Mild cognitive impairment (part 2): biological markers for diagnosis and prediction of dementia in Alzheimer's disease

Orestes V. Forlenza Breno S. Diniz Antonio L. Teixeira Florindo Stella Wagner Gattaz About the authors

Abstract

Objective:

To present a critical review of publications reporting on the rationale and clinical implications of the use of biomarkers for the early diagnosis of Alzheimer's disease (AD).

Methods:

We conducted a systematic search of the PubMed and Web of Science electronic databases, limited to articles published in English between 1999 and 2012, and based on the following terms: mild cognitive impairment, Alzheimer's disease OR dementia, biomarkers. We retrieved 1,130 articles, of which 175 were reviews. Overall, 955 original articles were eligible.

Results:

The following points were considered relevant for the present review: a) rationale for biomarkers research in AD and mild cognitive impairment (MCI); b) usefulness of distinct biomarkers for the diagnosis and prediction of AD; c) the role of multimodality biomarkers for the diagnosis and prediction of AD; d) the role of biomarkers in clinical trials of patients with AD and MCI; and e) current limitations to the widespread use of biomarkers in research and clinical settings.

Conclusion:

Different biomarkers are useful for the early diagnosis and prediction of AD in at-risk subjects. Nonetheless, important methodological limitations need to be overcome for widespread use of biomarkers in research and clinical settings.

Alzheimer's disease; mild cognitive impairment; biomarkers; neuroimaging; amyloid-β protein; Tau protein


Introduction

In view of growing life expectancy worldwide, Alzheimer's disease (AD), the most common dementing disorder in the elderly, will reach epidemic status within the next decades.11. Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement. 2007;3:186-91. This is a natural consequence not only of the age-dependent increase in the number of incident cases of AD, but also of the development of new diagnostic tools that will allow its early identification in elders with very mild symptoms of cognitive dysfunction, or even in asymptomatic individuals. In the current literature, the early diagnosis of AD subsumes the diagnosis of AD at pre-dementia stages. The identification of individuals at risk of dementia with no detectable clinical manifestations of this syndrome parallels the attempts to determine the risk of the future occurrence of major disease events in the light of measurable underlying susceptibility and/or pathological markers at early stages of the clinical trajectory of the disease. This has been the standpoint of good clinical practice in the management of several medical specialty, such as the assessment and modification of the risk of myocardial infarction in patients with dyslipidemia, diabetes mellitus and systemic hypertension in cardiology; the diagnosis of carcinoma in situ in oncology; or the prevention of fractures given the early recognition of osteopenia and osteoporosis in orthopedic surgery.

With respect to AD, there is little doubt that substantial progress has been accomplished in the pursuit of this target in the past decade. From a clinical perspective, it is still a difficult task to clinically differentiate incipient AD from normal cognitive aging and from subtle cognitive changes that arise in other forms of dementia at prodromal phases.22. Forlenza OV, Diniz BS, Gattaz WF. Diagnosis and biomarkers of predementia in Alzheimer's disease. BMC Med. 2010;8:89. In the early stages of AD, patients may present with mild but persistent (and often progressive) cognitive deficits, albeit not severe enough to warrant the diagnosis of dementia (e.g., patients with amnestic mild cognitive impairment [MCI]).33. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303-8.,44. Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, et al. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004;256:240-6. In this scenario, the assessment of biomarkers (cerebrospinal fluid [CSF] and peripheral biochemical markers, structural and functional neuroimaging and brain amyloid imaging) can help researchers and clinicians increase the sensitivity and specificity of clinical diagnosis. Despite being controversial and a matter of much debate in the literature, the systematic assessment of these biomarkers has been incorporated into recent revisions of AD and MCI diagnosis.5. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:270-9. 6. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:280-92. 5-77. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Jr., Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:263-9. In this review article, we address recent research developments in biomarkers for the early diagnosis of AD and the current limitations to their widespread clinical use. Finally, we discuss challenges and perspectives for the development of pharmaceutical compounds with disease-modifying properties in AD.

Methods

We carried out a systematic search of the PubMed and Web of Science electronic databases using the following broad MeSH terms: mild cognitive impairment, Alzheimer's disease OR dementia, biomarkers. We did not set any time or language limit to this search. We retrieved 1,130 articles, of which 175 were reviews. We reviewed the remaining 955 articles and included and critically summarized the findings of the most relevant articles in the following sections.

Results

AD biomarker development: from translational research to clinical practice

AD is a chronic neurodegenerative disease with well-defined pathological markers, i.e., neuritic plaques (NPs) and neurofibrillary tangles (NFTs), mostly affecting the medial temporal lobe and associative neocortical structures.88. Jellinger KA, Bancher C. Neuropathology of Alzheimer's disease: a critical update. J Neural Transm Suppl. 1998;54:77-95. The main component of NP is aggregated and insoluble β-amyloid42, whereas NFTs are the result of hyperphosphorylation of Tau protein in neurons.99. Iqbal K, Grundke-Iqbal I. Molecular mechanism of Alzheimer's neurofibrillary degeneration and therapeutic intervention. Ann N Y Acad Sci. 1996;777:132-8. Current models for the pathophysiology of AD are based on the β-amyloid hypothesis.1010. Selkoe DJ. The molecular pathology of Alzheimer's disease. Neuron. 1991;6:487-98.,1111. Hardy JA, Higgins GA. Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992;256:184-5.

