Repositioning Drugs to Reduce the Disparate Burden of Alzheimer’s Disease
Douglas Barthold & Julie Zissimopoulos
AD imposes a large, multifaceted, and disparate burden on individuals, families and society
The burden of Alzheimer’s Disease (AD) on afflicted individuals and the health system as a whole is substantial. The Alzheimer’s Association estimates that in 2016, 5.4 million people in the United States are living with AD.1 By 2050, the number of Americans with AD is estimated to reach 9.1 million.2 The health care expenditures associated with AD are projected to grow from $181 billion in 2010 to $1,140 billion in 2050 and to consume an ever larger portion of total US health expenditures.2 Additionally, caregiving by family consumes time and money, and may affect the health of caregivers.3
It is not necessary to completely prevent AD in order to reduce its burden. Zissimopoulos et al. (2015) found that delaying onset for just one year now will result in 20% lower prevalence of AD in 2050, declining from a projected 9.1 million to 7.8 million Americans with AD. This delay offers substantial cost reductions as well, saving $160 billion in health care costs and approximately 300 million hours of care by family members in the year 2050, for a total value of $223 billion in medical costs and informal caregiving cost savings. Innovations that delay onset of AD by 5 years can save over $600 billion in AD total costs in 2050.2
AD affects some populations more than others. The incidence rates for blacks and Hispanics are about twice as high as for whites (4.2%, 3.8%, and 1.9%, respectively).4 These groups are also disproportionately affected by other chronic conditions, including diabetes, hypertension, and hyperlipidemia.5-7 The socio‐environmental, behavioral, and biological factors that contribute to racial and ethnic disparities in AD may be exacerbated by disparities in access to health care services and in quality of care. There is concern that minorities receive care that falls short on several dimensions of quality, including safety, timeliness, effectiveness, efficiency, patient-centeredness, and equity.8 Racial and ethnic minority families consequently shoulder a high burden of Alzheimer’s disease.9
Identifying approved medications that affect risk of AD may reduce disparate burden of disease
Pharmaceutical therapies can help suppress symptoms of AD, but currently none can prevent or delay its onset and progression, and only a limited number of novel therapeutics are advancing through the development pipeline. With few prospective treatments targeting AD, identifying therapeutics for other conditions that have potential to prevent or treat AD is a promising approach for reducing risk of the disease and racial and ethnic disparities in risk. Multiple therapies for high-prevalence conditions such as diabetes, hypertension, hyperlipidemia, gastroesophageal reflux disease (GERD), and insomnia have been associated with AD risk. While the association of approved medication for non-AD conditions with AD varies across class of drugs, and lacks consensus across studies, there are some classes that show promise. For diabetes, glucagon-like peptides and amylin agonists both show protective associations with AD.10-12 Among hypertension drugs, beta-blockers and ACE inhibitors show protective associations.13-15 For insomnia, endocrine-metabolic agents and atypical antipsychotics appear to be protective.16-19 Two classes of GERD drugs, on the other hand, have shown evidence as risk factors for AD.20-22 Statins, used to treat hyperlipidemia, have shown mixed associations with AD.23,24
Some of these drugs are already widely prescribed and used by the elderly population, and could delay the onset of AD, but the evidence is incomplete. The work on statins is an example; many of the randomized controlled trials (RCTs) had short follow-up times, and disqualified patients with hyperlipidemia, who are the most likely to benefit from statins.25 Additionally, studies on statins and AD included insufficient samples of racial and ethnic minorities. The homogeneity of the study populations is especially problematic. Not only is race associated with variations in incidence of chronic disease and medication adherence, but the pharmacokinetic processes of drugs may also differ across racial and ethnic groups.5,8,26 Thus, even within classes of drugs, the treatment effectiveness of specific molecules is likely to vary across racial and ethnic groups. Identifying drugs that are prescribed for chronic conditions and impact AD, and analyzing differences in effectiveness across racial and ethnic groups, may aid in in reducing racial and ethnic disparities in AD.
A data-driven approach to reducing racial and ethnic disparities in Alzheimer’s disease
The prevailing paradigm in academic-based therapeutic development stands on the approach in which a discovery at the bench is followed by a search for a potential disease application. The poor reproducibility of preclinical discovery research and translational validity of animal models are two factors frequently cited for the high failure rate of AD drugs during Phase II and III clinical trials. A promising approach combines data from surveys, health records, medical claims records, and genetic data with statistical methods to identify and analyze current treatments for non-AD conditions that may delay or prevent Alzheimer’s disease. For example, pharmaceutical drugs and health care claims data from millions of Medicare beneficiaries provide insight into the diagnosed health conditions, prescribed drugs, diagnostic services, health care services, and treatments of older Americans. Studies based on these data benefit from large samples of racial and ethnic minorities, unlike studies based on data from small clinical trials. Studies that combine multiple rich data sources and rigorous methods can inform ways to reduce AD’s multifaceted burden and reduce racial and ethnic disparities in the disease.
Association As. 2015 Alzheimer's disease facts and figures. Alzheimer's & dementia: the journal of the Alzheimer's Association. 2015;11(3):332.
