Biomarker Modeling of Alzheimer’s Disease
2013; Cell Press; Volume: 80; Issue: 6 Linguagem: Inglês
10.1016/j.neuron.2013.12.003
ISSN1097-4199
AutoresClifford R. Jack, David M. Holtzman,
Tópico(s)Bioinformatics and Genomic Networks
ResumoAlzheimer’s disease (AD) is a slowly progressing disorder in which pathophysiological abnormalities, detectable in vivo by biomarkers, precede overt clinical symptoms by many years to decades. Five AD biomarkers are sufficiently validated to have been incorporated into clinical diagnostic criteria and commonly used in therapeutic trials. Current AD biomarkers fall into two categories: biomarkers of amyloid-β plaques and of tau-related neurodegeneration. Three of the five are imaging measures and two are cerebrospinal fluid analytes. AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping manner. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. In this Review, we discuss several time-dependent models of AD that take into consideration varying age of onset (early versus late) and the influence of aging and co-occurring brain pathologies that commonly arise in the elderly. Alzheimer’s disease (AD) is a slowly progressing disorder in which pathophysiological abnormalities, detectable in vivo by biomarkers, precede overt clinical symptoms by many years to decades. Five AD biomarkers are sufficiently validated to have been incorporated into clinical diagnostic criteria and commonly used in therapeutic trials. Current AD biomarkers fall into two categories: biomarkers of amyloid-β plaques and of tau-related neurodegeneration. Three of the five are imaging measures and two are cerebrospinal fluid analytes. AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping manner. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. In this Review, we discuss several time-dependent models of AD that take into consideration varying age of onset (early versus late) and the influence of aging and co-occurring brain pathologies that commonly arise in the elderly. Two well-known abnormal protein aggregates characterize Alzheimer’s disease (AD) pathologically (Hyman et al., 2012Hyman B.T. Phelps C.H. Beach T.G. Bigio E.H. Cairns N.J. Carrillo M.C. Dickson D.W. Duyckaerts C. Frosch M.P. Masliah E. et al.National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease.Alzheimers Dement. 2012; 8: 1-13Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). The hallmarks of amyloid-β (Aβ) deposits in AD are neuritic plaques and cerebral amyloid angiopathy (CAA). Neuritic plaques are extracellular and consist of a dense central fibrillar Aβ core with inflammatory cells and dystrophic neurites in its periphery. CAA is also extracellular and consists of fibrillar Aβ deposited in the wall of arterioles in both the leptomeninges and penetrating vessels (Johnson et al., 2007Johnson K.A. Gregas M. Becker J.A. Kinnecom C. Salat D.H. Moran E.K. Smith E.E. Rosand J. Rentz D.M. Klunk W.E. et al.Imaging of amyloid burden and distribution in cerebral amyloid angiopathy.Ann. Neurol. 2007; 62: 229-234Crossref PubMed Scopus (223) Google Scholar). The second major proteinopathy is aggregated tau, which are intracellular aggregates of hyperphosphorylated tau in the form of neurofibrillary tangles (NFTs). NFTs follow a stereotypic topographic progression pattern, first appearing in the brainstem and transentorhinal area, then progressing to the hippocampus, to paralimbic and adjacent medial-basal temporal cortex, to cortical association areas, and last to primary sensory-motor and visual areas (Braak and Braak, 1991Braak H. Braak E. Neuropathological stageing of Alzheimer-related changes.Acta Neuropathol. 1991; 82: 239-259Crossref PubMed Google Scholar). Another important pathological feature is neurodegeneration, which maps onto NFT distribution topographically (not onto β-amyloid distribution) and is characterized macroscopically as atrophy and microscopically as loss of neurons and neuronal processes (Braak and Braak, 1994Braak H. Braak E. Morphological criteria for the recognition of Alzheimer’s disease and the distribution pattern of cortical changes related to this disorder.Neurobiol. Aging. 