Briefly, such models support that the primary pathophysiologic event in AD is the overproduction or defective clearance of β-amyloid peptides in the brain, leading to their aggregation into more toxic species (i.e., amyloid dimers and oligomers) and, finally, to the deposition of NPs. These processes trigger the activation of neurotoxic cascades, a local inflammatory reaction, and cytoskeletal changes due to the hyperphosphorylation of Tau protein in neurons, which eventually cause neuronal dysfunction and death.1212. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature. 2004;430:631-9.

These pathological processes develop over a long period of time prior to the clinical manifestations of dementia syndrome1313. Braak H, Del Tredici K. The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol. 2011;121:171-81. and may be tracked by different methods, such as visualization of brain amyloid deposition by molecular neuroimaging,1414. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306-19. biochemical abnormalities in the CSF1515. Blennow K. Cerebrospinal fluid protein biomarkers for Alzheimer's disease. NeuroRx. 2004;1:213-25. and serum, and structural and functional brain changes.1616. Frisoni GB, Fox NC, Jack CR Jr., Scheltens P, Thompson PM. The clinical use of structural MRI in Alzheimer disease. Nat Rev Neurol. 2010;6:67-77. This framework serves as the basis for the search and ordering of biomarkers that can aid in the diagnosis of AD, the staging of progression of pathological processes, and, most importantly, the identification of patients at the earliest stages of the disease process, who would benefit most from therapies aimed at reducing the risk of progression to the clinical dementia stages of the disease.1717. Jack CR Jr., Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9:119-28.

The search and development of biological markers of AD pathogenesis

Translational research has been critical for the development of biomarker research in AD. Cumulative knowledge on the neurobiology and pathophysiology of the disease has yielded insights for the discovery of candidate markers of AD pathogenesis. Therefore, markers of intrinsic pathological processes that illustrate distinct phases of AD can be depicted in vivo and be used to support clinical diagnosis, especially at early stages, as well as to ascertain the biological effects of therapeutic approaches (disease modification).1818. Wagner JA. Biomarkers: principles, policies, and practice. Clin Pharmacol Ther. 2009;86:3-7. To have clinical utility, a good biomarker should reflect core pathological changes that pertain to the disease process, be validated by postmortem studies, and be sensitive to early changes in the disease process. If possible, the determination of such biomarkers should rely on non-invasive, simple to perform, and reliable methods, rendering them adequate for large-scale screenings.1919. Consensus report of the Working Group on: “Molecular and biochemical markers of Alzheimer's disease”. The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group. Neurobiol Aging. 1998;19:109-16. So far, no biomarkers tested for the diagnosis and prognosis of AD have achieved universal acceptance, nor fully met the proposed criteria for an ideal biomarker.

AD-related biomarkers can be summarized into three major categories, namely: a) molecular biomarkers that reflect core neuropathological changes in AD, e.g., evidence of significant accumulation of pathological amyloid-β species in the central nervous system (CNS), as shown by CSF analysis, or by in vivo molecular imaging with positron-emission tomography (PET); b) markers of downstream pathological changes triggered by core molecular changes, such as: evidence of neuronal injury, synaptic loss, and cytoskeletal damage (as shown by increased concentrations of total and phosphorylated Tau in the CSF); regional metabolism improved by effective connectivity, perfusional or structural changes affecting brain structures and detectable by neuroimaging methods such as structural magnetic resonance imaging (MRI) (e.g., evidence of medial temporal atrophy; decreased hippocampal or entorhinal cortex volume; rate of change in total brain or hippocampal volume; decreased regional gray- or white-matter volume in voxel-based morphometry [VBM] maps; abnormal pattern in diffusion tensor imaging [DTI]); or abnormal neurochemistry as shown by proton spectroscopy (+H-MRS); c) associated homeostatic changes detectable in peripheral fluids, such as markers of inflammation (interleukins, cytokines) and oxidative stress (isoprostanes), plasma Aβ40/Aβ42 ratio, platelet: amyloid precursor protein (APP) ratio, GSK3β activity, and other markers of synaptic damage or neurodegeneration.

Cerebrospinal fluid biomarkers

Given its intimate contact with the CNS, the CSF is a natural source of molecules related to intracerebral pathogenic processes, and has been extensively studied in AD.2020. Reiber H, Peter JB. Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci. 2001;184:101-22. Several potential diagnostic biomarkers were studied in AD, but the most consistent findings have been obtained with the measurement of CSF concentrations of β-amyloid42 (Aβ42), total Tau (T-Tau) and phosphorylated Tau (P-Tau).1515. Blennow K. Cerebrospinal fluid protein biomarkers for Alzheimer's disease. NeuroRx. 2004;1:213-25. These biomarkers reflect core neuropathological (and presumably pathophysiological) features of AD,2121. Wiltfang J, Lewczuk P, Riederer P, Grunblatt E, Hock C, Scheltens P, et al. Consensus paper of the WFSBP Task Force on Biological Markers of Dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia. World J Biol Psychiatry. 2005;6:69-84. and have been validated in postmortem studies.22. Buerger K, Ewers M, Pirttilä T, Zinkowski R, Alafuzoff I, Teipel SJ, et al. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain. 2006;129:3035-41. 23. Clark CM, Xie S, Chittams J, Ewbank D, Peskind E, Galasko D, et al. Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol. 2003;60:1696-702. 22-2424. Tapiola T, Alafuzoff I, Herukka SK, Parkkinen L, Hartikainen P, Soininen H, et al. Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol. 2009;66:382-9.

