see more data. There is debate, though, about when those data should be collected. Sabbagh and Cummings, for example, called for a phase 4 study after the potential approval, whereas Knopman and Schneider, want another phase 3 trial.

“If there's a future here, they need to do an adequate and well-controlled trial. At least 1, that's all that's needed. Now, you don't have to do a trial of 1600 patients over a year and a half necessarily. It could be a shorter, more focused trial,” Schneider explained. Either way, it seems, the doubt around the available data has been sowed.

The controversy surrounding aducanumab has seemingly brought about more questions than it has answered. Expectedly, many have brought forward opinions about the challenges of simply conducting a trial in Alzheimer disease—which is no walk in the park—and pointed to how an approval may impact future trials and which scales of measurement they use. Perhaps, though, it might push the field in the right direction. At the very least, this discussion has helped highlight the remaining obstacles in therapy assessment.

“I hope if we have an approval of the of the first disease modifying therapy, in a population of pre-dementia care, I hope that future trials continue to focus on the earliest stages, the pre-dementia phases,” Richard S. Isaacson, MD, director, Alzheimer’s Prevention Clinic, Weill Cornell Medicine, told 

. “I also hope that it pushes people to think about even earlier than that, meaning the preclinical or pre-symptomatic phases. I also hope that when trials are planned, they're planned in a way that stratifies outcomes based on genetics, not just clinical outcomes, but safety outcomes. It's really important to plan ahead. In terms of sex differences, we need to be very mindful that Alzheimer, in a lot of ways, is somewhat different in men versus women. We need to have diversity in our recruitment. The 

 belief for variants is different in terms of its impact in women versus men, and, for example, African Americans versus Caucasians. We're lumping all these folks together, who we may need to split up, in order to truly understand our outcomes. If we're mismatching everyone together, the data is going to be garbage in, garbage out.”

Ultimately, these challenges are not going to be addressed in the next 3 months, but the FDA will come to a decision on aducanumab by then. Whether an approval will in fact usher in a new era or set a precedent for trials in Alzheimer remains to be seen. The agency can still approve the therapy in spite of its Advisory Committee not recommending that path, and if it does, the impact that will have is at best an educated guess.

Probing the 2 sides for certainty leaves one without much certainty at all, and the last year of debate and data analysis has seemingly only muddied the water. Fortunately, though, through all of this, there has been an indisputable constant weighing on the minds and influencing the positions of both sides: the patients.

Articles

After a sudden reversal and complex analyses, aducanumab’s future rests in the hands of the FDA while the community stands split on if the available data are enough to justify an approval.

Support, Skepticism, and Statistics: The Aducanumab Saga 

This article, "Amyloid ß and Tau Pathology Linked to Dementia With Lewy Bodies Phenotype," was originally published in NeurologyLive.

The 2 Alzheimer disease pathologic proteins—amyloid-ß and tau—are common in individuals with probable 

 (DLB) and associated with the clinical phenotype.

Alzheimer's disease pathologic changes are common in DLB and are associated with the clinical phenotype. Amyloid-β is associated with cognitive impairment and tau pathology is associated with a lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.

Ultimately, the investigators observed that amyloid-β co-occurred with tau pathology in 15% of probable DLB patients, implying that about that percentage of probable DLB patients fulfill the biologic definition of Alzheimer, likely with mixed Lewy body disease pathology.

Conducted by Daniel Ferreira, PhD, assistant professor of neurobiology, care sciences and society, Division of Clinical Geriatrics, Karolinska Institut, and Department of Radiology, Mayo Clinic, and colleagues, the study stratified patients by amyloid-β (A+) and tau (T+) biomarker positivity, which was determined by cerebrospinal fluid (CSF) amyloid-β 1-42 and phosphorylated tau testing. The assessment included 417 patients with DLB.

Those who were A-T- made up the largest subgroup in the study population (n = 162; 39%), followed by A+T- (n = 135; 32%), A+T+ (n = 64; 15%), and A-T+ (n = 56; 13%). This distribution of amyloid-ß and tau pathology was strongly modulated by age (

 <.001) with the percentage of groups with an A+ biomarker doubling with older age.

