A full review of Alzheimer’s drug research, including current agents being studied for the prevention and treatment of the disease (and other dementias), emphasizes the need to develop and test drugs based on an understanding of the multiple effects of aging on the brain.
“Alzheimer’s is a complex disease with many different factors that contribute to its onset and progression,” said Dr. Howard Fillit, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation (ADDF), senior author of the review paper.
“Decades of research have revealed common processes that are relevant to understanding why the aging brain is vulnerable to Alzheimer’s disease. New therapeutics for Alzheimer’s disease will come from this understanding of the effects of aging on the brain.”
Old age is the leading risk factor for Alzheimer’s disease, a progressive neurodegenerative disease that affects 50 million people worldwide and around 5 million in the United States. With a growing aging population, the Centers for Disease Control and Prevention projects the burden of Alzheimer’s disease will nearly triple to 14 million Americans by 2060.
Currently, the approved drugs for Alzheimer’s disease are able to relieve some symptoms, but they do not stop disease progression. New treatments that can prevent, slow, or halt the disease are urgently needed to help the millions of people affected by dementia worldwide.
According to Fillit, the biology of aging itself provides numerous novel targets for new drug development for Alzheimer’s disease.
Along with old age, many biological processes go awry that have also been implicated in Alzheimer’s disease. For example, as people get older, they are more likely to have chronic systemic inflammation and neuroinflammation, which is linked to poor cognitive function.
Other aging problems include impaired clearance of toxic misfolded proteins, mitochondrial and metabolic dysfunctions (associated with diabetes), vascular problems, epigenetic changes (changes in gene regulation without alterations in the DNA sequence), and loss of synapses (points of communication between neurons).
“Our success in fighting Alzheimer’s disease will likely come from combination therapy — finding drugs that have positive effects on the malfunctions that happen as people age,” Fillit said.
“Combination therapies are the standard of care for other major diseases of aging, such as heart disease, cancer, and hypertension, and will likely be necessary in treating Alzheimer’s disease and other dementias.”
Later-phase (phase 3) Alzheimer’s trials tend to focus on drugs targeting beta-amyloid and tau, the classic pathological hallmarks of Alzheimer’s disease (of phase 3 trials, 52 percent are targeting amyloid or tau), but other strategies are gaining ground and are in phase 1 or 2 trials, according to the review paper.
Although therapeutic attempts to remove or decrease the production of beta-amyloid have been largely unsuccessful in altering the disease course of Alzheimer’s disease, said Fillit, researchers still learned important information from those clinical trials even if they didn’t immediately result in treatments. And recent clinical trials suggest that problems with clearance of beta-amyloid may yet prove fruitful.
“It is currently not known if these classic pathologies (amyloid and tau) represent valid drug targets and if these targets alone are sufficient to treat Alzheimer’s disease,” said Fillit.
“Targeting the common biological processes of aging may be an effective approach to developing therapies to prevent or delay age-related diseases, such as Alzheimer’s.”