The typical pattern for these CSF biomarkers in AD patients is commonly referred to as the AD signature in the CSF, i.e., low concentrations of Aβ42 and high concentrations of T-Tau and P-Tau. These findings reflect, respectively, the sinking and deposition of Aβ42 in plaques (in detriment of its clearance through the CSF) and axonal dysfunction leading to neuronal degeneration. The latter marker is perhaps specifically associated with AD, given the central role of P-Tau in the formation of paired helical filaments (PHFs) and NFTs.2525. Blennow K, Hampel H. CSF markers for incipient Alzheimer's disease. Lancet Neurol. 2003;2:605-13. A substantial body of evidence supports that the identification of the AD signature in the CSF has good diagnostic accuracy to differentiate cases of incipient AD from controls, and to predict conversion to dementia in samples of patients diagnosed clinically with MCI.2626. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5:228-34. However, the sensitivity/specificity profile for distinguishing AD from other dementia syndromes is significantly lower,27. Parnetti L, Lanari A, Saggese E, Spaccatini C, Gallai V. Cerebrospinal fluid biochemical markers in early detection and in differential diagnosis of dementia disorders in routine clinical practice. Neurol Sci. 2003;24:199-200. 28. Sunderland T, Linker G, Mirza N, Putnam KT, Friedman DL, Kimmel LH, et al. Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA. 2003;289:2094-103. 27-2929. Corrêa JD, Starling D, Teixeira AL, Caramelli P, Silva TA. Chemokines in CSF of Alzheimer's disease patients. Arq Neuropsiquiatr. 2011;69:455-9. which calls into question the advantage of routine assessment of these biomarkers in the diagnostic workup of established dementia syndromes.

In the mid- and late 1990s, several studies attempted to define whether these biomarkers could help in the diagnosis of MCI. Patients with MCI had intermediate CSF biomarker levels as compared to healthy elderly subjects and patients with AD.3030. Maruyama M, Arai H, Sugita M, Tanji H, Higuchi M, Okamura N, et al. Cerebrospinal fluid amyloid beta(1-42) levels in the mild cognitive impairment stage of Alzheimer's disease. Exp Neurol. 2001;172:433-6. Large-scale longitudinal studies of MCI cohorts addressing the progression to AD presented consistent findings confirming that, in samples of patients with MCI, the presence of the AD signature in the CSF has good sensitivity (> 80%) to discriminate converters from non-converters and to differentiate such cases from other (non-AD) dementia outcomes.2626. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5:228-34.,3131. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009;302:385-93.,3232. Riemenschneider M, Lautenschlager N, Wagenpfeil S, Diehl J, Drzezga A, Kurz A. Cerebrospinal fluid tau and beta-amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment. Arch Neurol. 2002;59:1729-34. These data have been extensively replicated in different research settings worldwide,33. Arai H, Ishiguro K, Ohno H, Moriyama M, Itoh N, Okamura N, et al. CSF phosphorylated tau protein and mild cognitive impairment: a prospective study. Exp Neurol. 2000;166:201-3. 34. Forlenza OV, Diniz BS, Talib LL, Radanovic M, Yassuda MS, Ojopi EB, et al. Clinical and biological predictors of Alzheimer's disease in patients with amnestic mild cognitive impairment. Rev Bras Psiquiatr. 2010;32:216-22. 35. Hampel H, Teipel SJ, Fuchsberger T, Andreasen N, Wiltfang J, Otto M, et al. Value of CSF beta-amyloid1-42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment. Mol Psychiatry. 2004;9:705-10. 33-3636. Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, et al. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol. 2009;65:403-13. and confirmed by meta-analyses.3737. Diniz BS, Pinto Junior JA, Forlenza OV. Do CSF total tau, phosphorylated tau, and beta-amyloid 42 help to predict progression of mild cognitive impairment to Alzheimer's disease? A systematic review and meta-analysis of the literature. World J Biol Psychiatry. 2008;9:172-82.,3838. Mitchell AJ. CSF phosphorylated tau in the diagnosis and prognosis of mild cognitive impairment and Alzheimer's disease: a meta-analysis of 51 studies. J Neurol Neurosurg Psychiatry. 2009;80:966-75. A recent study reported that the CSF pathological signature could be identified in subjects with MCI between 5 to 10 years before the clinical diagnosis of dementia.3939. Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O. Cerebrospinal fluid levels of beta-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry. 2012;69:98-106.

