Alzheimer’s disease (AD) research has followed a predictably discouraging pattern of hail and fail. New findings or treatments acclaimed as breakthroughs later produce disappointing results in clinical trials. This week’s interval between hope and despair was brutally brief. Confirmation that dementia rates are dropping (1, 2) was followed by the announcement another important AD treatment had failed (3).
AD research is organized around the Amyloid Cascade Hypothesis, a comprehensive synthesis of observations and experiments implicating the aggregation of amyloid-β (Aβ) molecules as the key causative factor of this dementia (4). The understanding of AD and other dementias has grown enormously over the past 25 years and efforts to control Aβ deposition or production have been spectacularly successful – in the laboratory. Although it appears some treatments probably hit their intended targets in human subjects, dementia has remained intractable, leading to concerns that the cornerstone hypothesis guiding AD research and therapy is erroneous (4). Additional clinical trials are underway, perhaps these will finally confirm or refute whether amyloid is the key determinant of AD dementia. Concern is understandable because the first anti-amyloid clinical trials in human subjects were initiated almost 15 years ago.
Ideas regarding how the events culminating in dementia are instigated and evolve are changing (5). The Amyloid Cascade Hypothesis has undergone modification and aspects of it may yet be proven to be seminal mechanisms in the pathology of dementia. However, more years will be required to determine whether hypothesis champions are vindicated or repudiated by clinical trial outcomes. Once an AD cure is in hand, more time will be needed to bring it to the public. Whether any future cure(s) will be successful in economic and practical terms is speculative.
The good news is confirming declining AD rates are real reminds us that there is cause for optimism. Although the strongest known risk factor for AD development is chronological age, dementia is not necessarily destiny. Other studies have revealed potentially controllable factors such as education, diet, stress management and medical care (6) may decrease AD development risk substantially. The bad news is that we do not have a solid understanding precisely why AD rates have declined. Many things may play a role in evading AD, which is (are) the most significant? Equally important, which environmental factors (7) or behaviors are most inimical to good brain function?
Has the understandable anxiousness to defeat AD led us to overlook some vitally important aspects of research? We noted an enticing correlation between amyloid deposits and brain malfunction and bet heavily a traditional pharmaceutical approach would eliminate them. Armed with a clear target and a plan to vanquish AD, we neglected to systematically examine many fundamental features of this dementia. Seeing that environmental and behavioral factors modify the threat of AD we are now in the unenviable position of being unable to explain precisely why this is so, how to facilitate cognitive function health retention and delineate the actions necessary to keep this positive trend alive.
Medical science has faced and successfully controlled intractable diseases. Remembering the story of Kuru, the fatal transmissible spongiform encephalopathy of the Fore people of Papua, New Guinea, may provide some inspiration (8). Deciphering the pathologic and epidemiologic events underlying Kuru required the combined efforts of physicians, neuroscientists, geneticists and anthropologists. More than a half century later all prion diseases remain incurable. However, despite the complete absence of any effective direct medical treatments, other interventions have enabled us to drive Kuru to extinction.
In light of the current situation and new findings it is vital to invigorate research into elucidating the basic environmental and behavioral influences that modify AD risk. As these initiatives bear fruit, a concerted effort to educate the public as to how they can proactively reduce their risk of dementia will be of supreme importance to the public health. These readily achievable steps may save many persons from dementia as we struggle toward an elusive AD cure.
(1) G. Kolata. 2016. U.S. Dementia Rates Are Dropping Even as Population Ages. The New York Times, 21 November 2016. http://nyti.ms/2eYS0zC
(2) L. Szabo. 2016. Dementia rates decline sharply among senior citizens. Kaiser Health News via PBS Newshour, 21 November 2016. http://www.pbs.org/newshour/rundown/dementia-rates-decline-sharply-among-senior-citizens/
(3) P. Belluck. 2016. Eli Lilly’s Experimental Alzheimer’s Drug Failed in Large Trial. The New York Times, 23 November 2016. http://nyti.ms/2f6v69u
(4) A. Abbott and E. Dolgin. 2016. Failed Alzheimer’s Trial Does Not Kill Leading Theory of Disease. Nature, 23 November 2016. go.nature.com/2f8asGi
(5) R. Jack et al. 2016. A/T/N: An Unbiased Descriptive Classification Scheme for Alzheimer Disease Biomarkers. Neurology 87(5):539-547. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970664/
(6) B. Larson et al. 2013. New Insights Into the Dementia Epidemic. The New England Journal of Medicine 369(24):2275-2277. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130738/
(7) L. Calderón-Garcidueñas et al. 2013. Early Alzheimer’s and Parkinson’s Disease Pathology in Urban Children: Friend versus Foe Responses – It Is Time to Face the Evidence. BioMed Research International 2013;2013:161687. doi: 10.1155/2013/161687. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581281/
(8) P. P. Liberski. 2013. Kuru: A Journey Back in Time from Papua New Guinea to the Neanderthals’ Extinction. Pathogens 2:472-505. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235695/