Importance of Apolipoprotein E in Vascular Dementia, Stroke Prevalence and Associated Cognitive Dysfunction
Received Date: Jan 18, 2018 / Accepted Date: Feb 05, 2018 / Published Date: Feb 12, 2018
Atherosclerosis, cerebral hypoperfusion or hypertension is the most common pathogenic risk factors in about half of all strokes patients and also found causative to vascular cognitive impairment (VCI). While the precise underlying mechanisms of the VCI are poorly understood, vascular dementia associated with Alzheimer’s disease (AD) and heart disease has shared a genetic link with Apolipoprotein E (APOE). Typically, APOE is well known for its effects on regulation of cholesterol metabolism. Epidemiological surveys also emphasized the improper functioning of an APOE harboring the allele epsilon4 (APOE4) genotype in the pathogenesis of cardiovascular disease, atherosclerosis and AD. Moreover, enhanced expression of APOE has been reported by astrocytes and oligodendrocytes in injured brain structures. The preclinical and clinical studies demonstrated a strong correlation between the APOE polymorphism and development of vascular disease and dementia. This paper summarizes an intriguing role of APOE4 genotype in the sick heart, prevalence of stroke and their association with occurrence of cognitive deterioration.
Keywords: Hypertension; Atherosclerosis; Dementia; Astrocytes; Vascular cognitive impairment
Cardiovascular disease (CVD) is a leading cause of death and disability in the world . The hemodynamic changes associated with CVD like heart failure, hypertension and atherosclerosis reported to alter the cognitive ability [2,3]. The cerebral hypoperfusion caused due to cardiac disease [4,5] also invariably linked to cognitive deficits in attention and memory and can lead to neurodegenerative disorders like Alzheimer’s disease (AD) [6-8]. It has been reported that, nearly 50% of AD risk is associated with traditional vascular risk factors and postmortem cases of AD have some form of vascular pathology [3,9]. Thus, therapeutic implications of controlling such vascular abnormalities in AD have presumed to be one of the most important inroads in the search to lower the rising prevalence of AD and vascular dementia [9,10]. While the underlying mechanisms of the vascular cognitive impairment (VCI) are poorly understood, many people have assume that AD and heart disease share a genetic link associated with Apolipoprotein E (APOE). Epidemiological surveys also support the neuropathologic link between presence of APOE harboring the allele epsilon4 (APOE4) genotype in cardiac abnormalities such as amyloid angiopathy and development of AD in elderly population. This article summarizes an intriguing role of APOE4 genotype in the sick heart, prevalence of stroke and their association with occurrence of cognitive deterioration.
APOE is a 34-kDa glycosylated protein that plays a critical role in the metabolism of fats in the peripheral parts and central nervous system (CNS). In addition to its well-characterized role in cholesterol metabolism, APOE has been up-regulated by astrocytes and oligodendrocytes in the injured brain structures, suggesting its role in the neural injury and repair [11,12]. Several studies proposed the improper functioning of APOE4 genotype in the pathogenesis of CVD, atherosclerosis and AD. With reference to AD, APOE4 has been shown to binds with amyloid β (Aβ) protein and facilitates its uptake, as well as enhances the production of Aβ and synergizes with Aβ toxicity [13,14]. The APOE knock out (APOE-/-) is a classic mouse model mainly employed to study the atherosclerosis, these mice also displayed an impairment of spatial memory compared with wild-type animals in the Morris water maze (MWM) assay indicating cognitive dysfunction, a core symptoms of AD. Additionally, APOE-/- mice showed several hallmarks of AD such as an increased inflammation, increased blood brain barrier permeability, micro vessel degeneration, reduction of neurogenesis and synapses, reduced clearance of Aβ and the presence of hyperphosphorylated tau . Moreover, vascular hypothesis proposed by  showed that advanced aging, a former head injury and APOE4 genotype became critical risk factors to AD by virtue of their potential to lower blood flow to the brain .
