Alzheimer's Disease in Clinical Trials

About Alzheimer’s Disease  

Alzheimer’s disease is a progressive brain disorder that gradually destroys memory and thinking skills, eventually impairing the ability to perform everyday tasks. It is a specific type of dementia, which is a broader term describing symptoms that affect memory, thinking, and social abilities. Alzheimer’s is most common in older adults; however, it is not a normal part of aging. Instead, it is caused by complex changes in the brain that lead to the loss of brain cells. 

One of the main causes of Alzheimer’s disease is the abnormal buildup of amyloid and tau proteins. In 1984, G. Glenner and C. Wong discovered that amyloid-beta (Aβ) proteins are the central component of the extracellular amyloid plaques found in Alzheimer’s disease (Glenner and Wong 1984). A year later, researchers identified tau protein as the key component forming neurofibrillary tangles, another hallmark of the disease (Grundke-Iqbal et al. 1986, Delacourte and Défossez 1986). 

The timeline of research targeting amyloid-beta and tau proteins in Alzheimer’s disease (AD) reflects a shift in scientific focus. Aβ was identified in the 1980s, since then sparking decades of attempts to develop anti-Aβ therapies. While most early trials failed, the early 2020s saw the approval of Aβ-clearing antibodies such as lecanemab (Leqembi®), which received accelerated approval from the U.S. FDA in January 2023 and was later converted to traditional approval after the Phase 3 CLARITY AD trial verified clinical benefit (van Dyck et al., 2023; U.S. FDA, 2023), and aducanumab (Aduhelm®), approved by the FDA in June 2021 under the accelerated approval pathway based on its effect of reducing amyloid-beta plaques (U.S. FDA, 2021). More recently, attention has turned to tau pathology, which is closely linked to neurodegeneration. Multiple anti-tau therapies are now in clinical trials. Current strategies suggest that the most effective treatments may need to target both Aβ and tau together to achieve better outcomes. 

How are Alzheimer’s Drugs Validated in IND-Enabling and Phase I Trials 

In Alzheimer’s drug development, biomarkers such as amyloid and tau levels are used to confirm the presence of disease-related targets and to demonstrate a drug’s ability to interact with those targets. This process helps validate the drug’s mechanism of action in humans. In Phase I clinical trials, Alzheimer’s drugs are tested for safety and appropriate dosage in a small group of healthy volunteers. These studies evaluate the drug’s absorption, distribution, metabolism, excretion, and toxicity (ADMET). Before Phase I begins, an Investigational New Drug (IND) application must be submitted to the FDA. This regulatory process authorises first-in-human testing and helps determine the drug’s pharmacokinetics and maximum tolerated dose (MTD), which are critical for designing subsequent, larger trials. Phase I studies for Alzheimer’s drugs often use advanced methods and tools such as magnetic resonance imaging (MRI) and position emission tomography (PET) to track biomarkers like amyloid and tau, as well as computational approaches including artificial intelligence (AI) and digital sensors. These technologies not only assess drug safety, target engagement, and disease progression, but also generate more sophisticated data than traditional methods. 

Electrophysiological Tools 

Methods such as electroencephalography (EEG) and transcranial magnetic stimulation (TMS) are increasingly used to evaluate brain network activity, cortical excitability, and drug-induced changes in neural function (Maiella et al. 2024). These techniques provide sensitive, real-time measures of target engagement and can help refine dosing, improve patient stratification, and offer early signals of therapeutic efficacy.