1994; 15 (discussion 379–380): 355-356Abstract Full Text PDF PubMed Scopus (85) Google Scholar, Terry et al., 1991Terry R.D. Masliah E. Salmon D.P. Butters N. DeTeresa R. Hill R. Hansen L.A. Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment.Ann. Neurol. 1991; 30: 572-580Crossref PubMed Scopus (1830) Google Scholar). Clinical-autopsy correlation studies demonstrate a much tighter correlation between NFT and cognitive impairment than between amyloid and cognitive impairment (Bennett et al., 2004Bennett D.A. Schneider J.A. Wilson R.S. Bienias J.L. Arnold S.E. Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function.Arch. Neurol. 2004; 61: 378-384Crossref PubMed Scopus (159) Google Scholar, Dickson et al., 1995Dickson D.W. Crystal H.A. Bevona C. Honer W. Vincent I. Davies P. Correlations of synaptic and pathological markers with cognition of the elderly.Neurobiol. Aging. 1995; 16 (discussion 298–304): 285-298Abstract Full Text PDF PubMed Scopus (260) Google Scholar, Gómez-Isla et al., 1997Gómez-Isla T. Hollister R. West H. Mui S. Growdon J.H. Petersen R.C. Parisi J.E. Hyman B.T. Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease.Ann. Neurol. 1997; 41: 17-24Crossref PubMed Scopus (634) Google Scholar, Ingelsson et al., 2004Ingelsson M. Fukumoto H. Newell K.L. Growdon J.H. Hedley-Whyte E.T. Frosch M.P. Albert M.S. Hyman B.T. Irizarry M.C. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain.Neurology. 2004; 62: 925-931Crossref PubMed Google Scholar). The tightest correlation between cognitive impairment and various autopsy features of AD though seems to be with neurodegeneration (Savva et al., 2009Savva G.M. Wharton S.B. Ince P.G. Forster G. Matthews F.E. Brayne C. Medical Research Council Cognitive Function and Ageing StudyAge, neuropathology, and dementia.N. Engl. J. Med. 2009; 360: 2302-2309Crossref PubMed Scopus (307) Google Scholar), specifically synapse loss (Terry et al., 1991Terry R.D. Masliah E. Salmon D.P. Butters N. DeTeresa R. Hill R. Hansen L.A. Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment.Ann. Neurol. 1991; 30: 572-580Crossref PubMed Scopus (1830) Google Scholar). Approximately 30% of cognitively normal elderly subjects have sufficient pathology to meet criteria for AD at autopsy (Knopman et al., 2003Knopman D.S. Parisi J.E. Salviati A. Floriach-Robert M. Boeve B.F. Ivnik R.J. Smith G.E. Dickson D.W. Johnson K.A. Petersen L.E. et al.Neuropathology of cognitively normal elderly.J. Neuropathol. Exp. Neurol. 2003; 62: 1087-1095Crossref PubMed Google Scholar, Price and Morris, 1999Price J.L. Morris J.C. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease.Ann. Neurol. 1999; 45: 358-368Crossref PubMed Scopus (857) Google Scholar); however, absence of cognitive symptoms is rarely seen in individuals with severe NFT burden. The accumulation of brain pathologies seems to be a nearly inevitable consequence of aging; very few elderly individuals have no findings at autopsy and the older the individual the more this holds true (Nelson et al., 2011Nelson P.T. Head E. Schmitt F.A. Davis P.R. Neltner J.H. Jicha G.A. Abner E.L. Smith C.D. Van Eldik L.J. Kryscio R.J. Scheff S.W. Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies.Acta Neuropathol. 2011; 121: 571-587Crossref PubMed Scopus (62) Google Scholar). The common age-associated brain pathologies are AD (plaques and tangles), medial temporal tangles without plaques, ischemic cerebrovascular disease (which includes not only macroscopic cortical and subcortical infarctions but also microinfarctions, which seem to be particularly important, and ischemic demyelination), hippocampal sclerosis, alpha synuclein deposits (Lewy bodies), TDP43 inclusions, and agyrophyllic grains (Markesbery et al., 2006Markesbery W.R. Schmitt F.A. Kryscio R.J. Davis D.G. Smith C.D. Wekstein D.R. Neuropathologic substrate of mild cognitive impairment.Arch. Neurol. 