That being said, APOE4 genotype polymorphisms may be a strongest genetic risk factor for dementia and accelerated cognitive decline seen in patients with sporadic- and late-AD [18-25], which was also associated with a higher degree and faster rate of neurodegeneration [25,26], a greater amyloid deposition and changes in cerebrospinal fluid measures of amyloid and tau . In AD, inheritance or cleavage of the APOE4 greatly increases AD risk by several folds if both alleles are present . A positive association of APOE polymorphism and increased risk for vascular dementia has been demonstrated in 14 out of 24 studies . In contrast, 9 studies reported that APOE4 allele does not confer risk for vascular dementia . Although the functional activity of APOE4 varies considerably, Baltimore longitudinal study of aging reported that carriers of this genotype had greater decline in cerebral blood flow . These findings underscore the importance of APOE genotype when considering biomarkers in early stages of AD or dementia . The deficiency of APOE leads to several cellular and molecular changes in the important brain structures associated with memory formation including the hippocampal CA1 and caudoputamen. Yet while an estimated 5.3 million of Americans suffer with AD, this CNS disorder is far less common than CVD. More than 85 million people in the USA are living with some form of CVD or the aftereffects of stroke, which also affects brain function. A meta-analysis of randomized controlled trials of antihypertensive therapy in the elderly indicated that lowering of the blood pressure led to decrease risk of stroke by 35% . The role of APOE4 allele has been reported in the risk of both ischemic and hemorrhagic stroke . However, most cases of dementia after stroke may be described under the umbrella term of VCI that needs to be explored in detailed.
Globally, stroke is the leading cause of long-term disability among adults and the second leading cause of death .The enhanced risk of cognitive impairment and incident dementia has also been reported in the stroke survivors [35-37]. Cognitive impairment is one of the most common sequelae following stroke with 40%-75% of stroke survivors experiencing some sort of cognitive deficit . The high cumulative risk of dementia or stroke or both conditions has been shown by the Framingham study  and the urgent need to improve knowledge regarding cognition and vascular conditions has been emphasized in a specific meeting providing harmonized standards . While involvement of APOE in CVD-associated stroke and cognitive impairment is enigmatic, APOE deficiency has been shown to worsen the ischemic outcome  and displayed increased neuronal damage following an episode of global cerebral ischemia . The infusion of APOE in APOE-deficient mice reversed these brain insults . In Canadian study of health and aging, the joint presence of stroke and APOE4 was associated with a greater risk of dementia compared with absence of these two factors . Although stroke and APOE4 were considered an independent risk factors for dementia , their combined effect is still debatable [43,44]. In aged stroke patients with early cognitive impairment, the presence of an APOE4 allele is associated with greater progression of cognitive decline  .The presence of one or two APOE4 alleles may be a significant independent risk factor for cognitive impairment in the early phase after stroke [46-53]. Collectively, APOE genotype and recurrent stroke may affect the relationship between a history of stroke and incident dementia risk.
- Roth GA, Johnson C, Abajobir A, Abd-Allah F, Abera SF, et al. (2017) Global regional and national burden of cardiovascular diseases for 10 causes 1990 to 2015. J Am Coll Cardiol 70: 1-25.
- Ajmani RS, Metter EJ, Jaykumar R, Ingram DK, Spangler EL, et al. (2000) Hemodynamic changes during aging associated with cerebral blood flow and impaired cognitive function. Neurobiol Aging 21: 257-69.
- Bink DI, Ritz K, Aronica E, van der Weerd L, Daemen MJ (2013) Mouse models to study the effect of cardiovascular risk factors on brain structure and cognition. J Cereb Blood Flow Metab 33: 1666-1684.
- Pullicino P, Mifsud V, Wong E, Graham S, Ali I, et al. (2001) Hypo perfusion related cerebral ischemia and cardiac left ventricular systolic dysfunction. J Stroke Cerebrovasc Dis 10: 178-182.
- Hoth KF, Poppas A, Moser DJ, Paul RH, Cohen RA(2008) Cardiac dysfunction and cognition in older adults with heart failure. Cogn Behav Neurol 21: 65-72.
- Duschek S, Matthias E, Schandry R (2005) Essential hypotension is accompanied by deficits in attention and working memory. Behav Med 30: 149-158.
- Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, et al.(2006) National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment harmonization standards. Stroke 37: 2220-2241.
- De la Torre JC (2012) Cerebral hemodynamics and vascular risk factors: Setting the stage for Alzheimer's disease. J Alzheimers Dis 32: 553-567.
