Hope for patients with Alzheimer’s disease

At the intersection of research and clinical care, there is hope for patients with Alzheimer's disease

By Stephanie Brooks

For nearly half a century, researchers in laboratories across Mass General Brigham have been investigating the cause of and searching for treatment options for Alzheimer's disease and related memory disorders. Under the umbrella of the Mass General Brigham Neuroscience Institute, today that work is leading to major advances in the field. For the first time, patients, families and clinicians have real hope.

Teresa Gomez-Isla, MD, PhD, is the chief of the Division of Memory Disorders in the Department of Neurology at Mass General Brigham and directs the Massachusetts Alzheimer's Disease Research Center. "Research directly impacts our clinical care models," she said when describing the developments happening at the intersection of clinical care and research. "Discoveries made in the lab quickly inform patient care, while lessons learned from patients help guide the next generation of research."

A legacy of discovery

More than 30 years ago, Dennis J. Selkoe, MD, co-director of the Ann Romney Center for Neurologic Diseases at Brigham and Women's Hospital, proposed and began advocating for the amyloid hypothesis, finding evidence to support the connection between beta-amyloid and the cause of Alzheimer's disease.

Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit and the McCance Center for Brain Health at Massachusetts General Hospital, began his career as a researcher and graduate student in the laboratory of geneticist James Gusella, PhD, at Massachusetts General Hospital. Tanzi applied the genetic mapping techniques learned in Gusella's lab to study chromosome 21 and eventually discovered the first Alzheimer's disease gene, the amyloid precursor protein (APP). Tanzi's lab later co-discovered two other early-onset familial Alzheimer's disease genes (presenilin 1 and presenilin 2), as well as what is currently considered the most promising new drug for someday safely lowering amyloid production (a gamma secretase modulator). In 2008, Tanzi also discovered the first immune-related Alzheimer's gene, CD33, which controls clearance of beta-amyloid in the brain, as shown with his colleague Ana Griciuc, PhD.

Since then, the work has continued in labs at Brigham and Women's Hospital and Massachusetts General Hospital with notable discoveries by many, including, but by no means limited to, Gomez-Isla, Selkoe, Tanzi, Bradley Hyman, MD, PhD, former director of the Massachusetts Alzheimer's Disease Research Center, Reisa Sperling, MD, and Gad Marshall, MD, from the Center for Alzheimer Research and Treatment, and Steven Arnold, MD, director for the Normal Pressure Hydrocephalus Program and the Clinical and Translational Research Unit.

Tracy Young-Pearse, PhD, is the Dennis J. Selkoe endowed chair in Neurology at Brigham and Women's Hospital. "The advances we are now seeing in the early detection and treatment of Alzheimer's disease are built on decades of basic research at Mass General Brigham. This work has allowed us to understand the causes of the disease and identify therapeutic targets that can be translated into clinical trials and, ultimately, better care for patients," she said.

Detecting disease earlier than ever before

One of the most significant breakthroughs in Alzheimer's care is the ability to detect disease much earlier. Historically, clinicians could only suspect a diagnosis based on symptoms and confirm it after death through examination of brain tissue. Today, sophisticated imaging techniques and emerging blood-based biomarkers allow clinicians to identify biological changes associated with Alzheimer's disease in living patients. Sperling and colleagues recently reported that the U.S. Food and Drug Administration (FDA)-approved blood biomarker pTau-217 can predict the probability of receiving an Alzheimer's disease diagnosis five to 10 years in advance.

"We can do PET scans to visualize changes that before you could only see under the microscope," Gomez-Isla said. "We also now have blood biomarkers that can make testing easier and more accessible. Mass General Brigham is a leader in this area, and we will begin implementing them as soon as they are approved for clinical use."

Gomez-Isla said she now sees patients with a family history of Alzheimer's disease, genetic risk factors or positive biomarker results coming to her before symptoms develop.

"We hope to build a dementia prevention program designed to help people understand their risks and address factors that may contribute to cognitive decline," she said. "In the meantime, we know from years of research that there are many modifiable risk factors, including cardiovascular health, exercise, depression and social isolation. The goal is to use evidence-based interventions to help people maintain brain health and potentially delay the onset of symptoms."