2006; 63: 38-46Crossref PubMed Scopus (266) Google Scholar, Schneider et al., 2009Schneider J.A. Arvanitakis Z. Leurgans S.E. Bennett D.A. The neuropathology of probable Alzheimer disease and mild cognitive impairment.Ann. Neurol. 2009; 66: 200-208Crossref PubMed Scopus (222) Google Scholar, Sonnen et al., 2011Sonnen J.A. Santa Cruz K. Hemmy L.S. Woltjer R. Leverenz J.B. Montine K.S. Jack C.R. Kaye J. Lim K. Larson E.B. et al.Ecology of the aging human brain.Arch. Neurol. 2011; 68: 1049-1056Crossref PubMed Scopus (35) Google Scholar, White, 2009White L. Brain lesions at autopsy in older Japanese-American men as related to cognitive impairment and dementia in the final years of life: a summary report from the Honolulu-Asia aging study.J. Alzheimers Dis. 2009; 18: 713-725PubMed Google Scholar). These same pathologies are also found in subjects who were cognitively normal at the time of death, albeit usually at lower overall pathological burdens than in demented subjects. The most common finding at autopsy in elderly persons who meet clinical and pathological criteria for AD dementia is mixed pathology—plaques and tangles plus one or more of the non-AD pathologies above. Throughout this paper therefore, AD is discussed from two perspectives: early onset, which is a reasonable model of “pure AD,” and late onset, which usually consists of AD plus one or more co-occurring pathological processes. AD is commonly categorized clinically as either early onset (onset of clinical symptoms before age 65) or late onset. Early-onset AD is uncommon, accounting for a few percent of cases at most. A proportion of early-onset AD cases occur in individuals with autosomal-dominant mutations in one of three genes: the amyloid precursor protein gene on chromosome 21, the presenilin-1 gene on chromosome 14, or the presenilin-2 gene on chromosome 1 (Goate et al., 1991Goate A. Chartier-Harlin M.C. Mullan M. Brown J. Crawford F. Fidani L. Giuffra L. Haynes A. Irving N. James L. et al.Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease.Nature. 1991; 349: 704-706Crossref PubMed Scopus (2001) Google Scholar, Levy-Lahad et al., 1995Levy-Lahad E. Wasco W. Poorkaj P. Romano D.M. Oshima J. Pettingell W.H. Yu C.E. Jondro P.D. Schmidt S.D. Wang K. et al.Candidate gene for the chromosome 1 familial Alzheimer’s disease locus.Science. 1995; 269: 973-977Crossref PubMed Google Scholar, Sherrington et al., 1995Sherrington R. Rogaev E.I. Liang Y. Rogaeva E.A. Levesque G. Ikeda M. Chi H. Lin C. Li G. Holman K. et al.Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease.Nature. 1995; 375: 754-760Crossref PubMed Google Scholar, St George-Hyslop et al., 1987St George-Hyslop P.H. Tanzi R.E. Polinsky R.J. Haines J.L. Nee L. Watkins P.C. Myers R.H. Feldman R.G. Pollen D. Drachman D. et al.The genetic defect causing familial Alzheimer’s disease maps on chromosome 21.Science. 1987; 235: 885-890Crossref PubMed Scopus (397) Google Scholar). Along with Down syndrome, all known autosomal-dominant mutations leading to AD influence processing of the amyloid precursor protein (APP) in a manner resulting in (1) increased production of Aβ42 or all Aβ species or (2) increased aggregation/decreased clearance of Aβ (Holtzman et al., 2011Holtzman D.M. Morris J.C. Goate A.M. Alzheimer’s disease: the challenge of the second century.Sci. Transl. Med. 2011; 3: sr1Google Scholar). These result in increasing the accumulation of oligomeric and fibrillar Aβ (Scheuner et al., 1996Scheuner D. Eckman C. Jensen M. Song X. Citron M. Suzuki N. Bird T.D. Hardy J. Hutton M. Kukull W. et al.Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease.Nat. Med. 1996; 2: 864-870Crossref PubMed Scopus (1754) Google Scholar). It is notable that primary tauopathies lead to forms of frontotemporal lobar degeneration, corticobasal degeneration, and progressive supranuclear palsy but never to pathological AD (i.e., not to Aβ accumulation). Animal models in which human amyloid precursor protein with or without presenilin mutations have been inserted into the mouse genome recapitulate the Aβ-linked aspects seen in autosomal-dominant AD, including increased CSF tau (Maia et al., 2013Maia L.F. Kaeser S.A. Reichwald J. Hruscha M. Martus P. Staufenbiel M. Jucker M. Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein.Sci. Transl. Med. 2013; 5: re2Crossref Scopus (9) Google Scholar). Transgenic mouse models of β-amyloidosis and cellular evidence indicate that Aβ exacerbates tauopathy (Lewis et al., 2001Lewis J. Dickson D.W. Lin W.L. Chisholm L. Corral A. Jones G. Yen S.H. Sahara N. Skipper L. Yager D. et al.Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.Science. 2001; 293: 1487-1491Crossref PubMed Scopus (832) Google Scholar, Oddo et al., 2004Oddo S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome.Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar) (perhaps by kindling the autopropagation of NFTs [Clavaguera et al., 2009Clavaguera F. Bolmont T. Crowther R.A. Abramowski D. Frank S. Probst A. Fraser G. Stalder A.K. Beibel M. Staufenbiel M. et al.Transmission and spreading of tauopathy in transgenic mouse brain.Nat. Cell Biol. 2009; 11: 909-913Crossref PubMed Scopus (405) Google Scholar, de Calignon et al., 2012de Calignon A. Polydoro M. Suárez-Calvet M. William C. Adamowicz D.H. Kopeikina K.J. Pitstick R. Sahara N. Ashe K.H. Carlson G.A. et al.Propagation of tau pathology in a model of early Alzheimer’s disease.Neuron. 2012; 73: 685-697Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, Frost et al., 2009Frost B. Jacks R.L. Diamond M.I. Propagation of tau misfolding from the outside to the inside of a cell.J. Biol. Chem. 2009; 284: 12845-12852Crossref PubMed Scopus (308) Google Scholar, Guo and Lee, 2011Guo J.L. Lee V.M. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles.J. Biol. Chem. 2011; 286: 15317-15331Crossref PubMed Scopus (115) Google Scholar]), not the reverse (Oddo et al., 2003Oddo S. Caccamo A. Kitazawa M. Tseng B.P. LaFerla F.M. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease.Neurobiol. Aging. 2003; 24: 1063-1070Abstract Full Text Full Text PDF PubMed Scopus (409) Google Scholar). The available genetic evidence points to Aβ overproduction of all Aβ species (APP duplication, APP Swedish mutation), relative Aβ42 versus Aβ40 overproduction (N-terminal APP mutations/presenilin mutations), or enhanced aggregation/decreased clearance (APP mutations within the Aβ domain) as causative in autosomal dominate AD (Holtzman et al., 2011Holtzman D.M. Morris J.C. Goate A.M. Alzheimer’s disease: the challenge of the second century.Sci. Transl. Med. 2011; 3: sr1Google Scholar). This has led to the amyloid cascade hypothesis, which asserts that dysfunction in the Aβ pathway is the initiating event in the disease (Glenner and Wong, 1984Glenner G.G. Wong C.W. Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein.Biochem. Biophys. Res. Commun. 1984; 122: 1131-1135Crossref PubMed Scopus (709) Google Scholar, Hardy and Selkoe, 2002Hardy J. Selkoe D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics.Science. 2002; 297: 353-356Crossref PubMed Scopus (5542) Google Scholar). Soluble Aβ, rather than insoluble Aβ, is felt to initiate the disease cascade (Hardy, 2009Hardy J. The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal.J. Neurochem. 2009; 110: 1129-1134Crossref PubMed Scopus (280) Google Scholar). A simple mechanistic diagram of the amyloid cascade hypothesis is shown below: over production/aggregation of Aβ42 → tauopathy → neurodegeneration → clinical symptoms. Late-onset AD accounts for the overwhelming majority of cases. While most autosomal-dominant AD is believed to usually be caused by overproduction and subsequent aggregation of Aβ42 (a more fibrillogenic form of Aβ) from the beginning of life, late-onset AD may most often be a disease of inadequate Aβ clearance, again leading to increased aggregation and accumulation (Mawuenyega et al., 2010Mawuenyega K.G. Sigurdson W. Ovod V. Munsell L. Kasten T. Morris J.C. Yarasheski K.E. Bateman R.J. