Adobe Stock
Alzheimer’s disease remains one of the most complex and devastating neurodegenerative disorders, affecting over 55 million people globally. With projections estimating this number will rise to 139 million by 2050, the urgency to develop effective treatments has never been greater.
Historically, AD drug development has been marked by setbacks and limited therapeutic success due to the disease’s complexity. This has also created difficulties in understanding and pinpointing exact causes and mechanisms at play. However, recently, we are seeing notable progress with innovative treatments that address underlying disease biology. Also, AD drug developers are recognizing the value of investing in earlier intervention strategies and diagnostics, including biomarker innovations, to put a focus on prevention and monitoring of AD progression instead of reactive treatment of symptoms.
For individuals likely to be diagnosed with AD, the mindset to identify AD earlier offers hope and the chance to redefine what it can mean to live well with the risk of the disease.
It is worth discussing what is driving the shift in mindset. Why is the focus on disease progression and earlier intervention, and what are the advances within AD research and development that are allowing clinical trial sponsors, researchers, regulators, patients, caregivers, etc., to rethink clinical trial design?
Why early intervention?
For decades, AD clinical research was primarily focused on evaluating biological changes in the brain, particularly the accumulation of amyloid beta and tau proteins. While these markers remain central to the disease pathology, the wait-and-see period of up to a decade before symptoms emerge presents a critical window for monitoring and intervention.
Early diagnosis not only improves treatment effectiveness but also empowers patients and families to plan for the future, participate in clinical trials and adopt lifestyle changes that may slow disease progression. Also, recent advances in disease-modifying therapies, such as monoclonal antibodies lecanemab-irmb and donanemab-azbt, have shown great promise when administered in early or mild symptomatic stages of AD by reducing amyloid plaques in the brain.
These are exciting advances for those living with mild AD. However, collectively, we need to think about AD in a wider context and explore all potential factors influencing disease pathology and how to address them while working toward prevention.
Image courtesy of IQVIA
Shifting from brain-centric to a systemic understanding
In recent years, a growing body of evidence that AD is a multifactorial, systemic condition with alternative pathways and mechanisms has suggested a new understanding of the disease. This broader understanding is prompting a shift in mindset and related investment from drug developers.
Gut-to-brain connection
Just as the gut microbiome plays a key role in digestion and supporting the immune system, it may also contribute to amyloid production and clearance. For example, a microbiome-modifying therapy approved in China in 2019 showed initial promise for improving cognitive function in patients with mild-to-moderate AD by reducing inflammation and amyloid accumulation. Though later withdrawn from the market, this clinical finding underscores the potential of targeting gut health in AD treatment and makes a compelling case for wider evaluation. Currently, the National Institute on Aging is funding research with the goal of understanding how such variables as aging, diet and environmental influencers may impact the gut-brain axis and the specific role in brain function.
Cholesterol’s role
Similarly, cholesterol metabolism has gained attention as a possible driver of AD pathology. The brain contains the highest concentration of cholesterol (about 25%) within the body, and higher levels of total cholesterol can contribute to neurodegeneration. Also, disruptions in cholesterol management and transport in the brain, especially in individuals with the apolipoprotein E4 (APOE4) genetic variant, have been linked to an increased risk of AD-related dementia. Therapeutic strategies targeting cholesterol regulation are now being explored as potential interventions. For example, in mice, cyclodextrin, a drug carrier, is showing to promote cholesterol transport and reduce buildup and amyloid plaque; however, further evaluation is needed.
A closer look at genetics and disease subtypes
Understanding the genetic underpinnings of AD is also critical. While most cases are sporadic, familial forms linked to genetic mutations (i.e., amyloid precursor protein, presenilin-1 and presenilin-2 genes) account for a small but significant subset. As noted above, the APOE4 allele has emerged as a genetic risk factor. These insights are influencing clinical trial design, with genetic screening increasingly used to improve target patient populations and personalize treatment strategies.