In total at age 55, the A+T+ group made up 8% of the cohort and the A+T- group made up 19%. At age 85, those groups consisted of 25% and 45% of the cohort, respectively.

In contrast, the percentage of the A-T- group decreased to a third with older age, to 61% at age 55 compared to 20% at age 85. The percentage of the A-T+ group remained relatively comparable across ages.

“The novelty of our study is that it demonstrates the frequency of amyloid-β and tau biomarkers and several influencing factors in probable DLB patients during life across a wide age range. In this context, we interpret A+T- as an Alzheimer’s pathologic change and A+T+ as AD, that is, AD likely concomitant to Lewy body disease pathology in this cohort,” Ferreira and colleagues wrote.

As well, the AT group distribution also varied according to sex (

<.001). APOE ε4 positive status for each group was as follows: A-T- (28%), A-T+ (50%), A+T- (59%), A+T+ (64%).

All told, 55% of the A+T+ were men compared with the A- groups (A-T- and A-T+), both of which consisted of 75% men. APOE ε4 carriers were more common ingroups who were A+ or T+ (A+T-, 59%; A-T+, 50%; A+T+, 64%) compared with the A-T- group (28%).

“When plotting sex and APOE versus age we observed that the percentage of A+T- and A+T+ seemed to increase in parallel with age in both men and women,” Ferreira et al. wrote. “In APOE ε4 carriers, we observed that the A+ groups achieved higher percentages at younger ages than in APOE ε4 non-carriers, which considerably reduced the percentage of A- groups over the age of 70 in APOE ε4 carriers.”

Of the tests the group ran for heterogeneity across centers, none were statistically significant except for Mini-Mental State Exam (MMSE) by APOE ε4 carrier status (

= .02). MMSE scores for the A-T- group was 23.6, the A-T+ group was 22.6, the A+T- group was 21.5, and for the A+T+ group was 20.3.

Those with 1 or 2 positive biomarkers tended to be older (

 <.05)compared with the A-T- group. Those differences in MMSE were found to be independent of age and associated with both the A+ and T+ biomarker positivity, with no significant interaction between A+ and T+ observed (

The percentage of A-T- decreased with age and A+ and T+ increased with age both in women and men. The A+ biomarker increased more in 

 ε4 carriers with age than in non-carriers and was the main predictor of lower cognitive performance when considered together with T+. As well, T+ was associated with a lower frequency of parkinsonism and probable rapid eye movement sleep behavior disorder.

“Our data from multiple sites across Europe and the United States indicate that amyloid-β pathology is common in probable DLB, increases with age, and contributes to global cognitive impairment,” Ferreira and colleagues concluded. “Tau pathology is relatively less common and when present it seems to influence Lewy body disease clinical phenotype with a lower frequency of clinical features of probable DLB.

“These data may help to advance our ability to distinguish the clinical phenotype associated to concomitant AD pathology in patients with probable DLB, with potential implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB,” they wrote.

The findings of this multicenter cohort may have implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.

Alzheimer Pathologic Changes Linked to Dementia With Lewy Bodies Phenotype

This article, "Transient Orthostatic Hypotension Appears Common in Parkinson Disease" was originally published in NeurologyLive.

New data shows transient orthostatic hypotension (tOH) is at least as common as classic orthostatic hypotension (cOH) in patients with 

 (PD) and occurs as an age-dependent phenomenon.

The new assessment included 173 patients with Parkinson and an age- and gender-matched control group of the same size, and uncovered that tOH occurred in 24% (n = 41) of those with Parkinson compared to 21% (n = 37) of controls (OR, 1.1; 95% CI, 0.6–2.0; 

 = .759), while cOH occurred in 19% (n = 32) and 0%, respectively, and 12% (n = 20) of those with Parkinson fulfilled OH criteria after a single minute of standing.

