Swank Center for Memory Care and Geriatric Consultation, ChristianaCare
Explore how researchers are recruiting the immune system to fight Alzheimer's disease.
Alzheimer’s disease (AD) continues to affect the lives of millions of Americans. As our elderly population increases, our need to help patients and caregivers cope with this illness will continue to escalate. Treatment of AD has already improved vastly as a result of deeper appreciation of patients’ and caregivers’ needs, our growing evidence base for the importance of lifestyle choices, and the availability of medications specifically indicated for the treatment of this brain disease. The medications currently approved by the FDA, unfortunately, have modest benefits and do not modify AD’s fundamental disease process. Researchers continue to search for better medications that will supplement other treatment approaches. In the search for disease-modifying medications, intense interest has focused on how the immune system can be recruited into the fight against AD.
Our immune systems act constantly to protect our bodies from invasion by infectious agents. In addition, immune system components monitor changes in our bodies’ own cells, for example by eliminating or limiting some cancers. The cells of the immune system include producers of antibodies and also cells that attack, poison, and scavenge invading organisms or our own damaged cells. As we age, the immune system becomes both less and more active.
The aging immune system responds less vigorously to some unfamiliar new provocations. This is thought to underlie, for example, the smaller production of new antibodies seen in older adults who are vaccinated. It may also help to explain the confusing but common clinical situation that occurs when an older adult with a potentially serious infection presents clinicians with a deceptively small fever or increase in disease-fighting white blood cells.
In some ways, though, the aging immune system also becomes more rather than less active. Our brains, which have a special immune system that is mostly separate from that of the rest of the body, are protected by specialized immune cells called microglia that attack various kinds of diseases with toxic substances including inflammatory cytokines. These substances can produce collateral damage, killing brain cells, and some researchers think the brain’s powerful immune response to amyloid plaques (one of the hallmarks of AD) explains the destructive effects of this brain disease.
Since the 1990s, researchers have been exploring ways in which the immune system’s effects could be recruited into the fight against AD. Early experiments showed that rodents with AD-like plaques induced by genetic manipulation could be immunized against toxic amyloid beta, the protein that aggregates into AD’s characteristic plaques. Remarkably, these experimental immunizations were shown to decrease the amount of brain amyloid (“amyloid load”) in these rodents while also improving their cognitive functioning.
Immunotherapy, which is the use of immunity-enhancing techniques as a medical treatment, has taken two basic forms in the fight against AD. In active immunization, a fragment of amyloid beta or a related antigen is administered in order to stimulate a response of both antibody-based and cellular immunity. Passive immunization, by contrast, relies upon the intravenous injection of pre-formed antibodies into an animal for the purpose of boosting resistance to the aggregation of amyloid beta or helping the immune system remove amyloid beta already aggregated into plaques. Although only a small fraction of intravenously administered antibodies pass the blood-brain barrier and enter the brain, their significant effects indicate the potential value of this treatment approach.
Active immunization seemed initially to be the most promising method, because vaccination might induce long-term protection after a small number of relatively inexpensive treatments. Evaluation of the first widely tested human anti-amyloid beta vaccine, however, was stopped in 2002 because its effects included an unacceptably high rate (6%) of meningoencephalitis, a type of central nervous system inflammation that can be fatal. The hope for an AD vaccine has not been fully abandoned, however, and several new vaccines believed less likely to cause meningoencephalitis are currently in testing.
Passive immunization has appeared a safer treatment approach to many investigators, though it requires repeated infusions and accrues greater expense. Infusion of pooled IGG (gamma globulin) has not proved as effective as originally hoped, but many investigators regard the use of “monoclonal” antibody infusions as promising. Monoclonal antibodies are all of an identical structure and they are designed to attack and help eliminate beta amyloid in various forms. Bapineuzumab, an early member of this class of medications, was pushed to the sideline because of associated adverse effects: brain swelling (vasogenic edema) and focal bleeding (micro-hemorrhages, later termed amyloid-related imaging abnormalities or ARIA). Testing of solanezumab as a treatment for mild dementia, a monoclonal antibody that targeted smaller amyloid beta molecules circulating in the blood, was halted in 2016 when the medication failed to demonstrate efficacy in clinical trials. Other monoclonal antibodies, including aducanumab, gantenerumab, and BAN2401 have also been developed. Use of the newer agents is less frequently associated with brain swelling and focal bleeding.
The proof of immunotherapy, ultimately, will be its ability to modify the course of AD. It would be fair to say at this point that both active and passive immunization against amyloid beta have been shown to reduce the brain’s amyloid load but not to produce significant cognitive benefit in patients with advanced AD. There is much greater hope, however, for beneficial effects of early intervention. Findings suggest that passive immunotherapy at a very early stage may have significant clinical effects, and several large scale trials are now underway to test the effects of passive immunotherapy in prodromal or early Alzheimer's disease in early stage human subjects whose diagnosis has been verified using PET amyloid scanning or cerebrospinal fluid analysis. Needless to say, the results of these trials are eagerly awaited by researchers, patients, and caregivers! We are already on the verge of possible FDA approval of one of the monoclonal antibodies as an Alzheimer’s disease treatment. On the basis of a re-analysis of data from trials of aducanumab, which was initially regarded as a failed treatment, Biogen submitted an application to the FDA for a treatment indication and the FDA’s decision is soon to be announced. It is likely that other immunotherapeutic agents will also be submitted to the FDA in the near future.
Immunotherapy is a powerful treatment approach that holds considerable promise for the future. Already it has improved the management of some serious cancers, and it may similarly improve our care of AD patients. Among the improvements of immunotherapy already being tested are the targeting of molecules other than amyloid beta, including disordered tau protein, and the development of safer and more effective antibodies. As the future unfolds, immunotherapy may be the first truly disease-modifying weapon in our efforts to reduce the devastating effects of AD.
Sources:
James Ellison, MD received his medical degree from UCSF in 1978 and trained in psychiatry at the Massachusetts General Hospital (1979-1982).
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