Alzheimers Disease: Biology, Etiology and Solutions

Alzheimers Disease Biology, Etiology and SolutionsIntroductionAlzheimers disease (AD) is a type of dementia characterized by the progressive loss in cognitive function due to neurode constituentration that results in gradual memory loss and eventually the inability to carry out tasks of practiceaday living. The two types of AD be distinguished by age of onset and etiologies early-onset AD develops prior to age 65 and has strong genetic associations while late-onset AD develops after age 65 with a more complex etiology. Late-onset AD accounts for 90-95% of AD cases (Harman 2002). Aging is a strong risk factor for developing late-onset AD. given(p) that the global population of people ages 65 and up is expected to increase from 26.6 million in 2006 to 106.8 million by 2050 (Brookmeyer et al. 2007) AD is a growing popular health concern in regards to disease management and development of innovative treatments. The prevalence of AD globally is 4.4%, with 1 in 10 people all over age 65 and nearly one-third of people over age 85 affected by dementia in developed countries (Qiu et al. 2009). AD prevalence is the greatest in East Asia, fol pocket-sizeed by Western Europe, South Asia, and North America (Prince et al. 2015). Disease burden is anticipated to be the greatest in low and middle-income countries with the fastest growth in the elderly population and limited access to care (Prince et al. 2015). By 2050, the U.S. population of adults with AD is projected to increase to 13.2 million. With 43% of AD patients requiring a high level of care, the financial and healthcare burden of AD is expected to rise (Qiu et al. 2009). Given that the burden of AD will increase over the coming decades with costly impacts on health care and genial services, it is necessary to continue AD research to find a creator and develop raw therapies. EtiologyAlzheimers disease is a multifactorial disease with several genetic, person, and lifestyle risk factors that contri thate t o development of disease. Although many risk factors for AD seduce been identified a cause has not yet been found. Of the genetic risk factors identified, apolipoprotein E alleles, with ethnic and sex variability in risk of developing AD, and TREM2 gene transitions have the strongest associations with AD. Lifestyle risk factors include high blood pressure, obesity, diabetes, and education. The development of AD requires a combination of these risk factors that induce the production of neuro noxious amyloid beta (A) and neurofibrillary tangles (NFTs), the agents of AD. Apolipoprotein E (apoE) has been identified as playing a role in AD pathology. ApoE is naturally produced and is involved in lipid transport (Ridge et al. 2013 2018 Feb 27). In AD it is fancy that apoE regulation of A is altered (Kanekiyo et al. 2014). There are three apoE alleles that differ in the risk they confer to AD the 2 and 3 alleles are custodial but the 4 allele increases risk for AD (Ridge et al. 2013). Additionally, it appears that ethnicity modulates the risk of AD conferred by the apoE 4 allele, conferring greater risk among Caucasians and Japanese than Afri place Americans and Hispanics (Ridge et al., 2013). The apoE 4 allele is an established risk factor for the development of AD however it is not causative and the risk that carrying this gene confers is likely modulated by other factors such as ethnicity and lifestyle. Mutations in the TREM2 gene have also been affect in AD pathology. The TREM2 gene codes for a receptor expressed in myeloid cells, the genius innate insubordinate cell in the brain (Hickman and El Khoury 2014) and in greater abundance in the hippocampus and neocortex, brain structures affected by neurodegeneration in AD (Guerreiro et al. 2013 Jan 9). A rare missense mutation in the TREM2 gene was identified in Islanders that confers significant risk of AD (Jonsson et al. 2013 Jan 9) and a loss of function mutation increases the risk of late-onset AD in het erozygous carriers (Hickman and El Khoury 2014). This loss of function mutation promotes the production of A and numbers A phagocytosis and degradation (Hickman and El Khoury 2014). In admittance to the genetic risk factors discussed