Alzheimer’s disease (AD) is a neurodegenerative disease that begins with mild cognitive impairment (MCI), and progresses through stages marked by increasing cognitive decline and psychiatric distress, culminating in severe dementia that makes it all but impossible for individuals to live independently. However, biological mechanisms driving AD progression can appear up to 20 years before the disease is diagnosed — providing an extended window for therapeutic interventions that can delay or alter AD’s course.
In November 2021, the 14th annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference brought together leading experts on the pathophysiology of AD. At the conference, these researchers presented their latest findings on cutting-edge Alzheimer’s therapies — as well as on the underlying physical causes and correlates of AD, and on new diagnostic techniques that may help doctors predict Alzheimer’s before it occurs, and intervene earlier in its progression.
These discoveries are particularly urgent for the 4,200 Americans who develop Alzheimer’s every day, and may be able to maintain their independence longer if the disease can be caught and treated sooner. In recognition of this reality, the federal government’s National Plan to Address Alzheimer’s Disease has proposed to effectively prevent AD by 2025 — a deadline that’s fast approaching, but may be possible to meet with the help of research findings presented at this year’s CTAD Conference.
Here, we’ll summarize the conference’s key presentations, and examine the potential of several promising new therapies and diagnostic techniques targeting Alzheimer’s disease.
Research presented at CTAD sheds new light on causes and correlates of Alzheimer’s.
The physiological pathology behind AD is highly complex, and it remains only incompletely understood. For example, while many experts blame a cascade of beta-amyloid protein deposits in the brain, other schools of thought focus on tau protein-based mechanisms, or on metabolic causes such as lipid dysregulation — or even vascular dysfunction. At the CTAD Conference, researchers presented brand-new data on many of these mechanisms, helping clarify the interrelationships among correlates and potential causes of the disease.
Several studies presented at the conference confirm the central role of beta-amyloid proteins in AD. A research project led by Kathryn V. Papp at Harvard Medical School, for example, found that people with higher amyloid burdens consistently perform worse than amyloid-negative people on a variety of cognitive tests, particularly the Preclinical Alzheimer’s Cognitive Composite (PACC). Research by Yan Sun at Qingdao Municipal Hospital supports this finding, reporting that a higher beta-amyloid burden is strongly associated with poorer overall cognition — without finding any significant associations between cognition and tau burden.
In fact, a team led by Lyduine E. Collij at Vrije Universiteit Amsterdam reports that regional accumulation of beta-amyloid proteins actually predicts memory decline in people who haven’t yet experienced any cognitive impairment. This means doctors may be able to identify patients at risk for memory decline, and intervene sooner, simply by tracking regional beta-amyloid deposits in their nervous systems. What’s more, a team led by Emrah Duzel at the Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) reported that amyloid treatments can help mitigate memory loss even in patients whose tau levels remain the same — while reducing tau proteins doesn’t appear to improve memory function even in amyloid-negative individuals.
Even so, many researchers remain convinced that a complete diagnostic framework for AD requires evidence of both beta-amyloid and tau pathology. For example, a team led by John A. Hey of Alzheon, Inc., presented the results of a phase-2 clinical trial in which elevated beta amyloid and tau levels in patients’ cerebrospinal fluid served as effective biomarkers for early-stage AD. A research project led by Charles S.Y. Yang of MagQu Co., meanwhile, found that beta-amyloid and tau protein levels in a person’s blood plasma can serve as reliable biomarkers for elevated AD risk in healthy adults.
Findings by Shi-Dong Chen’s team at Shanghai Medical College lend support to the latest findings on tau as a critical AD biomarker. These researchers report that plasma-tau levels are elevated in a variety of brain areas throughout all stages of the disease. A team led by Yu Guo at Fudan University, meanwhile, reports that a novel tau biomarker known as “plasma tau phosphorylated at threonine 181” (p-tau181) consistently correlates with a patient’s rate of cognitive decline. These findings indicate that while tau proteins may not be a root cause of AD, they’re at least reliable indicators of the disease’s presence and severity.
A growing number of researchers are also becoming convinced that circulatory problems may present a significant risk factor for Alzheimer’s-related cognitive impairment. For example, a study referenced by Patrick M. Moriarty at the University of Kansas Medical Center reports that nearly 80 percent of autopsy-confirmed AD cases show evidence of cerebral vascular disease. This indicates that vascular problems are very likely to be early risk factors for AD, and almost certainly play crucial roles in neurodegeneration and cognitive decline.
CTAD presenters outlined a diverse array of new therapeutic approaches to Alzheimer’s.
