Distinct Molecular Subtypes in Alzheimer’s Disease Inform Personalized Treatment Strategies

The scientific study of Alzheimer’s Disease (AD) is on the cusp of a revolution as growing evidence demonstrates that what was once perceived as “one disease” actually encompasses a spectrum of disease biology and clinical presentation. Significant advances in molecular profiling and biomarker research have generated high dimensional data which in turn is driving the application of novel analytical tools to define and characterise subtypes of AD patients.

For decades, Alzheimer’s Disease has been approached as a single disease, treated with one method of management. However, current research points to a new approach: treating Alzheimer’s Disease based on the molecular characteristics of each individual, including their genes and dietary habits.

The factors that contribute to the transition from a preclinical state to clinical symptoms of AD are not fixed. Several factors including amyloid and tau pathology, neuroinflammation, vascular factors, metabolic factors, and genetic risk factors interact to influence the rate of disease progression. Furthermore, lifestyle factors such as cardiovascular health, sleep, physical activity, education, and social engagement have been found to predict risk of disease as well as rate of disease progression.

New research has identified key brain proteins involved in Alzheimer’s disease, paving the way for more personalized treatment of the condition.

Although further research is needed to develop effective treatments for the disease, understanding the different forms of Alzheimer’s better could enable doctors to tailor care to individual patients.

Why It Matters

Alzheimer’s Disease is the most common cause of dementia worldwide affecting millions of people. It impacts memory, executive function and language abilities and results in a gradual loss of independence as the disease progresses. However, Alzheimer’s brings many challenges to families and those who care for people with the disease including emotional, physical and financial difficulties.

The global ageing population will translate to a massive rise in numbers of individuals affected with Alzheimer’s, so improved diagnosis, stratification and management is paramount.

Moving Beyond a One-Size-Fits-All Model

Despite advancements in research and clinical trials, the standard of care for Alzheimer’s patients remains the use of Cholinesterase inhibitors (Donepezil, Rivastigmine, Galantamine, and Exatigmine) and NMDA receptor antagonists (Memantine and Ebastine) to improve cognitive function. However, a new generation of compounds that have the potential to be “disease-modifying” by targeting Alzheimer’s pathology, primarily amyloid, have not received an enthusiastic reception from patients and their physicians.

• Dominant pathological processes
• Rate of cognitive decline
• Genetic risk factors (such as APOE status)
• Degree of vascular contribution
• Inflammatory activity
• Metabolic dysfunction

Alzheimer’s disease is now known to be biologically heterogeneous. What does this mean? That people with Alzheimer’s disease may be fundamentally different from one another.

This variability may contribute to individual variation in response to treatment.

Future treatment strategies may need to “carve out” patient subgroups based on disease mechanism in order to be effective.

The Role of Biomarkers in Subgroup Identification

Recent developments in biomarker science allow for sophisticated molecular stratification and are starting to translate into individualized diagnosis and therapy for brain tumors.

• Amyloid-beta accumulation
• Tau protein deposition
• Neurodegeneration markers (via imaging or cerebrospinal fluid)
• Neurofilament light chain
• Inflammatory markers
• Genetic variants

Key biomarkers include:

Current research utilises an AT(N) approach, attempting to classify and subtype patients based on the presence of Amyloid (A), Tau (T) and/or Neurodegeneration (N) pathology. These subtypes have been shown to reflect important biological categories not captured by standard clinical diagnosis.

In addition to these “omnic” analyses, blood-based biomarkers are becoming available for early diagnosis of specific disease patterns and time of initiation of targeted therapy.

Lifestyle Factors as Modifiers of Alzheimer’s Progression

Biology is only part of the story.

There is evidence to suggest that susceptibility to, and progression of, Alzheimer’s disease may be influenced by lifestyle factors. Factors that promote brain health through optimal cardiovascular health, regular physical activity, cognitive challenge, diet and sleep may potentially reduce risk of or delay progression of Alzheimer’s disease.

• Hypertension, diabetes, and hyperlipidemia increase dementia risk
• Physical exercise may support neuroplasticity
• Social engagement is associated with slower cognitive decline
• Mediterranean-style diets are linked to improved cognitive outcomes

Research shows that:

These elements can be used to give a more individual, holistic and patient-orientated touch to the management of diseases.

Who It Affects

As our knowledge of the subject area grows it is starting to have implications for individuals and organisations across the Healthcare sector.

Patients Living with Alzheimer’s Disease

Most patients with B-Cell Lymphoma are now treated as if they belonged to a single disease category. However, increasingly, patients with B-Cell Lymphoma are viewed as having a particular molecular or clinical subtype of B-Cell Lymphoma. A more individualized approach to diagnosis and treatment could be of benefit to patients.

There may be some patients in whom a greater proportion of disease is due to vascular factors versus inflammatory factors, and these patients would require individualized treatment approaches.

In addition to treatment, patients and their families are given advice on lifestyle modification, increasing cognitive activity and management of related medical conditions.

Families and Caregivers

Caregivers play an important role in the care of individuals with Alzheimer disease. Each situation is unique and a full understanding of the particular situation can help improve communication and realistic management of disease progression.

Assessing whether a patient’s disease is rapidly progressing or slowly progressing can aid in decision-making around end of life. But what about palliative care interventions that families can do at home to promote comfort through lifestyle changes?

