April 20 2017 Tahmeena Chowdhury, PhD

I recently attended the MIT Alumni Association webcast of an online faculty forum titled “The End of Alzheimer’s disease.”  This session presented an excellent opportunity to hear from panelists, Drs. Sarah Hopp (Massachusetts General Hospital), Matt Kaeberlein (University of Washington, Seattle), and Anant Paravastu (Georgia Tech), on new developments and potential therapies targeting this debilitating neurological disorder.  It was also very informative listening to audience questions and obtaining a better understanding of people’s concerns and thoughts on this disease.

The panel opened with an overview of the molecular pathology of Alzheimer’s disease (AD). Clinical symptoms of AD are attributed to the misfolding and oligomerization of proteins, such as amyloid-β (Aβ) peptide and tau, resulting in formation of amyloid plaques and neurofibrillary tangles.  The oligomers disrupt various, diverse molecular pathways, including dysregulation of ions in the calcineurin pathway and resulting loss of communication between neurons.  The loss of synaptic connections and neurons manifest in behavioral changes and deterioration of cognitive functions that are the hallmarks of AD.

The moderator, Barbara Moran, asked about the importance of inflammation in AD, a question that immediately grabbed my attention.  The disappointing study results of potential AD drugs over the last several years strongly suggest reassessing current therapeutic strategies, and I was keen to hear of recent developments that could support inflammation as a feasible treatment approach.  The panelists gave a brief overview of the lines of evidence linking inflammation to AD.  Inflammatory responses mediated by plaque-activated microglial cells in the brain have been implicated in AD.  Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has been demonstrated to have a beneficial effect on AD, albeit their use is associated with negative gastrointestinal and nephrologic effects.  Inflammation induced by senescent cells has also been proposed to play a role in AD.  With numbers increasing with age, these senescent cells secrete pro-inflammatory factors, leading to systemic inflammation.

Because of the complexity of how the inflammatory response affects AD pathology, targeting inflammation as a therapeutic approach poses a challenge.  Some inflammatory factors may have deleterious effects whereas others may actually be protective; the different stages of AD may also result in a differential response.  As more information on the mechanism of inflammation is uncovered, perhaps it will be possible to pharmacologically modulate levels and activities of specific players and, in combination with additional drugs, lead to an effective treatment strategy for AD.

For effective therapeutic intervention in general, both Drs. Hopp and Kaeberlein emphasized the importance of AD detection.  The possibility of an accurate detection of AD may increase the chances of treatment approaches being effective.  Diagnosis of AD is based mostly on clinical symptoms, e.g., loss of cognitive functions.  While levels of Aβ peptides can be detected in the blood and cerebrospinal fluid, no definitive imaging test is currently used in clinical settings to diagnose AD in patients prior to death; imaging can be performed on brain sections of deceased patients.  Positron emission tomography (PET) offers a powerful option as a diagnostic tool, allowing for detection of different stages of AD in living patients.  New PET techniques are already being used to image plaques and tangles in neurons under research settings and in clinical studies, but are not currently used for routine diagnosis in clinical settings.  It will be interesting to see if PET use in AD diagnosis becomes more common in medical practices, and what potential impact that has on clinical decisions made by physicians.

At this forum, the majority of the audience questions were regarding life styles and diets as risk factors for AD.  Most people agree that a healthy diet offers protection against onset of dementia.  Diabetes increases risk of AD about 2-fold, and people on vegan diets are generally at a lower risk for dementia and AD.  Glucose homeostasis has been linked to AD, with evidence suggesting involvement of insulin in amyloid plaque formation.  Despite these various links and correlations, a particular dietary guideline specific to AD prevention has not been established.

A question was posed regarding diet as a factor in the apparent lower incidence of AD in India, the answer to which was informative on both epidemiological and dietary points.  Curcumin, used in Indian cuisine, is a powerful antioxidant and share similarities with Congo Red, the original dye used to identify AD.  Studies in mice suggest that curcumin can cross the blood-brain barrier to bind amyloid plaques, with some evidence supporting an improvement in pathological traits of AD, e.g., decreases in cytokine levels and microglial activity.  Dr. Hopp pointed out, however, that the effectiveness of curcumin to treat AD in clinical settings has not been conclusively established.  In response to the same question, Dr. Paravastu appeared skeptical regarding epidemiological links to AD, due to the caveat of cases not being reported or not accurately diagnosed.  I think this is a valid point, especially when using data from countries where a substantial proportion of the population may not have access to quality healthcare.

In line with the forum’s topic, the panelists shared their thoughts on promising drugs to treat AD.  Current treatment options are disappointingly limited, and majority of recent studies on new drug candidates have failed at various stages of development.  Dr. Kaeberlein was an advocate of taking an aging-related approach to treating AD by delaying the molecular processes that lead to clinical decline in quality of life associated with aging.  United States Food and Drug Administration (FDA)-approved rapamycin, a potent inhibitor of the TOR pathway implicated in aging, has been demonstrated to decrease levels of Aβ peptides and tau, as well as improve cognitive functions in mouse models of AD.  Generic rapamycin is available, albeit no clinical trials to investigate its therapeutic role in AD are ongoing.  Several lines of evidence link mammalian TOR (mTOR) pathway with Aβ and tau pathologies; and having a well-studied, FDA-approved, and highly specific inhibitor of this pathway makes mTOR a promising target for therapy.  Dr. Kaeberlein also mentioned senolytics as potential therapeutic candidates to target inflammation associated with senescent cells, discussed above.  Dr. Paravastu emphasized the need for a multi-target tactic to treat AD, which I believe may be the most practical and efficient scheme.  Current approach has been focused on clearing plaques, but lack of effectiveness of the majority of candidate drugs strongly indicate the need to reassess this strategy.

One listener asked the question that perhaps all of us have been pondering:  how long until a cure for AD?  Dr. Kaeberlein’s response pertained to a “big picture” approach to combatting age-related disorders in general instead of focusing on cures for particular diseases, reiterating the importance of understanding the mechanism of aging and slowing it down to maximize health span at the population level.  Drs. Hopp and Paravastu, in contrast, gave a specific time range of 20 to 25 years until a curative treatment for AD.  Depending on how old we are, this prognostication may fill us with hope or dread on a personal level.  From a scientific perspective, however, the next few years promise to substantially expand our breadth of knowledge on AD and other age-related neurodegenerative diseases, as well as impact therapeutic strategies for complex diseases in general.

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