above, several lifestyle risk factors for AD have been identified including cardiovascular risk factors and obesity. Cardiovascular risk factors (smoking, hypertension, high cholesterol, and diabetes) in mid-life are associated with a 20-40% increased risk of AD in a dose-dependent fashion (Whitmer et al. 2005). Hypertension that develops in mid-life and persists into late-life is associated with a greater risk of dementia (McGrath et al. 2017). Furthermore, the risk of hypertension for AD in late-life might be influenced by sex, with females having a 65% increased risk of developing dementia if hypertensive in mid-life but no such association among males (Gilsanz et al. 2017). Midlife insulin resistance is also a risk factor for A accumulation (Ekbla d et al. 2018 Feb 23) and patients with diabetes and the apoE 4 allele have more A plaques and NFTs in the brain (Peila et al. 2002). Obesity is linked to AD via several single-nucleotide polymorphisms (Hinney et al. 2014). In people who are obese, leptin and adiponectin lose their neuro custodial role as the brain becomes resistant to leptin and the levels of adiponectin decrease (Letra et al. 2014). look into conducted by Nuzzo et al. (2015) further supports this association, finding that obese mice fed a high-fat diet had elevated A accumulation. Addressing these modifiable risk factors in mid-life may help reduce the risk of developing AD in late-life. Higher educational attainment and continued cognitive stimulation in later life are protective against AD. Amieva et al. (2014) found that individuals with AD who had education beyond 6 years of primary school showed delayed cognitive decline before diagnosis compared to individuals with less education. fighting(a) in cognitive leisure activities in late-life, like reading books, newspapers, and magazines, solving crossword puzzles, and attending courses and professional training, has a protective effect as salubrious (Sattler et al. 2012). Higher educational attainment may be associated with reduced risk of AD and delayed cognitive decline if AD develops because of its association with increased hippocampi and amygdaloid nucleuse size. In individuals with AD, the hippocampi are larger in those who had 20 years of cropal education compared to those with 6 years (Shpanskaya et al. 2014). The role of education in hippocampal size is further implicated by Tang, Varma, Miller, and Carlson (2017) who found that the left hippocampus is larger than the right, possibly due to education honing retrieval of verbal memory by the left hippocampus by means of increasing intellectual ability and literacy skills. BiologyAlzheimers disease results in the progressive loss of neurons in the cerebrum. The first structur es affected are the hippocampi followed by the amygdala (Pini et al. 2016). As the disease progresses so does neuronal loss throughout the cerebrum. In AD, A peptides and neurofibrillary tangles (NFTs) formed by tau protein cause synaptic damage that leads to apoptosis. Additionally, the innate immune system in the brain does not function properly in AD and therefore does not remove A peptides before they aggregate to form plaques. Amyloid beta is naturally produced in the brain by the cleavage of amyloid precursor protein (APP), but when APP is cleaved by -secretase A peptides are formed that can cause synaptic and mitochondrial damage and aggregate to form plaques (Querfurth and LaFerla 2010). In healthy individuals, A peptides are cleared by microglia and enzymes but these mechanisms deteriorate in individuals with AD and the A peptides accumulate and result in neurodegeneration (Sarlus and Heneka 2017). A plaques cause neuronal cell death by accumulating around neurons, impairin g normal function and inducing an unhealthy response. More attention late(a)ly has been given to A peptides, which lead to apoptosis in neurons through synaptic damage and inhibition of mitochondrial function. A peptides cause synaptic damage in the hippocampus by aggregating and creating pores in the cell membranes that allows calcium ion entry into the cell. Over time, these pores become non-selective and allow flux of large molecules like adenosine triphosphate and glucose that alters cell metabolism and disrupts