- Bergmann C, Sano M (2006) Cardiac risk factors and potential treatments in Alzheimer's disease. Neurol Res 8: 595-604
- De la Torre JC (2010) The vascular hypothesis of Alzheimer's disease: Bench to bedside and beyond. Neurodegener Dis 7: 116-21.
- Stoll G, Meuller HW, Trapp BD, Griffin JW (1989) Oligodendrocytes but not astrocytes express apolipoprotein E after injury of rat optic nerve. Glia 2: 170-176.
- Sheng H, Laskowitz DT, Mackensen GB, Kudo M, Pearlstein RD, et al. (1999) Apolipoprotein E deficiency worsens outcome from global cerebral ischemia in the mouse. Stroke 30: 1118-1124.
- Sadowski MJ, Pankiewicz J, Scholtzova H, Mehta PD, Prelli F, et al. (2006) Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach for Alzheimer's disease. Proc Natl Acad Sci USA 103: 18787-18792.
- Yang J, Ji Y, Mehta P, Bates KA, Sun Y, et al. (2011) Blocking the apolipoprotein E/amyloid b interaction reduces fibrillar vascular amyloid deposition and cerebral microhemorrhages in TgSwDI mice. J Alzheimers Dis 24: 269-285.
- Shibata M, Yamada S, Kumar SR, Calero M, Bading J, et al. (2000) Clearance of Alzheimer's amyloid-ss (1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 106: 1489-1499.
- De la Torre JC, Fortin T (1994) A chronic physiological rat model of dementia. Behav Brain Res 63: 35-40.
- Hanon O, Haulon S, Lenoir H, Seux ML, Rigaud AS, et al. (2005) Relationship between arterial stiffness and cognitive function in elderly subjects with complaints of memory loss. Stroke 36: 2193-2197.
- Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261: 921-923.
- Mayeux R, Small SA, Tang M, Tycko B, Stern Y (2001) Memory performance in healthy elderly without Alzheimer's disease: Effects of time and apolipoprotein-E. Neurobiol Aging 22: 683-689.
- Farlow MR, He Y, Tekin S, Xu J, Lane R, et al. (2004) Impact of APOE in mild cognitive impairment. Neurology 63: 1898-1901.
- Drzezga A, Becker JA, Van Dijk KR, Sreenivasan A, Talukdar T, et al. (2011) Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden. Brain 134: 1635-1646.
- Bertram L, Lill CM, Tanzi RE (2010) The genetics of Alzheimer disease: Back to the future. Neuron 68: 270-281.
- Caselli RJ, Dueck AC, Locke DE, Sabbagh MN, Ahern GL, et al. (2011) Cerebrovascular risk factors and preclinical memory decline in healthy APOE ε4 homozygotes. Neurology 76: 1078-1084.
- Kotze MJ, van Rensburg SJ (2012) Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer's disease. Metab Brain Dis 27: 255-266.
- Chai YL, Yeo HK, Wang J, Hilal S, Ikram MK, et al. (2016) Apolipoprotein ɛ4 is associated with dementia and cognitive impairment predominantly due to Alzheimer's disease and not with vascular cognitive impairment: A Singapore-based cohort. J Alzheimers Dis 51: 1111-1118.
- Caroli A, Frisoni GB (2010) The dynamics of Alzheimer's disease biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort. Neurobiol Aging 31: 1263-1274.
- Vemuri P, Wiste HJ, Weigand SD, Knopman DS, Shaw LM, et al. (2010) Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease. Ann Neurol 67: 308-316.
- Rohn TT (2013) Proteolytic cleavage of apolipoprotein E4 as the keystone for the heightened risk associated with Alzheimer's disease. Int J Mol Sci 14: 14908-14922.
- Rohn TT (2014) Is apolipoprotein E4 an important risk factor for vascular dementia? Int J Clin Exp Pathol 7: 3504-3511.
- Thambisetty M, Beason-Held L, An Y, Kraut MA, Resnick SM (2010) APOE ε4 genotype and longitudinal changes in cerebral blood flow in normal aging. Arch Neurol 67: 93-98.
- Risacher SL, Kim S, Shen L, Nho K, Foroud T, et al. (2013) The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI). Front Aging Neurosci 5:11.
- Bejan-Angoulvant T, Saadatian-Elahi M, Wright JM, Schron EB, Lindholm LH, et al. (2010) Treatment of hypertension in patients 80 years and older: The lower the better? A meta-analysis of randomized controlled trials. J Hypertens 28: 1366-1372.
