Reference

Introduction

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2. Caselli RJ, Reiman EM, Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 alle. Neurology 2004 62:1990-5.


3. Spilman P, Richardson A, Strong R, Galvan V. Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-B Levels in a Mouse Model of Alzheimer's Disease. PloS  One. 2010; 5(4): e9979.


4. Caccamo A, Richardson A, Strong R, Oddo S. Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-B and Tau. J Biol Chem 2010;285(17): 13107-13120. 


5.Majumder S, Richardson A, Strong R, Oddo S. Inducing Autophagy by Rapamycin Before, but not After, the Formation of plaques and Tangles Ameliorates cognitive Deficits. PLoS One. 2011; 6(9): e25416.


6. Lin AL, Halloran JJ, et al. Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease. J Cereb blood Flow metab 2013; 33:1412-1421.


7. Caccamo A, Oddo S. mTOR Regulates Tau Phosphorylation and Degradation: Implications for Alzheimer's Disease and Other Taupathies. Aging Cell. 2013 12:370-380.


8. Caccamo A, Oddo S. Genetic Reduction of Mammalian Target of Rapamycin Ameliorates Alzheimer's disease-Like Cognitive and Pathologic Deficits by Restoring Hippocampal Gene Expression Signature. J Neurosci 2014;34:7988-7998. 


9. Harrison DE, Strong R, Miller,RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460:392-395.


10.Miller RA, Harrison DE, Strong, R. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. aging Cell. 2014; 13:468-477.

 

11. Lin AL, Galvan V, Richardson A. Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Azlheimer's disease. J Cereb Blood flow Metab. 2015; 37(1):217-226.


12. Bell RD, Zlokovic BV. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012;485:512-516.


13. Halliday MR, Zlokovic BV. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer'sdisease. J Cereb Blood Flow Metab. 2016 Jan; 36(1): 216-227.


14. Wang AW, Lin AL. Rapamycin as a Novel Therapeutic for Alzheimer's Disease: Prevention Assessed Through Neuroimaging. The FASEB J. 2017; 31:814.6.


15. Lin AL, Richardson A. mTOR: Alzheimer's disease prevention for APOE4 carriers. Oncotarget. 2016 7(29): 44873-44874.


16. Fleisher AS, Apolipoprotein E epsilon4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease. Neurobiol Aging 2013; 34: 1-12.


17. Izaks GJ. The Association of APOE Genotype with cognitive function in Persons Aged 35 years or Older. PLos One. 2011; 6:e27415.


18. Reiman EM, Declining brain activity in cognitively normal apolipoprotein E epsilon 4  heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc natl Acad Sci USA 2001; 98: 3334-3339.


19. Reiman EM, Caselli Rj. Correlations between apolipoprotein E epsilon4 gene dose and brain-imaging measurements of regional hypometabolism. Proc natl Acad Sci USA 2005; 102:8299-302.


20. Thambisetty M, Resnick SM. APOE episilon4 genotype and longitudinal changes in cerebral blood low in normal aging. Arch Neurol-Chicago. 2010;67:93-98.


21. Reiman EM, et. al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci USA 2004;101:284-289.


22. Richardson A, Galvan V, Lin AL, Oddo, S. How longevity research can lead to therapies for Alzheimer's disease: The rapamycin story. Exp Gerontology 2014; 68:51-58.


23. Talboom JS, Oddo, S. The mammalian target of rapamycin at the crossroads between cognitive aging and Alzheimer's disease. NPJ Aging mech Dis. 2015; 1:15008.


Risk and Lifestyle

24. Sando SB. APOE e4 lowers age at onset and is ahigh risk factor for Alzheimer's disease: A case control study from central Norway. BMC Neurology 2008; 10.1186/1471-2377-8-9.


25. Elias-Sonnenschein LS. Predictive value of APOE-e4 allele for progression from MCI to AD-type dementia: a meta analysis. L Neurol Neurosurg Psychiatry 2011; 82(10):1149-56.


26. Wang PN. APOE e4 increases the risk of progression from amnestic mild cognitive impairment to Alzheimer's disease among ethnic chinese in Taiwan. J. neurol Neurosurg Psychiatry 2011; 82:(2)165-9.


27. Tschanz JT. Conversion to dementia from mild cognitive disorder--The Cache County Study. Neurology. 2006; 67(2):229


28. Kivipelto M. Apolipoprotein E epison4 magnifies lifestyle risks for dementia: a population-based study. J Cell Mol Med. 2008; (6B):2762-71.