homeostasis resulting in apoptosis (Seplveda et al. 2014). A also produces reactive oxygen species that initiate oxidative stress which leads to mitochondria in the cell releasing cytochrome C and inducing apoptosis (Querfurth and LaFerla 2010). Both A peptides and APP can enter the mitochondria where they disrupt the electron transport chain and ATP production (Caspersen et al. 2005 Reddy and Beal 2008). Synapses are sites of high mitochondrial operation because ATP i s needed for neurotransmitter release (Reddy and Beal 2008), so inhibition of mitochondrial activity by A also results in synaptic damage. NFTs are intracellular aggregations of hyperphosphorylated tau protein and also cause neurodegeneration. Tau protein is a component of the cytoskeleton of neural cells but when hyperphosphorylated tau proteins have an affinity for themselves and destabilize the cytoskeleton (Iqbal et al. 2005 Spillantini and Goedert 2013). Tau protein is phosphorylated by glycogen synthase kinase -3 (GSK-3) (Rankin et al. 2007) which can be activated by A peptides (Takashima 2006). Tau protein mediates synaptic damage by inhibiting extracellular signal-regulated kinase (ERK) signaling that is key in cell survival ( insolate et al. 2016). ApproachesCurrenttreatment of AD relies on two types of medications acetylcholine esteraseinhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonists.AChEIs work by slowing the degradation of acetylcholine (ACh) by i nhibitingacetylcholine esterase which allows more ACh action at the synapses (Nelson and Tabet 2015).When cholinergic neurons are lost during the course of AD, ACh synthesis andreceptor signaling are reduced (Auld et al. 2002). AChEIs are mosteffective in slowing progression of cognitive decline in mild to moderate casesand less effective in severe AD (Gillette-Guyonnet et al. 2011).Memantine is an NMDA receptor antagonist (Tariot et al. 2004) that helps mitigate theloss of NMDA receptor function due to A peptides (Snyder et al. 2005). Memantine is noteffective for mild cases of AD (Nelson and Tabet 2015)but it is effective in moderate to severe cases, especially when used incombination with AChEIs (Tariot et al. 2004). AlthoughAChEIs and NMDA receptor antagonists are the current pharmacologicalal treatmentsavailable for AD, they are lone(prenominal) able to slow the progression of the disease andlose effectiveness as AD progresses. The challenge in designing a drug toprevent or cu re AD is the multifactorial nature of the disease with genetic andlifestyle risk factors. Even when non-pharmacologic interventions (controllingblood pressure, cognitive stimulation therapy, healthy diet and exercise, andmaintaining social networks) (Nelson and Tabet 2015)are used as part of a comprehensive treatment plan and initiated early indisease progression, the best that current treatments can cracking is to slow thenatural progression of the disease With ADprevalence expected to increase worldwide across all races and ethnicities, theculture of different populations is an important good will when designingintervention strategies. Social and economic barriers that prevent access tohealth care and social services among different populations need to beunderstood to identify and implement the best treatment specific to thatpopulation. Cultures also differ in how they view AD-related cognitive declineand may consider the memory loss a part of normal aging and therefore delaysee king treatment. An awareness of how cognitive decline in older age isdefined culturally, how cultures differ in caring for the elderly, and howbarriers to AD care services impacts each cultures choice of treatment is keyto developing successful interventions. Proposed SolutionsThe greatestchallenge in developing treatment for AD that can prevent AD development orprogression is that a specific cause has not yet been identified. However,recent research has identified new pharmacologic targets involved in theproduction of A and new therapies to reduce A and tau pathology. Research by Hu, Das, Hou, He, and Yan (2018)identified the -secretase BACE1 as a potential pharmacological target for thetreatment of AD. In a mouse model of AD in adults with BACE1 inhibition, it wasobserved that synaptic function