There are also plans to launch a Center of Integrated Care and Discovery across the Mass General Brigham Neuroscience Institute focused on the prevention of Alzheimer's disease that will allow investigators across the healthcare system to collaborate more easily.

New therapies offer new possibilities

For patients who are diagnosed with Alzheimer's disease, early intervention is key to preserving quality of life.

Thanks to the foundational work of Mass General Brigham researchers and others, the FDA has approved two anti-amyloid antibodies for the treatment of Alzheimer's disease: lecanemab and donanemab. Both are intended for patients with mild cognitive impairment or mild dementia and are designed to slow the progression of disease.

The Mass General Brigham's Alzheimer Therapeutics Program (ATP), embedded within the Memory division, is leading the way in evaluating the efficacy of these treatments and offering patients who have received a devastating diagnosis a glimmer of hope. To date, over 1,000 patients have received lecanemab or donanemab as part of their clinical care in the ATP.

"At Mass General Brigham, we started implementing these new medications in the real world in our clinical practice," Gomez-Isla said. "These therapies require intravenous infusions and close monitoring. To do this, neurologists, nurses, physician assistants, radiologists, nuclear medicine specialists, infusion center personnel, social workers and other specialists have collaborated to design a safe pathway and plan of care for our patients. These therapies are already moving toward more convenient forms of treatment, including at-home injections. It is not a cure, but it is the first step in learning how to slow the disease. Hopefully, someday we will be able to halt its progression entirely or even prevent it from happening in the first place."

Additional therapeutic options on the horizon include, among others, tau-targeting therapies - which aim to reduce toxic tangles, slow cognitive decline and halt neurodegeneration - and an APOE2 gene therapy, which aims to lower amyloid plaque buildup and reduce neuroinflammation.

Supportive care for patients with more advanced disease

For patients whose disease has progressed past the point where anti-amyloid antibodies and other investigational therapeutics may be helpful, the Mass General Brigham Neuroscience Institute collaborative model gives them access to clinical trials and research opportunities across the many laboratories and departments within the health system that are working to find a cure. In addition, multidisciplinary teams provide support throughout the patient's journey. That includes support from social work, caregiver resources and support groups designed to improve quality of life for both patients and families.

"Much of what we know about Alzheimer's disease - and the treatments available today - was made possible by patients and families who generously donated brain tissue for research," Gomez-Isla said. "Their gifts allowed scientists to uncover key drivers of the disease, including the role of amyloid beta, while advancing our understanding of the broader biological processes involved and providing the foundation for developing and testing new therapies. We owe these donors an enormous debt of gratitude."

Hope lies ahead

Young-Pearse agreed with Gomez-Isla, emphasizing that while major advances have been made in the field of Alzheimer's disease and related memory disorders, there is still so much to learn.

"We're asking a new set of questions now: Why do some people develop Alzheimer's disease while others remain cognitively healthy? Why do some individuals accumulate amyloid in the brain without experiencing cognitive decline? What protects the brain from disease?" she said. "We are interested in using what we learn from individuals resilient to amyloid accumulation to develop new therapies to protect those vulnerable to disease."

One powerful tool helping researchers answer those questions is induced pluripotent stem cells (iPSCs). Scientists can reprogram a patient's blood cells into stem cells and then transform them into living brain cells in the laboratory. These cells retain the genetic characteristics of the individuals from whom they were derived, allowing researchers to study how different combinations of genetic risk and resilience factors influence brain health. Another is the "Alzheimer's in a dish™" model, which is a 3D human-neural-cell culture model and human brain organoid models developed by Tanzi and Doo Yeon Kim, PhD, of the Genetics and Aging Research Unit at Massachusetts General Hospital. That team is currently carrying out clinical trials of repurposed drugs and natural products that were discovered though the model. Another is miBrain, developed by Alice Stanton, PhD, which integrates all six major brain cell types, each from patient-derived cells, into a single vascularized, myelinated, immune competent, neural model that can be used to investigate Alzheimer's disease pathology.