29. Luchsinger JA. Caloric Intake and the risk of Alzheimer disease. Arch Neurol. 2002; 59(8):1258-63.


30. Geda YE. Caloric intake, aging, and mild cognitive impairment: a population based study. J Alzheimers Dis. 2013; 34(2):501-7.


Basic Science

31. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's  disease and other disorders. Nat Rev Neurosci. 2011; 12:723-738.


32. Zlokovic BV. Cerebrovascular effects of apolipoprotein E: implications for Alzheimer's disease. JAMA Neurol 2013; 70: 440-444.


33. Winkler EA, Zlokovic BV. The Pericyte: a forgotten cell type with important implications for Alzheimer's disease ?. Brain Pathol. 2014;24(4):371-86.


34. Tang Z, Pei JJ. mammalian Target of Rpamycin (mTOR) Mediates Tau Protein Dyshomeostasis. J Biol Chem 2013. 31; 288(22) 15556-15570.


35. Oddo S. The role of mTOR signaling in Alzheimer disease. Front Biosci. 2012; 4:941-952.


36. An WL, Pei JJ, Up-regulation of phos-phorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease. Am J Pathol. 2003;163:591-607.


37. Pei JJ. mTOR-dependent signaing in Alzheimer's disease. J  Cell Mol Med. 2008; 122525-2532.


38. Kickstein E. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. PNAS 2010; 107 (50):21830-21835.


Disease and Treatment

Rapamycin Story

39. Wu JJ. Increased mammalian lifespan and segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression. Cell Rep 2013; 4: 913-920.


40. Blagosklonny MV. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle. 2006;5:2087-2102.


41. Blagosklonny MV. mTOR-driven aging: speeding car without brakes. Cell Cycle. 2009;8:4055-4059.


42. Blagosklonny MV. Koschei the immortal and anti-aging drugs. Cell Death Dis. 2014;5:e1552.


43. Blagosklonny MV. Rejuvenating immunity: "anti-aging drug today" eight years later. Oncotarget. 2015; 6:19405-19412.


44. Blagosklonny MV. From rapalogs to anti-aging formula. Oncotarget. 2017; 8(22):35492-35507.


45. Kauffman HM. Maintenance immunosuppression with target-of--rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation. 2005 15;80(7):883-9.


46. Blagosklonny MV. Rapalogs in cancer prevention, Anti-aging or anticancer ?, Cancer Biol Ther. 2012; 13(14);1349-1354.


47. Flynn JM, Kennedy, BK. Late-life rapamycin treatment reverses age-related heart dysfunction. Aging Cell. 2013 12(5): 851-862.


48. Urfer SR, Kaeberlein M. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. GeroScience 2017; 39(2): 117-127. 


49.  Chen WQ. Oral rapamycin attenuates inflammation and enhances stability of atherosclerotic plaques in rabbits independent of serum lipid levels. Br J Pharmacol. 2009;156:941-951.


50. Kolosova NG, Blagosklonny MV. Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats. Am J Pathol. 2012;181:472-477.


51. Mannick JB. mTOR inhibition improves immune function in the elderly. Science translational medicine 2014; 6(268):268ra 179.


Obesity/Overweight

52. Weinstein AR. Relationship of physical activity vs body mass index with type 2 diabetes in women. JAMA. 2004; 292(10):1188-94. 


Diabetes

53. Peila R. Type 2 diabetes, APOE gene, and the risk of dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes. 2002; 51(4):1256-62.


54.  El-Lebedy D. Apolipoprotein E gene polymorphism and the risk of type 2 diabetes and cardiovascular disease. Cardiovasc Diabetol. 2016; 15:12.


55. Kahn SE. Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes. 1999; 48(2):241-53.


56..Zhang XX. Neuroendocrine hormone amylin in diabetes. World J Diabetes. 2016; 7(9):189-197.


57. Westermark P. Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation.  Proc Natl Acad Sci U S A. 1990; (13):5036-40.


58. Blagosklonny MV. TOR-centric view on insulin resistance and diabetic complications:perspective for endocrinologists and gerontologists. Cell Death and Dis. 2013; 4:e964.


Coronary artery disease

59. Song Y. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann Intern Med 2004; 141(2):137-47/


60. Wilson PW. Apolipoprotein E alleles, dyslipidemia, and coronary hart disease. The Framingham Offspring Study. JAMA.  1994; 272(21):1666-71.


61. Stengard JH. Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation. 1995; 91(2):265-9.


62. Ilveskoski E. Age-Dependent Association of apolipoprotein E Genotype with Coronary and Aortic Atherosclerosis in Middle-Age Men, An Autopsy Study. Circulation. 1999; 100:608-613.


