Alzheimer’s disease (AD) has a devastating impact on patients, caregivers, and society at large. The worldwide prevalence of AD and other forms of dementia is as high as 50 million, with 10 million new cases each year. Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU) is the first preventive trial testing the effectiveness of potential disease-modifying treatments that slow down the progression of the disease. If the trial is successful, it would substantially impact societies, healthcare systems, and economies.
Dementia is an umbrella term used to describe a cluster of symptoms including cognitive, memory, and language impairment. It is progressive in nature; the damage to the structure and chemistry of the brain, resulting from an injury, disease, or a stroke, and it gets worse over time. Depending upon the region of damage, the symptoms of dementia differ from patient to patient. Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder (characterized by the death of brain cells). It accounts for 75% of all dementia cases, making it the most common cause of dementia. It is not exclusive to older populations; however, late onset AD is a major cause of dependency in people over 65 years of age. It has a devastating impact on patients, caregivers, and society at large.
A combination of genetic and environmental risk factors has been implicated in AD. It is associated with three hallmark features: amyloid plaques, neurofibrillary tangles, and cerebral atrophy. Amyloid plaques are small lumps in the brain, formed due to an excessive build-up of a sticky protein called beta amyloid. This protein is neurotoxic; it leads to the death of neurons. Neurofibrillary tangles are misshapen, tangled filaments of tau protein. In a healthy brain, tau protein functions to facilitate conduction of nerve impulses by providing a scaffolding to neurons. Cerebral atrophy refers to the degeneration of brain tissue due to the death of neurons, particularly in the hippocampus and medial temporal lobes.
Another important feature of the disease is a deficiency of the neurotransmitter Acetylcholine in the brain. Therefore, pharmacological treatment for AD is primarily based on a category of drugs known as cholinesterease inhibitors, which includes drugs such as rivastigmine, donepezil, and galantamine. Memantine is another medication prescribed for AD, either by itself or in combination with donepezil. However, these are symptom management treatments that provide modest benefits to the patients without changing the underlying process of disease progression. Currently there are no disease-modifying therapy options available to slow down or halt the progression of the disease.
A study on the global burden of diseases revealed that the prevalence of AD and other types of dementia was as high as 40-50 million in 2016, with the number estimated to double by 2050. The rate of developing AD is observed to double every 5 years after the age of 65. The underlying brain pathology of AD precedes the onset of observable clinical symptoms by several years. It is possible that disease-modifying treatments have failed so far because the intervention occurs too late in the course of the disease. Moreover, the associated cognitive decline is slow and unpredictable, which makes longitudinal research difficult. Unless treatments that slow down or stop the progression of the disease are developed soon, a global health crisis is imminent.
Depending on the age of onset, AD can be classified into two types. While more than 95% of the patients with AD are diagnosed with sporadic or late onset AD, the remaining patients have a rarer form of the disease known as early onset familial or Autosomal Dominant AD (ADAD). These people are found to carry a genetic mutation of amyloid precursor proteins, Presilin 1 or Presilin 2, both of which affect the formation of amyloid in the brain. This supports the amyloid cascade hypothesis which identifies amyloid accumulation as the main pathogenic event leading to the neurodegenerative changes associated with the disease. Therefore, preventing amyloid accumulation is one of the primary targets of potential disease-modifying treatments.
Identification of individuals carrying the mutation predisposing them to ADAD (based on family history and genetic testing) before they become symptomatic gives rise to the possibility of clinically testing disease-modifying drugs early in the course of the disease. Due to the similarities in the brain pathology between the two types of AD, these research findings can be generalized.
Established in 2008, the Dominantly Inherited Alzheimer’s Network (DIAN) is an international registry for symptomatic and asymptomatic ADAD mutation carriers, as well as non-carriers. The asymptomatic participants undergo periodic cognitive assessments and clinical evaluations (such as cerebrospinal fluid and blood analysis, and magnetic resonance imaging) to identify changes leading up to symptomatic AD (biomarkers). It also provides the infrastructure for longitudinal clinical trials. The DIAN Trial Unit (DIAN-TU) was established in 2009, to coordinate and oversee clinical trials for potential disease-modifying drugs within the DIAN cohort. The DIAN trial was launched in 2012, making it the first AD preventive drug trial. It aimed to test the efficacy of beta amyloid antibody drugs, solanezumab and gantenerumab, in slowing down the cognitive decline and improving biomarkers associated with AD. It is now a phase III, randomized, double blind, placebo-controlled clinical trial. Mutation carriers are randomly assigned to either of the two treatment arms, wherein 75% of the participants receive the active drug, whereas 25% receive a placebo. Non-carrier subjects are assigned to either of the two matching placebo arms and serve as controls. Neither the participants nor the on-site staff is aware of the assignment of participants to the groups. A battery of cognitive assessments is periodically administered to track subtle cognitive changes from one’s baseline. The trial is currently active at 42 locations, across 17 countries.
The results of primary analysis, presented at the Advances in Alzheimer’s and Parkinson’s Therapies’ annual meeting in April 2020, were somewhat disheartening: both the drugs failed to meet the expected outcome. However, further analyses revealed that the administration of the drug gantenerumab showed an improvement in the disease biomarkers. DIAN-TU plans to extend the trial to continue studying the effects of gantenerumab in the hopes of obtaining more conclusive results. In addition to that, DIAN-TU also launched the Next Generation prevention trial to investigate two novel drug candidates.
Regardless of the outcome, clinical trials lead to invaluable insights into the progression of the disease which inform future research. DIAN-TU director Randall J. Bateman encourages patients and affected people by mentioning that the key to finding an effective treatment to stop AD lies in ongoing and continued research and trials.
Isha Puntambekar