All the above findings add to the evidence that AD has a wide range of causes and correlates, and may be predicted, diagnosed and addressed through a variety of therapeutic strategies. As CTAD presenters demonstrated, those strategies can involve a wide array of treatments — ranging from medications that inhibit the production of harmful proteins and enzymes, to therapies that alter patients’ metabolisms or stimulate their cardiovascular systems.
In the anti-protein category, a team led by Maria Maccecchini of Annovis Bio presented new research on the oral medication ANVS401, which inhibits the translation of amyloid and tau precursor proteins. In a double-blind, placebo-controlled study, Maccecchini and her team demonstrated that ANVS401 helps prevent inflammation, nerve cell death, and loss of function in people with Alzheimer’s. Meanwhile, a team led by Panayota Kolypetri at Harvard Medical School reports that the drug Protollin can actually “reprogram” certain brain cells to reabsorb beta-amyloid proteins before they accumulate into harmful plaques.
Another new approach targets the O-GlcNAcase (OGA) enzyme, which seems to be necessary for the accumulation of tau proteins on and around brain cells. By inhibiting OGA production with a single oral dose of the experimental medication LY3372689, a team led by William Kielbasa of Eli Lilly and Company was able to reduce patients’ OGA enzyme occupancy by a strikingly high 84 percent. Another team, led by Paul Goldsmith at Eli Lilly, tested a variety of dosage levels of LY3372689, and found that the medication appears to be safe even at doses as high as 16 mg — indicating that this treatment may be a frontrunner for fighting tau proteins.
Some research teams are targeting tau and amyloid proteins using monoclonal antibodies (mAbs) — lab-engineered molecules designed to mimic the antibodies produced naturally in the immune system. Pinteon Therapeutics, for example, has generated a humanized mAb known as PNT001, which specifically targets and destroys the cis-pT231 form of the tau protein. And a team led by Suhail Rasool at TrueBinding has created a new mAb known as TB006, which blocks production of a precursor protein (galectin-3) that is necessary for the formation of beta-amyloid plaques. Although these particular mAbs have only been tested on mice so far, they do show potential promise for people in the early stages of Alzheimer’s.
Meanwhile, other researchers are exploring therapies that help restore brain function and support the regeneration of damaged neurons (nerve cells). For example, a team led by Kazuo Shigematsu at Minami Kyoto Hospital discovered that repeated doses of adipose tissue-derived stem cells (ADSCs) can improve cognitive function in people with Alzheimer’s, even when their beta-amyloid levels remain unchanged. And a team led by Gerson D. Hernandez at the University of Arizona, Tucson reports that the naturally occurring steroid allopregnanolone can protect and even regenerate neurons in the hippocampus — a brain structure crucial for memory, which Alzheimer’s tends to target and damage with particular severity.
In fact, much of the research presented at CTAD indicates that Alzheimer’s involves a number of malfunctioning organs and bodily systems, beyond just the brain. For example, a team led by Duke University’s Paul V. Suhocki reports that gut microbes may be at least partially responsible for AD, since the digestive drug rifaximin can reduce levels of neurofilament light chain (NfL), a protein that serves as a biomarker for the disease. A study led by Thomas Lodeweyckx at Katholieke Universiteit Leuven, meanwhile, reports that a single dose of the drug clenbuterol can help restore healthy neurological function in people with AD, by increasing cerebral blood flow (CBF) in brain areas crucial for cognition and memory.
These discoveries align with the findings of Patrick Moriarty’s team at the University of Kansas Medical Center, who’ve had success treating Alzheimer’s by stimulating the vascular system. Their approach uses FDA-cleared external counterpulsation (ECP) technology developed by a team at Harvard University to rhythmically compress patients’ limbs in synchronization with their cardiac cycles — increasing overall blood flow and improving cognitive performance in people with mild AD. This indicates that vascular intervention can represent a viable therapeutic approach — in fact, the American Academy of Neurology considers ECP to be exercise, which is proven to help mitigate cognitive decline in people with Alzheimer’s.
New analytical approaches presented at CTAD can support earlier AD interventions.
Medical treatment is only one component of an effective Alzheimer’s intervention. The more accurately doctors can predict or detect a case of Alzheimer’s disease, the sooner they can take action to mitigate it — or, in the foreseeable future, perhaps even to prevent it. But in order to meet the government’s 2025 deadline for preventing AD, medical professionals will need a much more complete picture of the disease’s risk factors and biomarkers, along with analytical models that can detect very early-stage cases, or forecast them based on patient data. At the CTAD Conference, research teams presented their latest breakthroughs in all these areas, offering hope that AD may indeed be preventable within the current decade.
