Development, Application, and Results from a Precision-medicine Platform that Personalizes Multi-modal Treatment Plans for Mild Alzheimer’s Disease and At-risk Individuals

Author(s): Dorothy Keine*, John Q. Walker, Brian K. Kennedy, Marwan N. Sabbagh.

Journal Name: Current Aging Science

Volume 11 , Issue 3 , 2018

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Introduction: Alzheimer’s Disease (AD) is a progressive neurodegenerative condition in which individuals exhibit memory loss, dementia, and impaired metabolism. Nearly all previous single-treatment studies to treat AD have failed, likely because it is a complex disease with multiple underlying drivers contributing to risk, onset, and progression. Here, we explored the efficacy of a multi-therapy approach based on the disease risk factor status specific to individuals with AD diagnosis or concern.

Methods: Novel software from uMETHOD Health was designed to execute a precision-medicinebased approach to develop personalized treatment recommendations with the goal of slowing or reversing biologic drivers of AD. AD-associated inputs encompassed genomic data, bio-specimen measurements, imaging data (such as MRIs or PET scans), medical histories, medications, allergies, co-morbidities, relevant lifestyle factors, and results of neuropsychological testing. Algorithms were then employed to prioritize physiologic and lifestyle states with the highest probability of contributing to disease status, and these priorities were incorporated into a personalized care plan, which was delivered to physicians and supported by health coaches to increase adherence. The sample included 40 subjects with Subjective Cognitive Decline patients (SCD), and Mild Cognitive Impairment Patients (MCI).

Results: Software analysis was completed for 40 individuals. They remained on their treatment plan for an average of 8.4 months, equal to 2.8 iterations of care plans. 80% of individuals overall showed improved memory function scores or held steady, as measured by standardized cognitive evaluations. Cognitive assessments showed significant improvement in the SCD group (Composite P value .002, Executive P value .01), and the CNS-VS Executive domain showed significant results in the combined group as well (P value .01). There was also biomarker improvement over time observed from the blood panels. 8 out of 12 selected biomarkers showed slight, though statistically non-significant, improvement overall for symptomatic individuals, and 6 out of 12 for the overall population. Only one biomarker, homocysteine, showed significant improvement, though (P values .03, .04, .002).

Conclusions: Our analysis of these individuals lead to several interesting observations together suggesting that AD risk factors comprise a network of interlocking feedback loops that may be modifiable. Our findings indicate previously unidentified connectivity between AD risk factors, suggesting that treatment regimens should be tailored to the individual and multi-modal to simultaneously return several risk factors to a normative state. If successfully performed, the possibility to slow progression of AD and possibly reverse aspects of cognitive decline may become achievable.

Keywords: Alzheimer's disease, mild cognitive impairment, precision medicine, combination therapy, software, treatment.