Using these models, investigators can compare cells from individuals who developed Alzheimer's disease early, those who developed it later in life, those who accumulated amyloid but remained resilient and those who never developed significant disease markers at all. The approach provides valuable insights into disease mechanisms and may help predict which therapies will be most effective for different patients. Combinations of FDA-approved drugs and natural products, which slowed Alzheimer's pathology in these models, are now being tested in a new Alzheimer's Disease Clinical Trial Platform being carried out at the McCance Center for Brain Health, directed by Tanzi.

Young-Pearse said researchers are also exploring the role of the immune system in Alzheimer's disease. "Growing evidence suggests that immune cells may contribute to neurodegeneration while attempting to clear amyloid from the brain," she said. "Understanding and modulating those responses could open the door to an entirely new class of treatments."

What's most exciting for Young-Pearse is the fact that this cutting-edge research is taking place right here at Mass General Brigham and that the Neuroscience Institute structure allows researchers at both sites to collaborate and share their findings more efficiently than ever before and supports collaborations with scientists around the world, creating a major hub for discovery and advances in neuroscience.

"The Mass General Brigham Neuroscience Institute is founded on the idea that by integrating discovery, care, data and talent into a single engine, we can accelerate innovation and deliver measurable patient impact," said Merit Cudkowicz, MD, MSc, executive director of the Mass General Brigham Neuroscience Institute, where she holds the Carol and James Herscot Endowed Neuroscience Institute Chair. "The great strides we are seeing in the detection and treatment of Alzheimer's disease and other memory disorders is exactly what we're hoping to do across the array of neurological disorders. We will continue to investigate, we will share that knowledge with our colleagues and we will make advances in the care of our patients."

Timeline: Scientific discoveries in the race against Alzheimer's disease at Mass General Brigham, 1986-2026

These are just a few highlights of scientific contributions from Mass General Brigham investigators that have had a major impact on Alzheimer's research over the last four decades.

1986

Tau is a major component of neurofibrillary tangles

1987

Discovery of APP, the first early-onset familial Alzheimer's disease gene

1995

Discovery of the early-onset familial Alzheimer's disease genes, PSEN1 and PSEN 2

1999

Presenilins contain the catalytic active site of γ-secretase

2001

Multiphoton microscopy demonstrates plaques can be cleared by immunotherapy

2002

Soluble Aβ oligomers impair long term potentiation

2005

Tau suppression improves memory function in mouse model

2008

• Soluble Aβ dimers from Alzheimer's patients impair memory and synapses
• Completion of first Alzheimer's disease GWAS: CD33 - first innate immune microglial Alzheimer's disease gene

2009

• Alzheimer's-related brain dysfunction begins before clinical symptoms.
• Discovery of highly penetrant late-onset Alzheimer's missense mutations in ADAM10

2010

• First non-NSAID "next-generation" gamma secretase modulators
• Aβ is an antimicrobial peptide

2012

• Definition of clinical and imaging characteristics of ARIA in Abeta immunotherapy
• Propagation of tau species across synapses

2013

Description of phenotypic traits linked to resilience in human Alzheimer's disease brain

2014

First 3D neural-glial cell culture model of Alzheimer's disease showing Aβ induces tangles

2017

Complement C3 drives synaptic degradation around plaques

2019

• Amyloid facilitates tau accumulation in longitudinal PET scans.
• Opposite roles for CD33 and TREM3 in modulating microglial clearance of Aβ

2023

CD8+ T cells infiltrate Alzheimer's disease brain and exacerbate neuroinflammation

2025

• Clusterin acts as a resiliency factor in the brain
• p-Tau is an anti-viral protein that traps virus in tangles
• Synapses harboring tau oligomers are not cleared in resilient brains

2026

• Establishment of plasma p-tau217 as an early predictor of Alzheimer's disease
• Oligomeric tau species, derived from human Alzheimer's disease brain, impair electrophysiological activity in hippocampal neurons