The Alzheimer’s Drug Discovery Foundation (ADDF) awarded five new grants in May and June, totaling nearly $1.5 million. Three of these grants support clinical and preclinical drug programs that translate the latest findings about Alzheimer’s into drugs to treat it, while two others awards are funding international researchers working on biomarkers for early detection of frontotemporal dementia (FTD), Alzheimer’s, and related diseases.
Dr. Howard Fillit, Founding Executive Director and Chief Science Officer of the ADDF, says: “The ADDF is committed to funding novel ideas on the forefront of Alzheimer’s research. These grants will advance an epigenetic therapy, a drug with the potential to slow down the effects of aging on the brain, and another that could preserve memory in people with mild cognitive impairment. And our investments in biomarkers may help physicians detect and accurately diagnose different types of dementia so patients can get appropriate care.”
Paul Newhouse, MD, Vanderbilt University Medical Center
Long-Term Nicotine Treatment of Mild Cognitive Impairment
Could nicotine patches treat mild cognitive impairment, a condition that often precedes Alzheimer’s? Although smoking likely increases dementia risk, nicotine patches, which lack the toxic chemicals of cigarette smoke, may activate nicotine receptors in the brain to promote cognitive ability and slow Alzheimer’s. In an earlier pilot trial, nicotine patches appeared to improve attention and memory in patients with mild cognitive impairment (MCI). This trial, which has received funding from the NIH, includes 300 non-smokers with MCI and aims to determine whether nicotine patches can improve cognitive performance and reduce neurodegeneration and whether those effects are stronger in patients with the APOE4 genetic risk factor. Nicotine patches are widely available, safe, and affordable, so doctors could prescribe them immediately to patients if the trial finds positive effects.
Carmela R. Abraham, PhD, Boston University School of Medicine
Development of Klotho Enhancers as Novel Therapeutics for Alzheimer’s Disease
Aging is the leading risk factor for developing Alzheimer’s disease. Klotho protein, named for the Greek goddess who spins the thread of life, is a key regulator of biological pathways involved in aging and performs a neuroprotective role in the brain. Therefore, elevating Klotho levels is an intriguing strategy to protect neurons from cell death in age-related diseases, including Alzheimer’s and multiple sclerosis. With five previous years of ADDF funding, Dr. Abraham has identified a series of promising drug candidates, called “Klotho boosters,” that can enter the brain and induce Klotho production. In this new study, she and her team will continue to optimize their lead series of Klotho boosters to identify a lead candidate and backup compound for development.
Berkley Lynch, PhD, Rodin Therapeutics
Selective HDAC2 Inhibitors for the Treatment of Cognitive Deficits in Alzheimer's Disease
No existing drugs for the treatment of cognitive impairment work through epigenetic mechanisms, which alter gene expression. Epigenetic drugs for other diseases, including cancer, have been developed but have safety concerns. With previous funding from the ADDF, the team at Rodin Therapeutics has been developing highly specific epigenetic drug candidates for Alzheimer’s disease that minimizes the safety issues. This new study will test their safety and ability to increase brain proteins, improve brain function, and enhance cognition in preclinical animal studies. With these data in hand, the team plans to move its epigenetic drug program toward human clinical trials.
The following grants support the development of tools to advance our understanding of Alzheimer’s disease by tracking its progression, improving patient selection for clinical trials, and monitoring patient response to drugs in trials.
Mari DeMarco, PhD, DABCC, University of British Columbia
Quantitation of TDP-43 Isoforms in Cerebrospinal Fluid by Mass Spectrometry
Diagnosis of cognitive impairment is routinely based on imaging technologies (e.g., MRI) and clinical cognitive testing, but these techniques only have modest accuracy in differentiating frontotemporal dementia (FTD), Alzheimer’s disease, and other related dementias. Accurate diagnosis is particularly important in the early stages of disease when the potential for treatment is greatest. In this project, Dr. DeMarco seeks to develop a sensitive diagnostic biomarker for FTD that detects TDP-43 and tau—proteins that aggregate and are in FTD. The investigators will measure cerebrospinal fluid from FTD and Alzheimer’s patients using a highly sensitive approach known as mass spectrometry. If successful, this biomarker tool will improve diagnostic accuracy and allow for early detection of FTD and other related dementias.
Keith St. Lawrence, PhD, Lawson Health Research Institute
The Role of Perfusion MRI in Improving the Diagnosis of Frontotemporal Dementia Subtypes and Longitudinal Monitoring of Disease Progression
Neuroimaging is an important method for diagnosing frontotemporal dementia (FTD) and related disorders and monitoring disease progression over time. But commonly used techniques such as structural MRI or PET imaging lack sensitivity or are costly and time-consuming. Cerebral blood flow, which is linked to brain activity, may provide a better option to distinguish between different forms of dementia, including subtypes of FTD. Dr. St. Lawrence seeks to establish the use of perfusion MRI or arterial spin labeling (ASL) to measure cerebral blood flow to different brain regions and track long-term changes in brain function in FTD patients. If successful, these studies will lay the groundwork for using ASL imaging as a functional marker to monitor FTD progression over time and assess the benefits of emerging treatments for FTD patients.
This grant is funded through the ADDF’s partnership program with the Association for Frontotemporal Degeneration (AFTD).