Cell and gene therapies for AD are in early evaluation phases but show promise for targeting the disease at a cellular and genetic level to either protect, modify or replace neurons, reduce inflammation or boost the immune response.
For example, mitochondrial abnormalities, which reduce energy production and cellular health, are closely linked to amyloid and tau protein buildup and can contribute to toxin release and kill neurons. Researchers are exploring several mitochondria-targeted therapies to combat AD. Preclinical studies evaluating regulation of bioenergetic pathways to improve mitochondrial energy indicate a potential to reduce the risk of symptomatic AD.
Also, a study published in Signal Transduction and Targeted Therapy in May discussed the development of a targeted gene therapy that aims to preserve cognitive function in AD. Unlike removing amyloid plaques, this approach aims to reprogram unhealthy brain cells. In mice with AD symptoms, the therapy was shown to preserve hippocampal-dependent memory.
While initial evaluations are promising, further research is needed to determine the effectiveness of varying CAGTs in humans and whether we can successfully move from symptom management to disease modification. Variations in genetics, genders and cellular profiles of the brain must be accounted for.
Seeing the fuller scope of AD via biomarker breakthroughs
Though early intervention is critical, currently, accurate diagnosis of AD relies on a combination of insights from medical history, neurological exams, cognitive assessments and brain imaging, which is complex and challenging.
In recent years, detecting preclinical and early-stage AD pathologies has significantly evolved due to the increasing availability of precise, non-invasive biomarker tests, which aid screening and monitoring of patients, whether symptomatic or not, and those who may be at greater risk for AD. Measurable indicators found in serum, plasma and blood cells are enabling earlier and more accurate diagnosis, which is transforming clinical trials that have traditionally struggled with late-stage enrollment.
These clinical laboratory innovations are not only improving diagnostic accuracy but also AD clinical trial design, with biomarkers being used for patient inclusion/exclusion criteria, pharmacodynamic endpoints and exploratory analyses.
The era of blood-based biomarker testing
One of the most significant developments discussed at the 2025 Alzheimer’s Association International Conference was the emergence of blood-based biomarker tests. These tests can detect Alzheimer’s-related proteins with high accuracy, offer a less invasive and more accessible alternative to PET scans and spinal taps, and improve trial efficiency and availability.
Last year, the National Institute on Aging and the Alzheimer’s Association revised diagnostic criteria to incorporate blood-based biomarkers into routine evaluations, reflecting their growing clinical use. This October, the U.S. Food and Drug Administration cleared the first blood-based biomarker test to measure phosphorylated Tau 181 protein and aid in the initial assessments of AD and other potential causes of cognitive decline specifically in primary care settings for patients ages 55 and older. This pTau181 test received the CE marking in Europe in July. Earlier this year, Fujirebio Diagnostics’ Lumipulse G pTau217/β-Amyloid 1-42 Plasma Ratio also received FDA clearance to help healthcare providers identify patients with amyloid pathology associated with AD. It is indicated for adult patients, age 50 and older, presenting signs and symptoms of cognitive decline at specialized care settings.
Value in furthering biomarker discovery, validation and development
To better enable earlier diagnosis, identify and reach key patient populations and effectively monitor therapeutic efficacy, it is essential to also elevate clinical laboratory science, expertise and capabilities. Clinical lab teams need to continue pushing boundaries on biomarker discovery, validation and deployment to enable earlier diagnosis and intervention. This means expanding portfolios of assays that detect AD biomarkers, genetic markers and inflammation indicators and comply with regulatory standards. For example, there is recent interest in ocular testing as a non-invasive and cost-effective method for early detection of AD.
Looking beyond currently available AD-specific biomarkers and exploring alternative detection strategies may lead to more specific diagnoses, which can greatly influence clinical trials. Incorporating multiomic data from genomic, proteomic and metabolomic profiles alongside digital biomarkers offers a powerful strategy for improving AD diagnosis and clinical trial design. These complementary approaches can help identify individuals most likely to develop the disease earlier (prognostic application) and more accurately and enable timely intervention. Digital biomarkers, including passive data from wearables and cognitive assessments via apps, add real-world context and continuous monitoring capabilities.