change and A plaque governance was prevented.Although some clinical trials of BACE1 inhibitors have stalled, with Merckstopping its clinical trial of verubecestat in February 2018 (Merck 2018), there is still hope ofdeveloping pharmacologic treatments targeting A and tau proteins (Amgen 2017). A noveltherapeutic approach being researched is the use of optogenetic stimulation toreduce A and tau phosphorylation. Using a light flickering at 40 hertz, (Iaccarino et al. 2016)found they could stimulate brain waves called gamma oscillations in a mousemodel of AD and observed reduced A plaque formation and tau phosphorylation. Thismay lead to new non-invasive AD therapies, but more research is needed toinvestigate its effectiveness in humans. With treatmentapproaches that target the production of toxic A and abnormal tauphosphorylation, it is conceivable that in the future we may be better able toprevent and stop the progression of AD. ReferencesAmgen. 2017 Nov 2. Amgenand novartis announce expanded quislingism with banner alzheimers institutein pioneering prevention program. Amgen. accessed 2018 scotch 19.http//www.amgen.com/media/news-releases/2017/11/amgen-and-novartis -announce-expanded-collaboration-with-banner-alzheimers-institute-in-pioneering-prevention-program/.Amieva H, Mokri H, LeGoff M, Meillon C, Jacqmin-Gadda H, Foubert-Samier A, Orgogozo J-M, Stern Y,Dartigues J-F. 2014. Compensatory mechanisms in higher-educated subjects withAlzheimers disease a study of 20 years of cognitive decline. Brain13711671175. APOE gene. 2018 Feb 27.US Natl Libr Med. accessed 2018 Mar 5. https//ghr.nlm.nih.gov/gene/APOE.Auld DS, Kornecook TJ,Bastianetto S, Quirion R. 2002. Alzheimers disease and the basal forebraincholinergic system relations to -amyloid peptides, cognition, and treatmentstrategies. Prog Neurobiol. 68209245. Brookmeyer R, Johnson E,Ziegler-Graham K, Arrighi HM. 2007. Forecasting the global burden ofAlzheimers disease. Alzheimers Dement. J. Alzheimers Assoc. 3186191. Caspersen C, Wang N, YaoJ, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan SD. 2005.Mitochondrial Abeta a potential focal point for neuronal metabolic dysfunctioni n Alzheimers disease. FASEB J. 1920402041. Ekblad LL, Johansson J,Helin S, Viitanen M, Laine H, Puukka P, Jula A, Rinne JO. 2018 Feb 23. Midlifeinsulin resistance, APOE genotype, and late-life brain amyloid accumulation.Neurology10.1212/WNL.0000000000005214. Gillette-Guyonnet S,Andrieu S, Nourhashemi F, Gardette V, Coley N, Cantet C, Gauthier S, OussetP-J, Vellas B. 2011. Long-term progression of Alzheimers disease in patientsunder antidementia drugs. Alzheimers Dement J Alzheimers Assoc. 7579592. Gilsanz P, Mayeda ER,Glymour MM, Quesenberry CP, Mungas DM, DeCarli C, Dean A, Whitmer RA. 2017. egg-producing(prenominal) sex, early-onset hypertension, and risk of dementia. Neurology8918861893. Guerreiro R, Wojtas A,Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JSK,Younkin S, et al. 2013. TREM2 variants in Alzheimers disease. N Engl J Med.368117-127Harman D. 2002.Alzheimers disease Role of aging in pathogenesis. Ann. N. Y. Acad. Sci.959384395. Hickman SE, El Khoury J.2014. TREM2 and the neuroimmunology of Alzheimers disease. Biochem Pharmacol.88495498. Hinney A, Albayrak O,Antel J, Volckmar A-L, Sims R, Chapman J, Harold D, Gerrish A, Heid IM, WinklerTW, et al. 2014. Genetic variation at the CELF1 (CUGBP, elav-like family member1 gene) locus is genome-wide associated with Alzheimers disease and obesity. Am J MedGenet B Neuropsychiatr Genet. 165B(4)283-93Hu X, Das B, Hou H, HeW, Yan R. 2018. BACE1 gash in the adult mouse reverses preformed amyloiddeposition and improves cognitive functions. J Exp Med. jem.20171831Iaccarino HF, Singer AC,Martorell AJ, Rudenko A, Gao F, Gillingham TZ, Mathys H, Seo J, Kritskiy O,Abdurrob F, et al. 2016. Gamma frequency entrainment attenuates amyloid loadand modifies microglia. Nature 540230. Iqbal K, del C. AlonsoA, Chen S, Chohan MO, El-Akkad E, bell C-X, Khatoon S, Li B, Liu F, Rahman A,et al. 2005. Tau pathology in Alzheimer disease and other tauopathies. BiochimBiophys Acta. 1739(2-3)198210. Jonsson T, Stefansson H,Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J,Levey AI, Lah JJ, et al. 2013. Variant of TREM2 associated with the risk ofAlzheimers disease. N Engl J Med. 368107-116Kanekiyo T, Xu H, Bu G.2014. ApoE and A in Alzheimers disease unintended encounters or partners?Neuron 81740754. Letra L, Santana I,Seia R. 2014. Obesity as a risk factor for Alzheimers disease the role ofadipocytokines. Metab Brain Dis. 29563568. McGrath ER, Beiser AS,DeCarli C, Plourde KL, Vasan RS, Greenberg SM, Seshadri S. 2017. contrast pressurefrom mid to late life and risk of incident dementia. Neurology8924472454. Merck. 