[1]
Alzheimer's Association. [Online]. [cited 2017]. Available from:. http://www.alz.org/
[2]
WHO and Alzheimer’s Disease International. Geneva: World Health Organization. [Online]. Geneva: World Health Organization; 2012 [cited 2017]. Available from:. http://www.who.int/mental_health/publications/dementia_ report_2012/en/
[3]
World Health Organization. First WHO ministerial conference on global action against dementia: Meeting report. WHO Headquarters Geneva, Switzerland;. 2015.
[4]
Winblad B, Amouyel P, Andrieu S, et al. Defeating alzheimer’s disease and other dementias: A priority for European science and society. Lancet Neurol 2016; 15(5): 455-532.
[5]
Doraiswamy PM, Steffens DC. Combination therapy for early Alzheimer’s disease: What are we waiting for? J Am Geriatr Soc 1998; 46(10): 1322-4.
[6]
Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet 2017; 390(10113): 2673-734.
[7]
Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): A randomized controlled trial. Lancet 2015; 385(9984): 2255-63.
[8]
Bachurin S, Gavrilova S, Samsonova A, et al. Mild cognitive impairment due to alzheimer disease: Contemporary approaches to diagnostics and pharmacological intervention. Pharmacol Res 2017; 129: 216-26.
[9]
Moreno-Grau S, Rodriguez-Gomez O, Sanabria A, et al. Exploring APOE genotype effects on Alzheimer’s disease risk and amyloid β burden in individuals with subjective cognitive decline: The FundacioACE Healthy Brain Initiative (FACEHBI) study baseline results. Alzheimers Dementia J Alzheimers Assoc 2017; 14(5): 634-43.
[10]
Seifan A, Isaacson R. The alzheimer’s prevention clinic at Weill Cornell medical college/ New-York Presbyterian hospital: Risk stratification and personalized early intervention. J Prev Alzheimers Dis 2015; 2(4): 254-66.
[11]
Kane RL, Butler M, Fink HA, et al. Interventions to Prevent Age-Related Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer’s-Type Dementia Rockville, MD. Agency for Healthcare Research and Quality (US); 2017.
[12]
Cummings JL, Isaacson RS, Schmitt FA, et al. A practical algorithm for managing Alzheimer’s disease: What, when, and why? Ann Clin Transl Neurol 2015; 2(3): 307-23.
[13]
Østergaard SD, Mukherjee S, Sharp SJ, et al. Associations between potentially modifiable risk factors and Alzheimer disease: A Mendelian randomization study. PLoS Med 2015; 12(6): e1001841.
[14]
Stephenson D, Perry D, Bens C, et al. Charting a path toward combination therapy for Alzheimer’s disease. Expert Rev Neurother 2015; 15(1): 107-13.
[15]
Xu W, Tan L, Wang HF, et al. Meta-analysis of modifiable risk factors for Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2015; 86: 1284-5.
[16]
Norton S, Matthews FE, Barnes DE, et al. Potential for primary prevention of Alzheimer’s disease: An analysis of population-based data. Lancet Neurol 2014; 13(8): 788-94.
[17]
Morris MC, Tangney CC, Wang Y, et al. MIND diet associated with reduced incidence of Alzheimer’s disease. J Alzheimers Dement 2015; 11(9): 1007-14.
[18]
Paddock CP. Concussion linked to brain changes in people at genetic risk for Alzheimer’s. Medical News Today 2017.
[19]
Joubert LM, Manore M. Exercise, nutrition, and homocysteine. Int J Sport Nutr Exerc Metab 2006; 16(4): 341-61.
[20]
Rodrigue KM, Rieck JR, Kennedy KM, et al. Risk factors for β-Amyloid deposition in healthy aging: Vascular and genetic effects. JAMA Neurol 2013; 70(5): 600-6.
[21]
Hong H, Kim BS, Im H. Pathophysiological role of neuroinflammation in neurodegenerative diseases and psychiatric disorders. Int Neurol J 2016; 20(Suppl. 1): S2-7.
[22]
Chaker L, Wolters F, Korevaar TI, et al. Thyroid function and the risk of dementia: The rotterdam study. Neurology 2016; 87(16): 1688-95.
[23]
Rosales-Corral S, Tan DX, Manchester L, et al. Diabetes and alzheimer’s disease, two overlapping pathologies with the same ="background: Oxidative stress. Oxid Med Cell Longev 2015.
[http://dx.doi.org/10.1155/2015/985845]
[24]
Chatterjee S, Peters SAE, Woodward M, et al. Type 2 Diabetes as a risk factor for dementia in women compared with men: A pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia. Diabetes Care 2016; 39(2): 300-7.
[25]
Bucossi S, Ventriglia M, Panetta V, et al. Copper in alzheimer’s disease: A Meta-analysis of serum, plasma, and cerebrospinal fluid studies. J Alzheimers Dis 2011; 24(1): 175-85.