The aforementioned CSF biomarkers were also investigated in patients with subjective memory complaints (SMC) but no evidence of objective cognitive decline. These studies suggest that the AD signature may help predict the incidence of memory deficits, i.e., amnestic MCI.4040. Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007;64:343-9.,4141. Visser PJ, Verhey F, Knol DL, Scheltens P, Wahlund LO, Freund-Levi Y, et al. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol. 2009;8:619-27. More recently, abnormalities in CSF biomarkers have been correlated with poorer performance in memory and attention tasks4242. Nordlund A, Rolstad S, Klang O, Lind K, Pedersen M, Blennow K, et al. Episodic memory and speed/attention deficits are associated with Alzheimer-typical CSF abnormalities in MCI. J Int Neuropsychol Soc. 2008;14:582-90. and with worse functional performance in the instrumental abilities of daily living,4343. Pereira FS, Yassuda MS, Oliveira AM, Diniz BS, Radanovic M, Talib LL, et al. Profiles of functional deficits in mild cognitive impairment and dementia: benefits from objective measurement. J Int Neuropsychol Soc. 2010;16:297-305. both in cognitively healthy subjects and in those with MCI. In addition, studies of healthy elderly subjects showed that lower CSF Aβ42 levels predicted the emergence of SMC up to 3 years of follow-up.4444. Stomrud E, Hansson O, Blennow K, Minthon L, Londos E. Cerebrospinal fluid biomarkers predict decline in subjective cognitive function over 3 years in healthy elderly. Dement Geriatr Cogn Disord. 2007;24:118-24.

These findings demonstrate that the CSF biomarker pattern observed in AD patients can be identified at early stages of the disease process, starting from prodromal and even pre-symptomatic stages. This pattern distinguishes with good accuracy MCI patients who will progress to dementia from healthy individuals and stable cases of MCI. It may also help to discriminate slow- from rapid-converting cases of MCI, although with lower accuracy,. Therefore, the measurement of AD-related biomarkers in the CSF may be a useful tool to improve the diagnostic accuracy and predictive value of clinical classification of patients according to the definition of MCI.

Notwithstanding, there are still obstacles that need to be overcome to enable reliable use of AD biomarkers in clinical practice. Although the quantitation of CSF concentrations of these biomarkers using enzyme-linked immunoassay (ELISA) or multiplex techniques (e.g., xMAP-Luminex) has low coefficients of intra-laboratory variability (below 10%), high inter-laboratory variation (20 to 30%) is a major obstacle to the comparison of data generated in different settings. Multiple sources of bias include pre-assay (i.e., lumbar puncture protocol, sample handling and aliquot storing prior to experimentation), intra-assay (different methods and protocols for the determination of the actual concentrations of biomarkers), and post-assay variations (e.g., definition of reference ranges for patients and controls to guide the interpretation of results).4545. Mattsson N, Blennow K, Zetterberg H. Inter-laboratory variation in cerebrospinal fluid biomarkers for Alzheimer's disease: united we stand, divided we fall. Clin Chem Lab Med. 2010;48:603-7. This situation is a major limitation to the establishment of multicenter cooperation. The establishment of protocols to be shared by all involved laboratories4646. Mattsson N, Andreasson U, Persson S, Arai H, Batish SD, Bernardini S, et al. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement. 2011;7:386-95 e6. and the recent launch of a multicenter quality control program with over 40 laboratories around the world will hopefully overcome these limitations in the near future.4747. Blennow K, Hampel H, Weiner M, Zetterberg H. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol. 2010;6:131-44.

Peripheral biomarkers

Despite encouraging findings from CSF biomarker research, poor accessibility to samples is a relative disadvantage of this procedure. Although the cumulative experience of expert groups reinforces the large safety window of this procedure, one must acknowledge the fact that lumbar puncture is still an invasive method and requires qualified, trained personnel to perform it. Furthermore, CSF collection may raise ethical concerns and risk-to-benefit issues. Although the information gained from analysis of CSF biomarkers seems to be relevant for diagnostic accuracy, it may be questioned on the basis of the lack of validated therapeutic strategies to prevent AD. Therefore, other sources of AD-related biomarkers need to be defined. Several candidate biomarkers have been studied in plasma and peripheral blood cells, particularly leukocytes and platelets.

Different species of the amyloid-beta peptide may be measured in plasma. In particular, concentrations of Aβ40 and Aβ42 (in addition to the Aβ42/40 ratio) have been extensively analyzed in clinical and epidemiological studies. A significant increase in plasma levels of Aβ40, along with a decrease in Aβ42 (and in the Aβ42/40 ratio), has been reported to predict cognitive decline in MCI patients and healthy elders.4848. Graff-Radford NR, Crook JE, Lucas J, Boeve BF, Knopman DS, Ivnik RJ, et al. Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol. 2007;64:354-62.,4949. Sundelöf J, Giedraitis V, Irizarry MC, Sundström J, Ingelsson E, Rönnemaa E, et al. Plasma beta amyloid and the risk of Alzheimer disease and dementia in elderly men: a prospective, population-based cohort study. Arch Neurol. 2008;65:256-63. Increments in plasma Aβ42 have also been reported to predict AD in these subjects.5050. Assini A, Cammarata S, Vitali A, Colucci M, Giliberto L, Borghi R, et al. Plasma levels of amyloid beta-protein 42 are increased in women with mild cognitive impairment. Neurology. 2004;63:828-31.,5151. Blasko I, Jellinger K, Kemmler G, Krampla W, Jungwirth S, Wichart I, et al. Conversion from cognitive health to mild cognitive impairment and Alzheimer's disease: prediction by plasma amyloid beta 42, medial temporal lobe atrophy and homocysteine. Neurobiol Aging. 2008;29:1-11. Many studies have not found significant differences in the concentrations of these biomarkers in samples of MCI converters.5252. Hansson O, Zetterberg H, Vanmechelen E, Vanderstichele H, Andreasson U, Londos E, et al. Evaluation of plasma Abeta(40) and Abeta(42) as predictors of conversion to Alzheimer's disease in patients with mild cognitive impairment. Neurobiol Aging. 2010;31:357-67.,5353. Lopez OL, Kuller LH, Mehta PD, Becker JT, Gach HM, Sweet RA, et al. Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study. Neurology. 2008;70:1664-71. Therefore, the current evidence suggests that measurement of plasma Aβ as a biomarker for AD is still controversial and lacks the consistency observed for CSF biomarkers.