Notably, 40% (n = 69) of patients with Parkinson had a history of falls, 29% of which were due to syncope. PD patients with history of orthostatic intolerance and syncope had a more severe systolic BP fall and lower diastolic BP rise upon standing, most pronounced in the first 30 to 60 seconds.

“Transient blood pressure falls when changing to the upright position may be overlooked with bedside blood pressure measurements but contribute to orthostatic intolerance and syncope in Parkinson disease,” the authors, including Alessandra Fanciulli, MD, PhD, department of neurology, Medizinische Universität Innsbruck, wrote in conclusion. “Continuous non-invasive blood pressure monitoring upon standing may help identify a modifiable risk factor for syncope-related falls in parkinsonian patients.”

Pathological blood pressure regulation upon standing was observed in 41% (n = 71)of patients with Parkinson and 21% (n = 37) of controls. After adjustment for the total number of drugs, use of anti-hypotensive, anti-hypertensive and central nervous system-acting drugs other than dopaminergic medications, patients with Parkinson showed an OR of 2.0 (95% CI, 1.2–3.5; 

 = .013) for any form of orthostatic blood pressure dysregulation.

The researchers defined tOH as a systolic blood pressure fall of ≥20 mmHg or diastolic ≥10 mmHg resolving within the 1st minute upon standing, and cOH as a sustained systolic BP fall of ≥20 mmHg or diastolic ≥10 mmHg within 3 minutes upon standing. “In those with Parkinson, we reviewed the medical records of the 6 months preceding and following autonomic testing for a history of falls, syncope, and orthostatic intolerance,” they noted.

When comparing the Parkinson cohort with the age- and gender-matched patients with orthostatic intolerance but a negative neurological history, there were similar frequencies of initial OH (iOH), although delayed orthostatic blood pressure recovery was significantly more frequent in those with Parkinson than in controls (

In the 6 months following or prior to cardiovascular autonomic function testing, syncope was documented in 13% (n = 22) of patients with Parkinson, occurring upon standing in all but 2 patients and was associated with falls (

History of syncope was present in 17% of the Parkinson group who had an altered blood pressure regulation upon standing and in 10% of those without.

“Performing a standing test under continuous heart rate and blood pressure monitoring may thus help in identifying a modifiable cause of syncope-related falls in patients with a suggestive medical history,” the investigators wrote.

The frequency of syncope did not differ between PD patients diagnosed with tOH versus cOH at cardiovascular autonomic function testing (10% versus 23%, respectively).

Upon standing, those with Parkinson and a history of syncope showed lower absolute systolic blood pressure values after 30 seconds (

 = .016), as well as more severe systolic blood pressure falls, which were most pronounced after 30 seconds (

“To the best of our knowledge, this is the first study specifically investigating tOH in Parkinson,” the researchers said. “IOH40/20, as defined by the 2018 Guidelines for the Diagnosis and Management of Syncope of the European Society of Cardiology, occurred rarely. The observed frequency of delayed orthostatic blood pressure recovery was also lower than previously reported for the general aging population. Patients with Parkinson mostly showed milder transient orthostatic blood pressure changes, i.e., iOH20/10, but overall, tOH was at least as common as cOH in the present study.”

The group concluded by noting that in light of the frequency and potential impact on Parkinson-related symptoms, including tOH as an outcome measure in interventional trials targeting OH should be recommended.

Transient Orthostatic Hypotension Commonly Found in Parkinson Disease

This article, "Dementia-Related Psychosis Places Heavy Burden on Patients and Caretakers," was originally published in NeurologyLive.

New research shows laryngeal movement disorders could serve as a diagnostic biomarker for multiple system atrophy (MSA), which could help distinguish the disease from 

 following systematic assessments of laryngeal dysfunction identifying it as highly prevalent in this patient population.