A number of studies presented at the conference were focused on identifying optimal therapeutic approaches for individual cases of Alzheimer’s. For example, a team led by Ya-Nan Ou at Qingdao Municipal Hospital unveiled a mathematical model that can identify promising new drug targets by integrating genetic and protein data from a patient’s brain and blood samples. And a team led by Hugo Geerts at Certera demonstrated the effectiveness of quantitative systems pharmacology (QSP) — an emerging approach that uses computational models to describe dynamic interactions between drugs and diseases — at accurately analyzing patients’ individual Alzheimer’s pathologies from previous clinical trials, then systematically screening all possible treatment combinations in order to arrive at the most ideal set of therapies for each new patient.
Some of the most cutting-edge technology on display at CTAD represented the rapidly evolving field of artificial intelligence (AI) diagnostics. For example, a team led by Emil Fristed at Novoic Ltd. presented a speech-based AI system that can consistently detect amyloid-confirmed cases of AD by analyzing people’s speech patterns. And a team led by Thomas Cajgfinger at Bioclinica presented an algorithm that can detect amyloid-related imaging abnormalities (ARIA) in brain scans, even when trained technicians miss these telltale biomarkers of AD.
Other forward-looking researchers presented innovative techniques for predicting a case of Alzheimer’s before the disease occurs — or at least before it becomes clinically diagnosable using traditional methods. A team led by Marcela Cespedes at the Australian E-Health Research Centre, for example, demonstrated that they can accurately predict cognitive decline in people who haven’t yet been diagnosed with AD by creating a mathematical trajectory of those people’s scores on cognitive exams like the PACC. And a research group led by Jason R. Bock at Embic Corporation showed that by analyzing wordlist memory (WLM) test results using a type of mathematical model known as hierarchical Bayesian cognitive processing (HBCP), they can detect preclinical cases of AD before any observable cognitive decline has occurred.
Also contributing to the field of predictive diagnostic breakthroughs, a team led by Ghazal Mirabnahrazam at Simon Fraser University demonstrated a machine-learning system that can predict a person’s AD trajectory by integrating data from genetic tests with information collected in magnetic resonance imaging (MRI) brain scans. And a development team led by Sharon Cohen of the Toronto Memory Program showed that by processing retinal scans using hyperspectral imaging technology, then training a machine-learning algorithm to recognize telltale signs of preclinical Alzheimer’s in those images, they were able to predict occurrences of AD in many cases where the disease was not yet detectable clinically.
On a broader scale, Francesca Vitali of the Center for Innovation in Brain Science presented her team’s “Targeted-Risk-AD-Prevention” (TRAP) Strategy, which leverages a novel combination of text-mining and natural language processing algorithms to identify unnoticed AD risk factors in the data from previously published clinical studies. Using this approach, Vitali’s team was able to identify 364 Alzheimer’s risk factors, along with 629 FDA-approved medicines for treating those risk factors in a preventative manner. They believe this strategy places effective Alzheimer’s prevention “within reach” by the government deadline of 2025.
Still, to meet the goals of the National Plan to Address Alzheimer’s Disease, clinicians will need to integrate all the above components into a cohesive strategy for identifying at-risk individuals, pinpointing those individuals’ risk factors, prescribing preventative measures, and — in cases where AD has already begun to inflict neurological damage — selecting data-driven treatment combinations uniquely tailored to each patient’s pathology.
But as computerized diagnostic systems begin to demonstrate their effectiveness in clinical environments, doctors may soon be able to detect the disease before it has a chance to inflict serious damage. Once clinicians are able to reference hundreds or even thousands of relevant biomarkers for AD, the current diagnostic paradigm may have to expand to encompass cases currently classified as “preclinical,” which can then be addressed via non-pharmaceutical early-stage interventions — such as cognitive training, healthy lifestyle modifications, and techniques like the external counterpulsation (ECP) therapy developed at Harvard.
At the same time, as machine-learning algorithms identify more previously unknown risk factors for AD, clinicians’ strategies are rapidly shifting toward prevention as a top priority. This shift has driven rapid evolution in today’s toolkit of interventions, which now range from cognitive training and memory practice to dietary regimens and aerobic exercise. Even for people already in the disease’s early stages, such a whole-body approach to treatment has been shown to provide far more comprehensive protection than a medication-only strategy — in fact, a multi-pronged defense can often delay cognitive decline by years.
For all these reasons, the overall message at 2021’s CTAD Conference was one of hope. While four years might seem like a short timeframe in which to conquer such a complex disease, the challenge is made less daunting by the sheer volume of clinical data now being gathered and analyzed — and by the international community of researchers dedicated to defeating AD using every strategy, technique and technology they can develop. Many of the experts in attendance at CTAD are convinced that the goal of prevention is reachable within the next decade. And with the help and cooperation of patients and their families, they may very well be right.