Plasma markers related to inflammatory and neurotrophic cascades have also been addressed in studies with MCI and AD patients. Changes in inflammatory and neurotrophic cascades have been described in the pathogenesis of AD, and can be identified at the prodromal stages of the MCI-dementia continuum.5454. Diniz BS, Teixeira AL. Brain-derived neurotrophic factor and Alzheimer's disease: physiopathology and beyond. Neuromolecular Med. 2011;13:217-22.,5555. Teixeira AL, Barbosa IG, Diniz BS, Kummer A. Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function. Biomark Med. 2010;4:871-87. Although these homeostatic imbalances may be secondary to core pathological processes, measurement of these biomarkers may still be suitable to investigate risk of AD or to determine cumulative changes that are required for the expression of the dementia phenotype in addition to amyloid and Tau pathology.5656. Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S. New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res Rev. 2008;59:201-20.,5757. Mrak RE. Neuropathology and the neuroinflammation idea. J Alzheimers Dis. 2009;18:473-81. Studies have consistently reported elevated levels of pro-inflammatory cytokines in patients with AD and MCI.58. Forlenza OV, Diniz BS, Talib LL, Mendonça VA, Ojopi EB, Gattaz WF, et al. Increased serum IL-1beta level in Alzheimer's disease and mild cognitive impairment. Dement Geriatr Cogn Disord. 2009;28:507-12. 59. Tan ZS, Beiser AS, Vasan RS, Roubenoff R, Dinarello CA, Harris TB, et al. Inflammatory markers and the risk of Alzheimer disease: the Framingham study. Neurology. 2007;68:1902-8. 58-6060. Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2003;74:1200-5. Longitudinal studies have shown that higher levels of pro-inflammatory cytokines constitute independent and strong predictors of MCI-AD conversion.6161. Buchhave P, Zetterberg H, Blennow K, Minthon L, Janciauskiene S, Hansson O. Soluble TNF receptors are associated with Abeta metabolism and conversion to dementia in subjects with mild cognitive impairment. Neurobiol Aging. 2010;31:1877-84.,6262. Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonça VA, Gattaz WF, et al. Higher serum sTNFR1 level predicts conversion from mild cognitive impairment to Alzheimer's disease. J Alzheimers Dis. 2010;22:1305-11. Likewise, lack of neurotrophic support, as indicated by reduced concentrations of brain-derived neurotrophic factor (BDNF), has been demonstrated in patients with AD and MCI, and indicates a higher risk of progression from MCI to AD.63. Yasutake C, Kuroda K, Yanagawa T, Okamura T, Yoneda H. Serum BDNF, TNF-alpha and IL-1beta levels in dementia patients: comparison between Alzheimer's disease and vascular dementia. Eur Arch Psychiatry Clin Neurosci. 2006;256:402-6. 64. Forlenza OV, Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonça VA, et al. Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment. World J Biol Psychiatry. 2010;11:774-80. 63-6565. Hashimoto R, Hirata Y, Asada T, Yamashita F, Nemoto K, Mori T, et al. Effect of the brain-derived neurotrophic factor and the apolipoprotein E polymorphisms on disease progression in preclinical Alzheimer's disease. Genes Brain Behav. 2009;8:43-52. Nevertheless, these findings may be less specific, since significant changes in these cascades have also been observed in other neuropsychiatric and neurodegenerative conditions, such as major depression, bipolar disorder, schizophrenia, and Parkinson's disease.66. Diniz BS, Teixeira AL, Talib L, Gattaz WF, Forlenza OV. Interleukin-1beta serum levels is increased in antidepressant-free elderly depressed patients. Am J Geriatr Psychiatry. 2010;18:172-6. 67. Diniz BS, Teixeira AL, Talib LL, Mendonça VA, Gattaz WF, Forlenza OV. Serum brain-derived neurotrophic factor level is reduced in antidepressant-free patients with late-life depression. World J Biol Psychiatry. 2010;11:550-5. 68. Diniz BS, Teixeira AL, Talib LL, Mendonça VA, Gattaz WF, Forlenza OV. Increased soluble TNF receptor 2 in antidepressant-free patients with late-life depression. J Psychiatr Res. 2010;44:917-20. 69. Barbosa IG, Huguet RB, Mendonca VA, Sousa LP, Neves FS, Bauer ME, et al. Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder. Eur Arch Psychiatry Clin Neurosci. 2011;261:139-43. 70. Barbosa IG, Huguet RB, Mendonça VA, Neves FS, Reis HJ, Bauer ME, et al. Increased plasma levels of brain-derived neurotrophic factor in patients with long-term bipolar disorder. Neurosci Lett. 2010;475:95-8. 66-7171. Scalzo P, Kümmer A, Bretas TL, Cardoso F, Teixeira AL. Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson's disease. J Neurol. 2010;257:540-5.