[26]
Singh I, Sagare AP, Coma M, et al. Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance. Proc Natl Acad Sci USA 2013.
[http://dx.doi.org/10.1073/pnas.1302212110]
[27]
Lövheim H, Gilthorpe J, Adolfsson R, et al. Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimers Dement 2015; 11(6): 593-9.
[28]
Lovheim H, Gilthorpe J, Johansson A, et al. Herpes simplex infection and the risk of Alzheimer’s disease- A nested case-control study. Alzheimers Dement 2015; 11(6): 587-92.
[29]
Itzhaki RF, Lathe R, Balin BJ, et al. Microbes and Alzheimer’s disease. J Alzheimers Dis 2016; 51(4): 979-84.
[30]
Bezprozvanny I, Mattson MP. Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 2008; 31(19): 454-63.
[31]
Campbell N, Boustani M, Limbil T, et al. The cognitive impact of anticholinergics: A clinical review. Clin Interv Aging 2009; 4: 225-33.
[32]
Han L, Agostini JV, Allore HG. Cumulative anticholinergic exposure is associated with poor memory and executive function in older men. J Am Geriatr Soc 2008; 56(12): 2203-10.
[33]
Hirai K, Aliev G, Ninomura A, et al. Mitochondrial abnormalities in alzheimer’s disease. J Neurosci 2001; 21(9): 3017-23.
[34]
García-Escudero V, Martín-Maestro P, Perry G, et al. Deconstructing mitochondrial dysfunction in alzheimer disease. Oxid Med Cell Longev 2013; 2013
[http://dx.doi.org/10.1155/2013/162152]
[35]
Xu W, Tan L, Wang H, et al. Meta-analysis of modifiable risk factors for Alzheimer’s disease. Cognitive Neurol 2015; 86(12): 1299-306.
[36]
Chakrabarti S, Khemka V, Banerjee A, et al. Metabolic risk factors of sporadic alzheimer’s disease: Implications in the Pathology, Pathogenesis and Treatment. Aging Dis 2015; 6(4): 282-99.
[37]
Cerutti-Kopplin D, Feine J, Padilha DM, et al. Tooth Loss Increases the Risk of Diminished Cognitive Function: A Systematic Review and Meta-analysis. JDR Clin Trans Res 2016; 10-9.
[38]
Last W. Health Science. [Online]. 2016 [cited 2017]. Available from: www.health¬science-spirit.com\pyroluria.htm.
[39]
Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science 2013; 342(6156): 373-.
[40]
Ferreira LK, Tamashiro-Duran JH, Squarzoni P, et al. The link between cardiovascular risk, Alzheimer’s disease, and mild cognitive impairment: Support from recent functional neuroimaging studies. Br J Psychiatry 2014; 36(4): 344-57.
[41]
Kim HA, Miller AA, Drummond GR, et al. Vascular cognitive impairment and Alzheimer’s disease: Role of cerebral hypoperfusion and oxidative stress. Naunyn Schmiedebergs Arch Pharmacol 2012; 385(10): 953-9.
[42]
Ohio State University. Wexner Medical Center. [Online]. 2017. Available from:. https://wexnermedical.osu.edu/brain-spine-neuro/memory-disorders/sage
[43]
Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2015; 53(4): 695-9.
[44]
Scharre DW, Chang SI, Murden RA, et al. Self-administered Gerocognitive Examination (SAGE): A brief cognitive assessment Instrument for Mild Cognitive Impairment (MCI) and early dementia. Alzheimer Dis Assoc Disord 2010; 24(1): 64-71.
[45]
Gualtieri CT, Johnson LG. Reliability and validity of a computerized neurocognitive test battery, CNS Vital Signs. Arch Clin Neuropsychol 2006; 21(7): 623-43.
[46]
Galvin J. The prevention of alzheimer’s disease: Lessons learned and applied. J Am Geriatr Soc 2017; 65(10): 2128-33.
[47]
Isaacson R. Is alzheimer’s prevention possible? J Am Geriatr Soc 2017; 65(10): 2153-4.
[48]
Obama white house archives. [Online].; 2015 [cited 2017]. Available from:.https://obamawhitehouse.archives.gov/node/333101
[49]
National Institutes of Health: All of Us Research Program. [Online]. 2017 [cited 2017]. Available from:. https://allofus.nih.gov/
[50]
Scharre D, Chang S, Nagaraja H, et al. Longitudinal Changes in Self-Administered Gerocognitive Examination (SAGE) and Mini-Mental State Exam (MMSE) Score for Subjective Cognitive Impairment (SCI), Mild Cognitive Impairment (MCI), Dementia Converters, and Alzheimer’s Disease (AD) Patients. Alzheimers Dement J Alzheimers Assoc 2015; 11(7): 570.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 11
ISSUE: 3
Year: 2018
Page: [173 - 181]
Pages: 9
DOI: 10.2174/1874609811666181019101430

Article Metrics

PDF: 43
HTML: 4
EPUB: 1