The prevalence of Alzheimer’s disease is expected to rise with the aging of the population, increasing the urgency of developing new treatments. Drugs currently to treat Alzheimer’s include cholinesterase inhibitors and memantine, both of which help support neurotransmitters important to memory function. These drugs provide symptomatic relief and may slow symptoms of cognitive decline for some people for a limited time. But they neither halt nor reverse disease progression because they do not target the underlying molecular pathways believed to be involved in Alzheimer’s.
Translational research is a multidisciplinary, multi-step process that uses basic science discoveries to develop medicines or other interventions that improve health. The process of discovering and developing drugs for neurological disorders like Alzheimer’s is extremely challenging and expensive. It takes 10 to 15 years from the discovery of a new therapeutic target until a new drug reaches the market, with an average cost of about $1.8 billion (Paul et al., 2010).
Intensive efforts are underway in translational research to identify and test therapies that interfere with a variety of processes involved in the development of Alzheimer’s. A range of cellular and molecular pathways, from abnormal deposits of amyloid and tau proteins to the potentially protective roles played by growth-factor molecules, are being explored.
The National Institutes of Health (NIH) supports several innovative programs that foster preclinical drug development and testing of novel compounds. For example, the National Institute on Aging (NIA)-funded Alzheimer’s Disease Cooperative Study (ADCS) helps test new agents. NIA also leads the Alzheimer’s Disease Translational Research Program, which supports early drug discovery and preclinical drug development research by academic scientists and small biotechnology companies, with the goal of discovering new drug candidates for the treatment and prevention of Alzheimer’s disease, mild cognitive impairment (MCI), and age-related cognitive decline. To date, this program has resulted in more than 60 projects supporting early drug discovery and preclinical drug development. Several of these compounds have been selected by pharmaceutical companies for further development. (For more on these programs, go to Supporting Infrastructure and Initiatives).
Investigators in NIA’s Intramural Research Program (IRP) also play a critical role in advancing translational research. For example Posiphen, a drug candidate designed and developed by IRP scientists—was shown to be well tolerated in more than 120 healthy volunteers (Maccecchini et al., 2012). An additional study in five patients with MCI demonstrated Posiphen’s ability to lower levels of tau, inflammatory biomarkers, and metabolites of the amyloid precursor protein (APP). While these results, announced in July 2012, are preliminary, they provide key data needed to move the drug toward further clinical testing.
Beta-amyloid is generated from its precursor protein, APP, by the enzyme gamma-secretase. It is thought that drugs that inhibit this enzyme could reduce beta-amyloid accumulation. However, gamma-secretase is also involved in processing another protein, Notch, which has many critical biological functions—so drugs that completely block gamma-secretase activity carry a high risk of negative side effects.
Rockefeller University, New York City, researchers may have found a way to sidestep this problem (He et al., 2010). They discovered a new brain protein, called gamma-secretase activating protein (GSAP), which specifically promotes gamma-secretase binding to APP but not to Notch. Moreover, they showed that GSAP’s activity can be inhibited by an anti-cancer drug, imatinib. Imatinib reduced beta-amyloid production by 40 to 50 percent both in tissue samples and in Alzheimer’s model mice, while having no effect on Notch processing. This result suggests that inhibiting GSAP offers a promising approach for lowering beta-amyloid levels while avoiding toxic side effects.
The gene APOE is linked to late-onset Alzheimer’s disease. It produces a protein called apolipoprotein E (ApoE) that plays a critical role in the accumulation and clearance of beta-amyloid in the brain. Recent studies have suggested that increasing, rather than decreasing, human ApoE levels may be a promising therapeutic approach. However, a study by Washington University, St. Louis, researchers found that increasing human ApoE levels in a mouse model of Alzheimer’s made the pathology worse (Kim et al., 2011). Mice with twice the amount of human ApoE developed more severe beta-amyloid plaque loads, and their brains contained higher numbers of activated microglia (a sign of brain inflammation like that seen in people with Alzheimer’s). These findings suggest that strategies to decrease ApoE levels in the brain could be explored as a prevention or treatment of Alzheimer’s disease.
Researchers are developing therapies that target tau, the protein involved in tangle development. Tau plays a key role in stabilizing microtubules, the protein rods that help transport molecules and other specialized components within neurons. Loss of that function is thought to contribute to the pathology seen in Alzheimer’s and other neurodegenerative diseases.
A microtubule-stabilizing drug, paclitaxel, had previously been found to improve symptoms of neurodegeneration in a mouse model of tau disease, but it was difficult to deliver the drug to the brain. University of Pennsylvania, Philadelphia, researchers analyzed a series of other microtubule-stabilizing agents, and identified several that could penetrate the brain and stabilize brain microtubules when administered to mice (Brunden et al., 2011). The drug discovery strategy reported in this study could lead to new agents for treating Alzheimer’s disease.
Allopregnanolone is a hormone recently shown to promote neurogenesis, reduce brain pathology, and improve cognition in Alzheimer’s model mice. A team led by University of Southern California, Los Angeles, researchers assessed the effectiveness of allopregnanolone treatment in Alzheimer’s model mice at different stages of disease progression (Chen et al., 2011). Hormone treatment was most effective in promoting neurogenesis and reducing brain pathology when initiated during the early stages of the disease, before beta-amyloid plaques began to form and before declines in neurogenesis. This study suggests that in humans, allopregnanolone treatment may have the most benefit for patients in the earliest stages of the disorder.