Zissimopoulos J, Crimmins E, St Clair P. The Value of Delaying Alzheimer’s Disease Onset. Forum for Health Economics and Policy. 2015;18(1):25-39.
Emanuel EJ, Fairclough DL, Slutsman J, Emanuel LL. Understanding economic and other burdens of terminal illness: the experience of patients and their caregivers. Annals of internal medicine. 2000;132(6):451-459.
Tang M-X, Cross P, Andrews H, et al. Incidence of AD in African-Americans, Caribbean hispanics, and caucasians in northern Manhattan. Neurology. 2001;56(1):49-56.
Pleis JR, Lucas JW, Ward BW. Summary health statistics for US adults: National Health Interview Survey, 2008. Vital and health statistics. Series 10, Data from the National Health Survey. 2009(242):1-157.
Ratanawongsa N, Zikmund-Fisher BJ, Couper MP, Van Hoewyk J, Powe NR. Race, ethnicity, and shared decision making for hyperlipidemia and hypertension treatment: the DECISIONS survey. Medical Decision Making. 2010;30(5 suppl):65S-76S.
Mensah GA, Mokdad AH, Ford ES, Greenlund KJ, Croft JB. State of disparities in cardiovascular health in the United States. Circulation. 2005;111(10):1233-1241.
Nelson AR, Smedley BD, Stith AY. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care (full printed version). National Academies Press; 2002.
Navaie-Waliser M, Feldman PH, Gould DA, Levine C, Kuerbis AN, Donelan K. The experiences and challenges of informal caregivers common themes and differences among Whites, Blacks, and Hispanics. The Gerontologist. 2001;41(6):733-741.
McClean PL, Parthsarathy V, Faivre E, Hölscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. The Journal of Neuroscience. 2011;31(17):6587-6594.
Yang Y, Zhang J, Ma D, et al. Subcutaneous administration of liraglutide ameliorates Alzheimer-associated tau hyperphosphorylation in rats with type 2 diabetes. Journal of Alzheimer's Disease. 2013;37(3):637-648.
Adler BL, Yarchoan M, Hwang HM, et al. Neuroprotective effects of the amylin analogue pramlintide on Alzheimer's disease pathogenesis and cognition. Neurobiology of aging. 2014;35(4):793-801.
Davies NM, Kehoe PG, Ben-Shlomo Y, Martin RM. Associations of anti-hypertensive treatments with Alzheimer's disease, vascular dementia, and other dementias. Journal of Alzheimer's Disease. 2011;26(4):699-708.
Forette F, Seux M-L, Staessen JA, et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Archives of internal medicine. 2002;162(18):2046-2052.
Hajjar I, Catoe H, Sixta S, et al. Cross-sectional and longitudinal association between antihypertensive medications and cognitive impairment in an elderly population. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2005;60(1):67-73.
Stefanova NA, Maksimova KY, Kiseleva E, Rudnitskaya EA, Muraleva NA, Kolosova NG. Melatonin attenuates impairments of structural hippocampal neuroplasticity in OXYS rats during active progression of Alzheimer's disease‐like pathology. Journal of pineal research. 2015;59(2):163-177.
O’Neal-Moffitt G, Delic V, Bradshaw P, Olcese J. Prophylactic melatonin significantly reduces Alzheimer’s neuropathology and associated cognitive deficits independent of antioxidant pathways in AβPPswe/PS1 mice. Molecular neurodegeneration. 2015;10(1):1-21.
Lauterbach EC. Repurposing psychiatric medicines to target activated microglia in anxious mild cognitive impairment and early Parkinson’s disease. American Journal of Neurodegenerative Disease. 2016;5(1):29.
Yin Y, Liu Y, Zhuang J, et al. Low-Dose Atypical Antipsychotic Risperidone Improves the 5-Year Outcome in Alzheimer's Disease Patients with Sleep Disturbances. Pharmacology. 2015;96(3-4):155-162.
Gomm W, von Holt K, Thomé F, et al. Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis. JAMA neurology. 2016.
Haenisch B, von Holt K, Wiese B, et al. Risk of dementia in elderly patients with the use of proton pump inhibitors. European archives of psychiatry and clinical neuroscience. 2015;265(5):419-428.
Vogiatzoglou A, Smith AD, Nurk E, et al. Cognitive Function in an Elderly Population: Interaction Between Vitamin B12 Status, Depression, and Apolipoprotein E [Latin Small Letter Open E] 4: The Hordaland Homocysteine Study. Psychosomatic medicine. 2013;75(1):20-29.
Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Annals of internal medicine. 2013;159(10):688-697.
Zandi PP, Sparks DL, Khachaturian AS, et al. Do statins reduce risk of incident dementia and Alzheimer disease?: The Cache County Study. Archives of General Psychiatry. 2005;62(2):217-224.
Sano M, Bell K, Galasko D, et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011;77(6):556-563.
Burroughs VJ, Maxey RW, Levy RA. Racial and ethnic differences in response to medicines: towards individualized pharmaceutical treatment. Journal of the National Medical Association. 2002;94(10 Suppl):1.