Conducted by a group including Georg Ebersbach, MD, chief physician, Parkinson Clinic, Movement Disorders Hospital, Kliniken Beelitz GmbH, the study found that with flexible endoscopic evaluation of swallowing (FEES), 93% of patients (n = 53) with MSA demonstrated laryngeal dysfunction compared with only 1.8% of patients (n = 1) in the matched Parkinson cohort (

In total, the study included 57 patients with MSA and 57 patients with Parkinson disease. In the MSA group 43 patients presented with more than 1 laryngeal symptom on FEES.

“FEES is becoming increasingly available in neurology departments worldwide, and we therefore suggest that whenever MSA is suspected, patients should undergo a systematic and standardized endoscopic MSA‐FEES task protocol assessment of laryngeal function to improve diagnostic certainty of MSA and delineation from Parkinson, taking other clinical signs into account,” Ebersbach and colleagues concluded. “Furthermore, we suggest that endoscopic laryngeal findings, above all the occurrence of irregular arytenoid cartilages movements, should be implemented into the next revised diagnostic criteria for MSA.”


Of those with MSA, 43.9% (n = 25) showed clinically overt laryngeal dysfunction with inspiratory stridor, compared to none of the patients with Parkinson.

The investigators noted there was “considerable discrepancy” between overt clinical symptoms of laryngeal pathology and the abnormalities observed during the task protocol, which has been somewhat identified by prior literature in 2019 showing the difficultly in diagnosing inspiratory stridor in MSA.

Additionally, they pointed to the work of Ozawa et al. in 2010, showing that irregular arytenoid cartilages movements (iACM)—which investigators observed in 91.2% (n = 52) of those with MSA compared to 0% of the Parkinson cohort (sensitivity, 0.9; specificity, 1.0; 

 <.0001)—are likely to precede the clinical onset of inspiratory stridor, which might explain their observations of its occurrence of iACM without inspiratory stridor.

Ebersbach and colleagues observed that iACM were present at rest in 80.7% (n = 46) of the MSA group, and could be provoked in an additional 10.5% (n = 6) patients during a newly designed positioning task.

“Therefore, laryngeal function should be assessed as early as possible, even without clinical evidence of laryngeal motion abnormalities, when MSA is suspected,” Ebersbach and colleagues wrote. “To further support this recommendation, we performed a subgroup analysis and showed that laryngeal motion abnormalities are present as early as 1 year after disease onset.

The aforementioned analysis revealed that the frequency of laryngeal findings was independent of MSA phenotype (χ

 = 0.15) and a diagnostic level of certainty (χ

The MSA cohort did have some significant differences from the matched Parkinson cohort, coming with shorter disease duration (MSA: 4 years [interquartile range (IQR), 3–5]; Parkinson: 7 years [IQR, 5–10]; 

 <.0001), higher disease severity (MSA: Hoehn and Yahr stage, 4 [IQR, 3–4]; Parkinson: stage, 3 [IQR, 2–4]; 

 <.0001), and more physical impairment (MSA: Unified Parkinson's Disease Rating Scale motor score, 35.5 [IQR, 29.8–41.8]; Parkinson: motor score, 28 [IQR, 19–36]; 

Additional analysis showed that patients with MSA had higher rates of vocal fold motion impairment (75.4%; n = 43; At rest: 66.7% [n = 38]), paradoxical vocal fold motion (33.3%; n = 19), and vocal fold fixation (19.3%; n = 11). In comparison, 1 patient with Parkinson showed vocal fold motion impairment.

The investigators identified a number of unknowns that require further study, including if laryngeal abnormalities allow for delineation of MSA from 4R‐tauopathies, as well as in the debate around the underlying pathology of laryngeal symptoms in MSA.

“An international multicenter study under guidance of the Movement Disorders Society MSA study group is under way to collect longitudinal data on laryngopharyngeal findings in patients with MSA using the MSA‐FEES task protocol,” they wrote. “In addition, systematic laryngeal assessment with the FEES task protocol will also be performed in patients with 4R‐tauopathies and the results compared with patients with MSA and Parkinson.”

Considerable discrepancy found between overt clinical symptoms of laryngeal pathology and abnormalities observed during a task protocol.