Neurologists and Geriatric Specialists

There will be a growing need for clinicians across a variety of disciplines to receive training to interpret biomarker and precision medicine tests to accurately diagnose and treat their patients. This training will be necessary for neurologists, geriatricians, primary care physicians and memory clinic specialists, each with differing needs with respect to the newer neuroimaging and clinical biomarkers.

• Advanced imaging
• Blood biomarker panels
• Genetic counseling
• Risk stratification tools

Diagnostic pathways may increasingly incorporate:

Future management of adult patients with relapsing remitting multiple sclerosis will also include consideration of disease modifying treatments and an individualised risk-benefit assessment.

Healthcare Systems and Policymakers

Healthcare for people with Alzheimer’s disease will become even more complex in the future.

• Expanded access to diagnostic testing
• Specialized memory clinics
• Multidisciplinary teams
• Long-term care planning resources

Personalized care may require:

Biomarker tests and precision therapies are being introduced into clinical practice and key decisions are being made by policymakers regarding models of reimbursement for these tests and treatments. From a policy perspective, these decisions are crucial as they will shape how limited healthcare resources are allocated to support the care and management of cancer patients, and how early intervention with these novel therapies could impact long-term outcomes for cancer patients.

What Changes

Abstract: There is potential for the shift to personalized Alzheimer’s care to transform clinical practice, research and health policy.

Development of Targeted Treatment Plans

As new therapies are engineered to target at disease mechanisms in addition to removal of amyloid deposits, the critical need to identify patients that would derive benefit from such therapies is expected to increase.

Patients with heavy amyloid deposition may not be treated as well by this drug as those with less amyloid and more non-amloid forms of brain disease.

Achieving greater accuracy in dental treatment planning allows the dentist to work “more on target” as opposed to taking a more general approach.

Integration of Preventive and Lifestyle Medicine

Exercise, weight loss, stress reduction, and other lifestyle changes may help manage Alzheimer’s disease symptoms, according to new research.

• Structured exercise prescriptions
• Cardiovascular risk management
• Sleep optimization programs
• Nutrition counseling
• Cognitive stimulation interventions

Future care models may include:

Although these strategies do not replace pharmacologic pain management, they can serve as an adjunct to enhance recovery.

Enhanced Communication and Shared Decision-Making

Personalized care requires improved clinician-patient communication.

• The biological drivers of their disease
• The expected rate of progression
• The goals of treatment
• The risks and benefits of interventions

Patients and families should understand:

Shared decision making builds trust between patients and their providers and ensures that patients receive the care that is most important to them.

Research and Clinical Trial Innovation

As clinical trials gradually start to include biomarkers in trial design to stratify patients, studies may potentially obtain better results with less variability.

• Inflammation-dominant subtypes
• Metabolic-related cognitive decline
• Sex-specific differences in disease expression
• Genetic risk modifiers

Future research may explore:

By implementing a Precision recruitment strategy, we are working to increase the validity and speed to market of developing a treatment for psychiatric and medical disorders.

The Future of Alzheimer’s Precision Medicine

There is little in current therapeutic regimens for treatment of Alzheimer’s Disease that suggests that a single medication will be efficacious for all patients with this disease. However, progress is being made in the recognition that Alzheimer’s Disease exists as more than one biologically distinct clinical subgroup.

Although precision medicine will not lead to a cure for every case of cancer, it will offer more-informed patient-specific treatment and subsequent clinical decision-making for the oncologist.

Integrating data from multiple levels of analysis including molecular, genetic, behavioral and clinical data can help health providers to move towards a more individualised patient management approach by allowing them to formulate treatment on the basis of patient specific characteristics.

As we reported previously, many areas of medicine are moving towards molecular stratification. While oncology, cardiology and rheumatology have long since adopted molecular stratification into routine clinical decision making, it seems Neurology is next in line.

Could Alzheimer’s care look vastly different in 10 years? More than ever, researchers, patients and families are working together to make quality care and support for those affected by Alzheimer’s a top priority. Scientists are zeroing in on biological and environmental factors that may influence Alzheimer’s development and progression. And clinical trials are gaining momentum to better understand treatments and potential cures for the disease.

Conclusion: Toward More Compassionate and Effective Alzheimer’s Care

Alzheimer’s Disease has long been viewed and treated as a single illness. But as new research emerges, many scientists are beginning to recognize Alzheimer’s as a collection of clinically and pathologically related illnesses.

This book moves the field forward by going beyond standard treatments and focuses on using precision diagnostics and patient centric approaches to improve outcomes. Patients and families learn about their child’s disease.

Most importantly, it truly corresponds with real life and actually represents the variability and individuality of the many disciplines within the Medical Sciences.

Future research may focus on further defining subgroups and their respective treatment targets, with the goal of being able to treat patients based on their biological profile as well as their clinical/psychological experience of illness.

This book goes beyond the science of the disease to grapple with what personalized Alzheimer’s care looks like and how it will shape the lives of individuals and families suffering from it.

References:

https://pmc.ncbi.nlm.nih.gov/articles/PMC12741474/ https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.71106 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250278 https://pmc.ncbi.nlm.nih.gov/articles/PMC11485305/ https://www.science.org/doi/10.1126/sciadv.abb5398