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease.Science. 2010; 330: 1774Crossref PubMed Scopus (390) Google Scholar). While deterministic genetic mutations for sporadic AD have not been found, genetics nonetheless plays a very important role in risk. The ε4 allele of the apolipoprotein E (APOE) gene is the major known genetic risk factor (Roses, 1994Roses A.D. Apolipoprotein E affects the rate of Alzheimer disease expression: beta-amyloid burden is a secondary consequence dependent on APOE genotype and duration of disease.J. Neuropathol. Exp. Neurol. 1994; 53: 429-437Crossref PubMed Google Scholar). The ε4 allele of APOE increases the risk of developing AD and also lowers the mean age at onset of the disease in a dose-dependent fashion (Corder et al., 1993Corder E.H. Saunders A.M. Strittmatter W.J. Schmechel D.E. Gaskell P.C. Small G.W. Roses A.D. Haines J.L. Pericak-Vance M.A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families.Science. 1993; 261: 921-923Crossref PubMed Google Scholar, Strittmatter et al., 1993Strittmatter W.J. Weisgraber K.H. Huang D.Y. Dong L.M. Salvesen G.S. Pericak-Vance M. Schmechel D. Saunders A.M. Goldgaber D. Roses A.D. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease.Proc. Natl. Acad. Sci. USA. 1993; 90: 8098-8102Crossref PubMed Google Scholar). The major mechanism by which APOE ε4 contributes to AD pathogenesis appears to be by modulating the aggregation and clearance of Aβ peptide (Castellano et al., 2011Castellano J.M. Kim J. Stewart F.R. Jiang H. DeMattos R.B. Patterson B.W. Fagan A.M. Morris J.C. Mawuenyega K.G. Cruchaga C. et al.Human apoE isoforms differentially regulate brain amyloid-β peptide clearance.Sci. Transl. Med. 2011; 3: 89ra57Crossref PubMed Scopus (178) Google Scholar, Kim et al., 2009Kim J. Basak J.M. Holtzman D.M. The role of apolipoprotein E in Alzheimer’s disease.Neuron. 2009; 63: 287-303Abstract Full Text Full Text PDF PubMed Scopus (403) Google Scholar), leading to increased deposition (Morris et al., 2010Morris J.C. Roe C.M. Xiong C. Fagan A.M. Goate A.M. Holtzman D.M. Mintun M.A. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging.Ann. Neurol. 2010; 67: 122-131Crossref PubMed Scopus (255) Google Scholar, Vemuri et al., 2010Vemuri P. Wiste H.J. Weigand S.D. Knopman D.S. Shaw L.M. Trojanowski J.Q. Aisen P.S. Weiner M. Petersen R.C. Jack Jr., C.R. Alzheimer’s Disease Neuroimaging InitiativeEffect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease.Ann. Neurol. 2010; 67: 308-316PubMed Google Scholar), which implicates this pathway in causation of late-onset AD. However, APOE is also implicated in many functions other than Aβ trafficking that may contribute to AD pathogenesis, including regulating brain lipid metabolism, neuronal repair, synaptic function, inflammation, and mitochondrial function (Bu, 2009Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy.Nat. Rev. Neurosci. 2009; 10: 333-344Crossref PubMed Scopus (329) Google Scholar, Mahley and Huang, 2009Mahley R.W. Huang Y. Alzheimer disease: multiple causes, multiple effects of apolipoprotein E4, and multiple therapeutic approaches.Ann. Neurol. 2009; 65: 623-625Crossref PubMed Scopus (28) Google Scholar). The effect of any specific genetic variant other than APOE4 at the population level is minor. Risk variants, including those of CLU, CR1, PICALM, CD33, APP, A673T, ABCA7, EPHA1, TREM 2, SORL1, and BIN1, do point to Aβ but also to alternative pathways including immunologic, inflammatory, neurotropic, endocytosis, cholesterol metabolism, ubiquitination, and tau (Bertram et al., 2008Bertram L. Lange C. Mullin K. Parkinson M. Hsiao M. Hogan M.F. Schjeide B.M. Hooli B. Divito J. Ionita I. et al.Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE.Am. J. Hum. Genet. 2008; 83: 623-632Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, Griciuc et al., 2013Griciuc A. Serrano-Pozo A. Parrado A.R. Lesinski A.N. Asselin C.N. Mullin K. Hooli B. Choi S.H. Hyman B.T. Tanzi R.E. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta.Neuron. 2013; 78: 631-643Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, Guerreiro et al., 2013Guerreiro R. Wojtas A. Bras J. Carrasquillo M. Rogaeva E. Majounie E. Cruchaga C. Sassi C. Kauwe J.S. Younkin S. et al.Alzheimer Genetic Analysis GroupTREM2 variants in Alzheimer’s disease.N. Engl. J. Med. 2013; 368: 117-127Crossref PubMed Scopus (204) Google Scholar, Harold et al., 2009Harold D. Abraham R. Hollingworth P. Sims R. Gerrish A. Hamshere M.L. Pahwa J.S. Moskvina V. Dowzell K. Williams A. et al.Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease.Nat. Genet. 2009; 41: 1088-1093Crossref PubMed Scopus (898) Google Scholar, Hollingworth et al., 2011Hollingworth P. Harold D. Sims R. Gerrish A. Lambert J.C. Carrasquillo M.M. Abraham R. Hamshere M.L. Pahwa J.S. Moskvina V. et al.Alzheimer’s Disease Neuroimaging InitiativeCHARGE consortiumEADI1 consortiumCommon variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease.Nat. Genet. 2011; 43: 429-435Crossref PubMed Scopus (418) Google Scholar, Jonsson et al., 2013Jonsson T. Stefansson H. Steinberg S. Jonsdottir I. Jonsson P.V. Snaedal J. Bjornsson S. Huttenlocher J. Levey A.I. Lah J.J. et al.Variant of TREM2 associated with the risk of Alzheimer’s disease.N. Engl. J. Med. 2013; 368: 107-116Crossref PubMed Scopus (188) Google Scholar, Lambert et al., 2009Lambert J.C. Heath S. Even G. Campion D. Sleegers K. Hiltunen M. Combarros O. Zelenika D. Bullido M.J. Tavernier B. et al.European Alzheimer’s Disease Initiative InvestigatorsGenome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease.Nat. Genet. 2009; 41: 1094-1099Crossref PubMed Scopus (810) Google Scholar, Naj et al., 2011Naj A.C. Jun G. Beecham G.W. Wang L.S. Vardarajan B.N. Buros J. Gallins P.J. Buxbaum J.D. Jarvik G.P. Crane P.K. et al.Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease.Nat. Genet. 2011; 43: 436-441Crossref PubMed Scopus (436) Google Scholar, Seshadri et al., 2010Seshadri S. Fitzpatrick A.L. Ikram M.A. DeStefano A.L. Gudnason V. Boada M. Bis J.C. Smith A.V. Carassquillo M.M. Lambert J.C. et al.CHARGE ConsortiumGERAD1 ConsortiumEADI1 ConsortiumGenome-wide analysis of genetic loci associated with Alzheimer disease.JAMA. 2010; 303: 1832-1840Crossref PubMed Scopus (389) Google Scholar). Thus, from a genetics standpoint, sporadic AD is complex. Late-onset AD is also more complex than early onset from a pathological perspective. As noted above, late-onset AD typically occurs along with other age-related pathologies. In fact, the contribution of pathologies such as hippocampal sclerosis and cerebrovascular disease to dementia seems to increase relative to AD pathology with advancing age beyond 85 years (Nelson et al., 2011Nelson P.T. Head E. Schmitt F.A. Davis P.R. Neltner J.H. Jicha G.A. Abner E.L. Smith C.D. Van Eldik L.J. Kryscio R.J. Scheff S.W. Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies.Acta Neuropathol. 2011; 121: 571-587Crossref PubMed Scopus (62) Google Scholar). A further complicating factor is the fact that subcortical and medial temporal tauopathy exists at autopsy very commonly by middle age in individuals who have no plaques (Braak and Braak, 1997Braak H. Braak E. Frequency of stages of Alzheimer-related lesions in different age categories.Neurobiol. Aging. 1997; 18: 351-357Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar, Braak and Del Tredici, 2011Braak H. Del Tredici K. The pathological process underlying Alzheimer’s disease in individuals under thirty.Acta Neuropathol. 2011; 121: 171-181Crossref PubMed Scopus (156) Google Scholar, Haroutunian et al., 1999Haroutunian V. Purohit D.P. Perl D.P. Marin D. Khan K. Lantz M. Davis K.L. Mohs R.C. Neurofibrillary tangles in nondemented elderly subjects and mild Alzheimer disease.Arch. Neurol. 1999; 56: 713-718Crossref PubMed Scopus (148) Google Scholar, Price and Morris, 1999Price J.L. Morris J.C. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease.Ann. Neurol. 1999; 45: 358-368Crossref PubMed Scopus (857) Google Scholar). For example, in autopsies numbering in the thousands, Braak and Braak (Braak and Braak, 1997Braak H. Braak E. Frequency of stages of Alzheimer-related lesions in different age categories.Neurobiol. Aging. 1997; 18: 351-357Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar) find that by the late 70s, nearly all individuals (97%) have some tauopathy, while only 17% have β-amyloid deposits. The fact that brainstem and medial temporal lobe tau commonly precedes amyloid plaques has led some to suggest that a different pathogenic model should exist for late-onset versus early-onset AD. The initiating event in the molecular cascade that eventually leads to clinical and pathological AD has been controversial for decades. The amyloid cascade hypothesis (Glenner and Wong, 1984Glenner G.G. Wong C.W. Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein.Biochem. Biophys. Res. Commun. 1984; 122: 1131-1135Crossref PubMed Scopus (709) Google Scholar, Hardy and Selkoe, 2002Hardy J. Selkoe D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics.Science. 2002; 297: 353-356Crossref PubMed Scopus (5542) Google Scholar) assumes serial causal events initiated by abnormal Aβ production/aggregation. As discussed above, this seems to be a reasonable pathogenic model of early-onset AD. An alternative position is that tau hyperphosphorylation and Aβ elevation are independently arising pathophysiological processes that interact with pathogenic synergy (Duyckaerts, 2011Duyckaerts C. Tau pathology in children and young adults: can you still be unconditionally baptist?.Acta Neuropathol. 2011; 121: 145-147Crossref PubMed Scopus (21) Google Scholar, Duyckaerts et al., 1997Duyckaerts C. Uchihara T. Seilhean D. He Y. Hauw J.J. Dissociation of Alzheimer type pathology in a disconnected piece of cortex.Acta Neuropathol. 1997; 93: 501-507Crossref PubMed Scopus (24) Google Scholar, Mesulam, 1999Mesulam M.M. Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles.Neuron. 1999; 24: 521-529Abstract Full Text Full Text PDF PubMed Google Scholar, Small and Duff, 2008Small S.A. Duff K. Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis.Neuron. 2008; 60: 534-542Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar), which is particularly germane to late-onset AD (Chételat, 2013Chételat G. Alzheimer disease: Aβ-independent processes-rethinking preclinical AD.Nat. Rev. Neurol. 2013; 9: 123-124Crossref PubMed Scopus (27) Google Scholar, Desikan et al., 2011Desikan R.S. McEvoy L.K. Thompson W.K. Holland D. Roddey J.C. Blennow K. Aisen P.S. Brewer J.B. Hyman B.T. Dale A.M. Alzheimer’s Disease Neuroimaging InitiativeAmyloid-β associated volume loss occurs only in the presence of phospho-tau.Ann. Neurol. 2011; 70: 657-661Crossref PubMed Scopus (31) Google Scholar, Jack et al., 2013aJack Jr., C.R. Knopman D.S. Jagust W.J. Petersen R.C. Weiner M.W. Aisen P.S. Shaw L.M. Vemuri P. Wiste H.J. Weigand S.D. et al.Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers.Lancet Neurol. 2013; 12: 207-216Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, Knopman et al., 2012Knopman D.S. Jack Jr., C.R. Wiste H.J. Weigand S.D. Vemuri P. Lowe V.J. Kantarci K. Gunter J.L. Senjem M.L. Mielke M.M. et al.Brain injury biomarkers are not dependent on β-amyloid in normal elderly.Ann. Neurol. 2012; 73: 472-480Crossref Scopus (27) Google Scholar, Knopman et al., 2013Knopman D.S. Jack Jr., C.R. Wiste H.J. Weigand S.D. Vemuri P. Lowe V.J. Kantarci K. Gunter J.L. Senjem M.L. Mielke M.M. et al.Selective worsening of brain injury biomarker abnormalities in cognitively normal elderly persons with β-amyloidosis.JAMA Neurol. 2013; 70: 1030-1038Crossref PubMed Scopus (15) Google Scholar). A sequence of pathological events proposed by Price and Morris, 1999Price J.L. Morris J.C. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease.Ann. Neuro
Referência(s)