Blood cells, namely leukocytes and platelets, may also be an important source of AD-related biomarkers, since they can provide insights on the systemic modulation of biological cascades that are supposedly altered in AD. For instance, platelets represent the most important source of circulating APP, and the regulatory loops of peripheral APP metabolism seem to parallel intracerebral homeostasis. The APP ratio is a promising peripheral biomarker that can be readily determined in platelets, addressing the proportion of 130kDA to 110kDa isoforms of the secreted, non-amyloidogenic metabolic product of APP released by secretase cleavage (sAPP). The APP ratio indirectly reflects the equilibrium between amyloidogenic and non-amyloidogenic APP processing. A reduction in APP ratio (indicative of reduced expression of 130kDa fragments, or increased expression of 110kDa sAPP) may reflect the predominant production of shorter (beta-cleaved) secreted products of APP.7272. Tang K, Hynan LS, Baskin F, Rosenberg RN. Platelet amyloid precursor protein processing: a bio-marker for Alzheimer's disease. J Neurol Sci. 2006;240:53-8. A reduction in APP ratio has been found in patients with early AD and MCI subjects in cross-sectional analyses7373. Padovani A, Borroni B, Colciaghi F, Pettenati C, Cottini E, Agosti C, et al. Abnormalities in the pattern of platelet amyloid precursor protein forms in patients with mild cognitive impairment and Alzheimer disease. Arch Neurol. 2002;59:71-5.,7474. Zainaghi IA, Forlenza OV, Gattaz WF. Abnormal APP processing in platelets of patients with Alzheimer's disease: correlations with membrane fluidity and cognitive decline. Psychopharmacology (Berl). 2007;192:547-53. and predicts the progression from MCI to AD.7575. Zainaghi IA, Talib LL, Diniz BS, Gattaz WF, Forlenza OV. Reduced platelet amyloid precursor protein ratio (APP ratio) predicts conversion from mild cognitive impairment to Alzheimer's disease. J Neural Transm. 2012;119:815-9. This finding still requires validation in larger samples and longitudinal studies.

Determination of the enzymatic activity of glycogen synthase kinase (GSK-3β) in distinct biological sources has also been suggested as a promising biomarker for AD. GSK-3β is the main Tau-kinase in neurons, being thus primarily involved in the regulation of the phosphorylation state of Tau. In addition, it has also been shown to participate in the regulation of APP processing.7676. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer's disease. J Neurochem. 2008;104:1433-9. Recent studies have shown a significant increase in GSK-3β activity in the leukocytes and platelets of patients with MCI and AD,7777. Hye A, Kerr F, Archer N, Foy C, Poppe M, Brown R, et al. Glycogen synthase kinase-3 is increased in white cells early in Alzheimer's disease. Neurosci Lett. 2005;373:1-4.,7878. Forlenza OV, Torres CA, Talib LL, de Paula VJ, Joaquim HP, Diniz BS, et al. Increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer's disease. J Psychiatr Res. 2011;45:220-4. thus pointing to its potential as a biomarker of early AD. Nonetheless, as is the case for APP ratio, data on GSK-3β activity as a candidate biomarker for AD are limited by the lack of specificity for AD, relative small sample sizes, the lack of longitudinal studies.7979. Diniz BS, Talib LL, Joaquim HP, de Paula VR, Gattaz WF, Forlenza OV. Platelet GSK3B activity in patients with late-life depression: marker of depressive episode severity and cognitive impairment? World J Biol Psychiatry. 2011;12:216-22.

Imaging biomarkers

The substantial development of neuroimaging techniques in the last decade has contributed decisively to the search for non-invasive methods to ascertain the pathological changes that evolve in the AD brain. These advances range from new protocols for the analysis of structural MRI (such as volumetric assessments of regions of interest and VBM based on statistical maps) to functional imaging based on PET, addressing metabolic changes and, more recently, in vivo intracerebral imaging of amyloid and Tau.

Structural neuroimaging

The main structural changes observed in AD are global cerebral volume loss, increased ventricular volumes, and more intense regional atrophy in the hippocampal formation and the entorhinal cortex. Topographic gray matter loss correlates with Braak stages and may be already present in patients with very mild AD.8080. Busatto GF, Diniz BS, Zanetti MV. Voxel-based morphometry in Alzheimer's disease. Expert Rev Neurother. 2008;8:1691-702.,8181. Kantarci K, Jack CR Jr. Neuroimaging in Alzheimer disease: an evidence-based review. Neuroimaging Clin N Am. 2003;13:197-209.