2018 Feb 13.Merck announces discontinuation of APECS study evaluating verubecestat(MK-8931) for the treatment of people with prodromal Alzheimers disease.MERCK. accessed 2018 Mar 19.http//www.mrknewsroom.com/news-release/research-and-development-news/merck-announces-discontinuation-apecs-study-evaluating-ve.Nelson L, Tabet N. 2015.Slowing the prog ression of Alzheimers disease what works? Ageing Res. Rev.23193209. Nuzzo D, Picone P,Baldassano S, Caruana L, Messina E, Marino Gammazza A, Cappello F, Mul F, DiCarlo M. 2015. Insulin resistance as common molecular denominator linking obesityto Alzheimers disease. Curr Alzheimer Res. 12723735.Peila R, Rodriguez BL,Launer LJ. 2002. grapheme 2 diabetes, APOE gene, and the risk for dementia andrelated pathologies the Honolulu-Asia aging study. Diabetes. 5112561262. Pini L, Pievani M,Bocchetta M, Altomare D, Bosco P, Cavedo E, Galluzzi S, Marizzoni M, FrisoniGB. 2016. Brain atrophy in Alzheimers disease and aging. Ageing Res Rev.302548. Prince M, Wimo A, Guerchet M, Ali G-C, Wu Y-T, Prina M. 2015. World Alzheimer Report 2015 The global impact of dementia An analysis of prevalence, incidence, cost and trends. accessed 2018 March 18Qiu C, Kivipelto M, vonStrauss E. 2009. Epidemiology of Alzheimers disease occurrence, determinants,and strategies toward intervention. Dialogues Cli. Neuros ci. 11111128.Querfurth HW, LaFerlaFM. 2010. Alzheimers Disease. N Engl J Med. 362329344. Rankin CA, Sun Q,Gamblin TC. 2007. Tau phosphorylation by GSK-3 promotes tangle-like filamentmorphology. Mol Neurodegener. 212. Reddy PH, Beal MF. 2008.Amyloid beta, mitochondrial dysfunction and synaptic damage implications forcognitive decline in aging and Alzheimers disease. Trends Mol Med. 144553. Ridge PG, Ebbert MTW,Kauwe JSK. 2013. Genetics of Alzheimers disease. BioMed Res Int. 2013254-954.Sarlus H, Heneka MT.2017. Microglia in Alzheimers disease. J. Clin Invest. 12732403249. Sattler C, Toro P,Schnknecht P, Schrder. 2012. Cognitive activity, education and socioeconomicstatus as preventive factors for mild cognitive impairment and Alzheimersdisease. Psychiatry Res. 1969095.Seplveda FJ, Fierro H,Fernandez E, Castillo C, Peoples RW, Opazo C, Aguayo LG. 2014. Nature of theneurotoxic membrane actions of amyloid- on hippocampal neurons in Alzheimersdisease. Neurobiol Aging. 35472481. Shpanskay a KS, ChoudhuryKR, Hostage C, Murphy KR, Petrella JR, Doraiswamy PM. 2014. educationalattainment and hippocampal atrophy in the Alzheimers disease neuroimaging initiativecohort. J Neuroradiol. 41350357. Snyder EM, Nong Y,Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, GourasGK, et al. 2005. Regulation of NMDA receptor trafficking by amyloid-. NatNeurosci. 810511058. Spillantini MG, GoedertM. 2013. Tau pathology and neurodegeneration. gig Neurol. 12609622.Sun X-Y, Tuo Q-Z,Liuyang Z-Y, Xie A-J, Feng X-L, Yan X, Qiu M, Li S, Wang X-L, Cao F-Y, et al.2016. Extrasynaptic NMDA receptor-induced tau overexpression mediates neuronaldeath through suppressing survival signaling ERK phosphorylation. Cell DeathDis. 7(11)e2449. Takashima A. 2006. GSK-3is essential in the pathogenesis of Alzheimers disease. J Alzheimers Dis. 9309317.Tang X, Varma VR, MillerMI, Carlson MC. 2017. Education is associated with sub-regions of thehippocampus and the amygdala vulnerable to neurop athologies of Alzheimersdisease. Brain Struct Funct. 22214691479. Tariot PN, Farlow MR,Grossberg GT, Graham SM, McDonald S, Gergel I. 2004. Memantine treatment inpatients with moderate to severe Alzheimer disease already receiving donepezila randomized controlled trial. JAMA. 291317324. Whitmer RA, Sidney S,Selby J, Johnston SC, Yaffe K. 2005. Midlife cardiovascular risk factors andrisk of dementia in late life. Neurology. 64277281.