- Sudlow C, Martínez González NA, Kim J, Clark C (2006) Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls. Stroke 37: 364-370.
- Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371: 1612-1623.
- Leys D, Henon H, Mackowiak-Cordoliani MA, Pasquier F (2005) Poststroke dementia. Lancet Neurol 4: 752-759.
- Knopman DS, Roberts RO, Geda YE, Boeve BF, Pankratz VS, et al. (2009) Association of prior stroke with cognitive function and cognitive impairment: A population-based study. Arch Neurol 66: 614-619.
- Kalaria RN, Akinyemi R, Ihara M (2016) Stroke injury, cognitive impairment and vascular dementia. Biochim Biophys Acta 1862: 915-925.
- Vakhnina NV, Nikitina LY, Parfenov VA, Yakhno NN (2009) Post-stroke cognitive impairments. Neurosci Behav Physiol 39: 719-724.
- Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R, et al. (2006) The lifetime risk of stroke: Estimates from the Framingham study. Stroke 37: 345-350.
- Jin YP, Ostbye T, Feightner JW, Di Legge S, Hachinski V (2008) Joint effect of stroke and APOE 4 on dementia risk: The Canadian Study of Health and Aging. Neurology 70: 9-16.
- Horsburgh K, Graham DI, Stewart J, Nicoll JA (1999) Influence of apolipoprotein E genotype on neuronal damage and apoE immunoreactivity in human hippocampus following global ischemia. J Neuropathol Exp Neurol 58: 227-234.
- Dik MG, Deeg DJ, Bouter LM, Corder EH, Kok A, et al. (2000) Stroke and apolipoprotein E epsilon4 are independent risk factors for cognitive decline: A population-based study. Stroke 31: 2431-2436.
- Slooter AJ, Tang MX, van Duijn CM, Stern Y, Ott A, et al. (1997) Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation. JAMA 277: 818-821.
- Arpa A, del Ser T, Goda G, Barba R, Bornstein B (2003) Apolipoprotein E, angiotensin-converting enzyme and alpha-1-antichymotrypsin genotypes are not associated with post-stroke dementia. J Neurol Sci 210: 77-82.
- Ballard CG, Morris CM, Rao H, O'Brien JT, Barber R, et al. (2004) APOE epsilon4 and cognitive decline in older stroke patients with early cognitive impairment. Neurology 63: 1399-1402.
- Wagle J, Farner L, Flekkoy K, Wyller TB, Sandvik L, et al. (2009) Association between ApoE epsilon4 and cognitive impairment after stroke. Dement Geriatr Cogn Disord 27: 525-533.
- Barthel H, Gertz HJ, Dresel S, Peters O, Bartenstein P, et al. (2011) Cerebral amyloid-β PET with florbetaben (18F) in patients with Alzheimer's disease and healthy controls: A multicentre phase 2 diagnostic study. Lancet Neurol 10: 424-435.
- De la Torre JC (2008) Pathophysiology of neuronal energy crisis in Alzheimer's disease. Neurodegener Dis 5: 126-132.
- Drzezga A, Grimmer T, Henriksen G, Mühlau M, Perneczky R, et al. (2009) Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology 72: 1487-1494.
- Huang Y (2010) Mechanisms linking apolipoprotein E isoforms with cardiovascular and neurological diseases. Curr Opin Lipidol 21: 337-345.
- Jacova C, Pearce LA, Costello R, McClure LA, Holliday SL, et al. (2012) Cognitive impairment in lacunar strokes: The SPS3 trial. Ann Neurol 72: 351-362.
- Mahley RW, Huang Y (2012) Apolipoprotein E sets the stage: Response to injury triggers neuropathology. Neuron; 76: 871-885.
- Ostergaard L, Aamand R, Gutiérrez-Jiménez E, Ho YC, Blicher JU, et al. (2013) The capillary dysfunction hypothesis of Alzheimer's disease. Neurobiol Aging 34: 1018-1031.
Citation: Dandekar MP (2018) Importance of Apolipoprotein E in Vascular Dementia, Stroke Prevalence and Associated Cognitive Dysfunction. J Pharma Reports 3: 140.
Copyright: © 2018 Dandekar MP. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.