Individuals with MCI usually exhibit structural changes that are intermediate to those observed in AD and those seen in healthy controls. Those with MCI usually display mild, but significant, volume loss in specific brain regions, notably the hippocampal and parahippocampal structures, and decreased cortical thickness.82. Apostolova LG, Dinov ID, Dutton RA, Hayashi KM, Toga AW, Cummings JL, et al. 3D comparison of hippocampal atrophy in amnestic mild cognitive impairment and Alzheimer's disease. Brain. 2006;129:2867-73. 83. Seo SW, Im K, Lee JM, Kim YH, Kim ST, Kim SY, et al. Cortical thickness in single- versus multiple-domain amnestic mild cognitive impairment. Neuroimage. 2007;36:289-97. 82-8484. Singh V, Chertkow H, Lerch JP, Evans AC, Dorr AE, Kabani NJ. Spatial patterns of cortical thinning in mild cognitive impairment and Alzheimer's disease. Brain. 2006;129:2885-93. Longitudinal studies have shown that MCI-converter patients have more intense volume reductions in the hippocampal and parahippocampal structures, and, to a lesser extent, in the posterior cingulate cortex, middle and inferior temporal gyri, fusiform gyrus, posterior cingulate gyrus, precuneus, temporoparietal junction, and frontal cortex.85. Chételat G, Landeau B, Eustache F, Mézenge F, Viader F, de la Sayette V, et al. Using voxel-based morphometry to map the structural changes associated with rapid conversion in MCI: a longitudinal MRI study. Neuroimage. 2005;27:934-46. 86. Davatzikos C, Xu F, An Y, Fan Y, Resnick SM. Longitudinal progression of Alzheimer's-like patterns of atrophy in normal older adults: the SPARE-AD index. Brain. 2009;132:2026-35. 87. Tapiola T, Pennanen C, Tapiola M, Tervo S, Kivipelto M, Hänninen T, et al. MRI of hippocampus and entorhinal cortex in mild cognitive impairment: a follow-up study. Neurobiol Aging. 2008;29:31-8. 85-8888. Hämäläinen A, Tervo S, Grau-Olivares M, Niskanen E, Pennanen C, Huuskonen J, et al. Voxel-based morphometry to detect brain atrophy in progressive mild cognitive impairment. Neuroimage. 2007;37:1122-31. Another interesting finding from longitudinal studies is the accelerated gray matter loss in MCI converters as compared to MCI-stable subjects.8989. Ridha BH, Barnes J, Bartlett JW, Godbolt A, Pepple T, Rossor MN, et al. Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study. Lancet Neurol. 2006;5:828-34. A recent meta-analytical study showed a consistent finding of decreased left hippocampal volumes in converter vs. stable MCI patients.9090. Ferreira LK, Diniz BS, Forlenza OV, Busatto GF, Zanetti MV. Neurostructural predictors of Alzheimer's disease: a meta-analysis of VBM studies. Neurobiol Aging. 2011;32:1733-41. Altogether, these findings suggest that the characterization of regional volumetric changes in critical brain areas by structural neuroimaging may be a useful biomarker for the identification of subjects at increased risk of developing clinical AD. Of particular interest, the characterization of hippocampal and parahippocampal atrophy as well as acceleration of gray matter loss in longitudinal evaluations are important predictors of dementia outcome at early stages of AD.

Functional neuroimaging and in vivo molecular imaging (Aβ and Tau)

The main metabolic changes observed in the AD brain on FDG-PET and SPECT scans are global reductions, respectively, in cerebral metabolism and perfusion, which occur with greater intensity in the temporoparietal junction, temporal, parietal and frontal lobes, hippocampal formation, and posterior cingulate cortex.91. Mielke R, Pietrzyk U, Jacobs A, Fink GR, Ichimiya A, Kessler J, et al. HMPAO SPET and FDG PET in Alzheimer's disease and vascular dementia: comparison of perfusion and metabolic pattern. Eur J Nucl Med. 1994;21:1052-60. 92. Herholz K, Salmon E, Perani D, Baron JC, Holthoff V, Frolich L, et al. Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET. Neuroimage. 2002;17:302-16. 91-9393. Mosconi L, Perani D, Sorbi S, Herholz K, Nacmias B, Holthoff V, et al. MCI conversion to dementia and the APOE genotype: a prediction study with FDG-PET. Neurology. 2004;63:2332-40. As is the case for most methods of structural neuroimaging, patients with MCI show an intermediate pattern of changes between healthy elders and patients with AD.9494. Mosconi L, Tsui WH, Herholz K, Pupi A, Drzezga A, Lucignani G, et al. Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias. J Nucl Med. 2008;49:390-8.,9595. Nobili F, Salmaso D, Morbelli S, Girtler N, Piccardo A, Brugnolo A, et al. Principal component analysis of FDG PET in amnestic MCI. Eur J Nucl Med Mol Imaging. 2008;35:2191-202. Likewise, in prospective studies, MCI converters show a pattern of cerebral hypometabolism and/or hypoperfusion that is largely similar to that of patients with mild AD, particularly in the posterior cingulate cortex and the hippocampal regions.96. Chetelat G, Desgranges B, de la Sayette V, Viader F, Eustache F, Baron JC. Mild cognitive impairment: Can FDG-PET predict who is to rapidly convert to Alzheimer's disease? Neurology. 2003;60:1374-7. 97. de Leon MJ, Convit A, Wolf OT, Tarshish CY, DeSanti S, Rusinek H, et al. Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET). Proc Natl Acad Sci U S A. 2001;98:10966-71. 96-9898. Drzezga A, Grimmer T, Riemenschneider M, Lautenschlager N, Siebner H, Alexopoulus P, et al. Prediction of individual clinical outcome in MCI by means of genetic assessment and (18)F-FDG PET. J Nucl Med. 2005;46:1625-32.