Together, these tools can reduce the inclusion of false-positive cases in studies, enhance patient stratification and provide promise for improved validity and outcomes of AD research.
Humanizing AD
Though the needs and challenges of those living with AD have always been a priority for research, their inclusion in the changing way clinical researchers are evaluating earlier interventions and diagnostics is critical to successful outcomes that ultimately impact their care. Beyond science and tech, what else is needed to further humanize clinical research and make it more effective?
First-line integration
In 2024, the Alzheimer’s Association introduced the first new guidelines in more than 20 years for diagnosing Alzheimer’s disease or related forms of cognitive impairment or dementia. The update equips primary care providers, typically the first professionals to examine symptomatic patients, to identify cognitive decline early, which has improved referral rates and diagnostic accuracy.
Growing willingness to know
Finally and most importantly, as patients become more active partners in research that impacts their treatment and health outcomes, there is an increased awareness and willingness to engage in earlier testing to know whether they are at risk for debilitating diseases like AD. A recent survey by the Alzheimer’s Association revealed that four out of five Americans want to know whether they have the disease before symptoms interfere with daily life. Ninety-one percent would take a simple blood test, though very few are familiar with procedures like blood biomarker tests, and 80% said they would ask their provider to test them rather than wait for the suggestion.
Senior leadership of the Alzheimer’s Association has called for “advancing toward diagnostic testing that is simple to administer and widely available.”
A new era of systemic solutions
As this therapeutic focus moves forward, the message is clear: to best fight Alzheimer’s, it is essential to hold a holistic view and approach that goes beyond the brain in clinical research strategies.
By also embracing a systemic view that advances biomarker innovations and prioritizes early intervention, AD stakeholders are redefining what’s possible in AD care. But the success of systemic-focused solutions to better provide accessible and responsible Alzheimer’s care will require a continued convergence of scientific insight, tech-enabled advances and clinical design innovations that keep the patient in mind.
About the Authors:
Marek Bieniek, M.D., Senior Director, Medical Strategy, CNS Center of Excellence, R&DS Design and Delivery Innovation, IQVIA
Marek is a board-certified neurologist with more than 25 years of experience in neurology, more than a decade of medical affairs experience in the pharmaceutical industry primarily related to multiple sclerosis and Alzheimer’s disease, and over six years of experience in clinical research. His clinical and industry roles were primarily related to multiple sclerosis, dementia and rare diseases. In his current role with IQVIA’s CNS Center of Excellence, Marek applies his extensive practical knowledge of all stages of medicines’ lifecycles to support development of innovative therapies for neurological disorders.
Anu Chaudhary, PhD, Global Technical Lead Immunology, IQVIA Laboratories
Anu is the technical lead for Global Immunology Testing at IQVIA Laboratories and oversees assay development and execution to support clinical testing needs. Trained in chemistry, cell biology, microbiology and immunology, Anu has more than 28 years of experience in basic and clinical research, assay development and drug discovery.
Anu earned her Ph.D. from SUNY-Stony Brook and performed postdoctoral studies at Harvard Medical School and the Fred Hutchinson Cancer Research Center.
Joanna Pulawska, PhD, Therapeutic Area Head, CNS, IQVIA Biotech
Joanna Pulawska oversees global operations and strategic delivery across clinical trials in CNS and CVRM therapeutic areas at IQVIA Biotech. With over 20 years of experience in global clinical research, she has held senior leadership roles in various therapeutic areas, including oncology, neurology, immunology and cardiovascular diseases.
Joanna earned her Ph.D. in Molecular Biology from the University of Toronto and holds an MSc from the University of Warsaw.
Filed Under: Neurological Disease