63. Gerdes LU. The apolipoprotein episilon4 allele determines prognosis and the effect on prognosis of simvastin in survivors of myocardial infarction: a substudy of the Scandinavian simvastin survival study. Circulation. 200; 101(12):1366-71.


Hypertension

64. Rodrigue KM. Risk Factors for Amyloid Deposition in healthy Aging. JAMA Neurol. 2013; 7095): 600-606.


65. Guo Z. Apolipoprotein E Genotypes and the Incidence of Alzheimer's Disease among Persons Aged 75 Years and Older: Variation by Use of Antihypertensive Medication?. AJE. 2001; 153(3):225-231.


66. de Frias CM. Hypertension moderates the effect of APOE on 21-year cognitive trajectories. Psychol Aging. 2014 29(2):431-9.


67. Launer LJ. Midlife blood pressure and dementia: the Honolulu-Asia aging study. neurobiol Aging. 2000; 21(1):49-55.


68. Khachaturian AS. Antihypertensive medication use and incident Alzheimer disease: the Cache County Study. Arch neurol. 2006; 63(5):686-92.


Metformin

69. Moreira PI. Metformin in the diabetic brain: friend or foe?. Ann Transl Med. 2014; 2(6): 54.


70. Knowler WC. Reduction in the incidence of type 2 diabetes with lifestyle intervention on metformin. N Engl J Med. 2002; 346(6):393-403.


71. Banister CA. Can people with type 2 diabete lie longer than those without ? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes metab. 2014;16(11):1165-73.


Statins

72. Bettermann K Statins, risk of dementia, and cognitive function: secondary analysis of ginko evaluation of memory study. J Stroke cerebrovascular Dis. 2012; 21(6):436-44.


73. Haag MD. Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry. 2009; 80(1):13-7.


74. Jick H. Statins and the risk of dementia. Lancet 2000;  356(9242):1627-31.


75. Cramer C. useof statins and incidence of dementia and cognitive impairment without dementia in a cohort study. Neurology. 2008; 71(5): 344-350. 


76. Dufouil C. APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study. Neurology. 2005; 64(9):1531-8.


77. Solomon A. Lipid-lowering treatment is related to decreased risk of dementia: a population-based study (FINRISK).  Neurodegener. Dis. 2010; 7(1-3):180-2.


78. Wolozin B. Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med. 2007; 5:20.


79. Li G. Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology. 2004; 63(9):1624-8. 


80. Wong WB. Statins in the prevention of dementia and Alzheimer's disease: a meta-analysis of observational studies and an assessment of confounding. Pharmacoepidemiol Drug Saf. 2013; 22(4):345-58.


Angiotensin II blocking


81. Sink KM. Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from Cardiovascular Health Study. Arch Intern Med. 2009; 169(13):1195-202. 


82. Li NC. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465.


83. Qiu Wq. Angiotensin Converting Enzyme Inhibitors and the Reduced Risk of Alzheimer's Disease in the Absence of Apolipoproein E4 Allele. J Alzheimerers Dis. 2013; 37(2):421-428.


Diet and Lifestyle

84. Eskelinen MH, Kivipelto M. Caffeine as a protective factor in dementia and Alzheimer's disease. J Alzheimers Dis. 2010;20 Supp 1:S167-74.


85. Chen, X. Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer's disease and Parkinson's disease. J Alzheimers Dis. 2010; 20(Suppl 1): S127-S141. 


86. Zhou W. Meta-analysis of APOE4 allele and outcome after traumatic brain injury. J Neurotrauma 2008;25(4):279-90.


Physical Activity

87. Podewis LJ. Physical activity, APOE genotype, and dementia risk: finding from the Cardiovascular Health Cognition Study. Am J Epidemiol. 2005; 161(7):639-51.


Normal Aging Brain

88. Halloran J, Austad SN, Strong R, Richardson A, Galvan V. Chronic inhibition of mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience. 2012; 223:102-113.


89. Majumder S, Caccamo A, Strong R, Richardson A, Oddo, S. Life-long rapamycin administration ameliorates age-dependent cogntive deficits by reducing IL-B and enhancing NMDA signaling. Aging Cell. 2012; 11(2): 326-335.


90. Trompet S. Genetic variation in interleukin-1 beta converting enzyme associates with cognitive function. The PROSPER study. Brain. 2008; 131(4):1069-77.


91. Fontan-Lozano A. Caloric Restriction Increases consolidation and Facilitates Synaptic Plasticity through Mechanisms Dependent on NR2B subunits of NMDA Receptor. J Neuroscience 2007; 27(38):10185-10195. 


92. Witte AV. Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A. 2009; 106(4): 1255-1260.