The development of new techniques for in vivo visualization and quantitation of Aβ and Tau deposits within the brain is undoubtedly a major achievement in the field of AD biomarker research. The first compound used in humans was the Pittsburgh compound B (PiB),9999. Mathis CA, Wang Y, Holt DP, Huang GF, Debnath ML, Klunk WE. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J Med Chem. 2003;46:2740-54. which is a 11C-labeled compound with a high binding affinity for intracerebral Aβ in mature amyloid plaques.1414. Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306-19. Other compounds have subsequently been made available, such as the amyloid-binding compound 18F-BAY94-9172100100. Rowe CC, Ackerman U, Browne W, Mulligan R, Pike KL, O'Keefe G, et al. Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism. Lancet Neurol. 2008;7:129-35. and the dual, amyloid and Tau-binding compound FDDNP, which has the additional property of mapping the occurrence of NFTs and amyloid plaques within the brain.101101. Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, et al. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med. 2006;355:2652-63.

In patients with AD, there is an increased global cortical retention of PiB (and other compounds), especially in specific brain regions, such as the striatum, cingulate, temporal, and parietal frontal cortices.102102. Edison P, Archer HA, Hinz R, Hammers A, Pavese N, Tai YF, et al. Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study. Neurology. 2007;68:501-8. Studies with amyloid imaging have a very high sensitivity (over 90%) but their specificity is age-dependent, since there is increasing deposition of Aβ in the aging brain.103103. Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, et al. Imaging beta-amyloid burden in aging and dementia. Neurology. 2007;68:1718-25. Important studies have shown negative correlations between intracerebral amyloid content (as shown by PiB scans) and CSF concentrations of Aβ42 in patients with mild AD (CDR = 0.5 or CDR = 1) as compared with controls.104104. Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006;59:512-9. This finding has been recently replicated by the same group of investigators in a larger sample.105105. Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, et al. Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease. EMBO Mol Med. 2009;1:371-80.

As observed in other neuroimaging modalities, PiB retention rates are also increased in patients with amnestic MCI, though at a lower rate than observed in patients with AD. In most studies, PiB retention rates (global and regional) correlate with cognitive performance.106106. Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging. 2008;29:1456-65.,107107. Kemppainen NM, Aalto S, Wilson IA, Nagren K, Helin S, Bruck A, et al. PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment. Neurology. 2007;68:1603-6. A positive PiB scan predicts conversion from MCI to AD (55% of PiB-positive patients with MCI progressed to AD in 2 years, vs. 10% of PiB-negative patients).103103. Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, et al. Imaging beta-amyloid burden in aging and dementia. Neurology. 2007;68:1718-25. Interestingly, retention of PiB was also observed in elderly subjects without cognitive symptoms, but higher PiB retention at baseline correlated with worse cognitive performance and faster cognitive decline upon follow-up.108. Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008;65:1509-17. 109. Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, et al. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2009;106:6820-5. 110. Resnick SM, Sojkova J, Zhou Y, An Y, Ye W, Holt DP, et al. Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB. Neurology. 2010;74:807-15. 108-111111. Villemagne VL, Pike KE, Darby D, Maruff P, Savage G, Ng S, et al. Abeta deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer's disease. Neuropsychologia. 2008;46:1688-97. These studies also showed that despite higher PiB retention, some individuals did not have significant brain atrophy.112112. Josephs KA, Whitwell JL, Ahmed Z, Shiung MM, Weigand SD, Knopman DS, et al. Beta-amyloid burden is not associated with rates of brain atrophy. Ann Neurol. 2008;63:204-12. In addition, PiB-positive patients with MCI had a higher rate of conversion to AD than PiB-negative patients with MCI. In MCI converters, the higher the PiB retention rate, the faster the conversion to AD (within 1 year of follow-up).106106. Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging. 2008;29:1456-65.,113113. Okello A, Koivunen J, Edison P, Archer HA, Turkheimer FE, Nagren K, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology. 2009;73:754-60. Altogether, data from functional imaging also show that changes observed in AD patients can be found not only in patients with MCI, particularly in MCI converters, but also in elderly subjects without cognitive impairment at higher risk of developing dementia.

Temporal dynamics of AD biomarkers

The current most accepted hypothesis of AD pathophysiology posits that increased production or reduced clearance of Aβ42 is the initial event that leads to neuronal dysfunction and, ultimately, to the neurodegenerative features of AD.1212. Mattson MP. Pathways towards and away from Alzheimer's disease. Nature. 2004;430:631-9. Therefore, it is plausible to hypothesize that changes in biomarkers of cerebral Aβ42 would precede changes in other AD-related biomarkers. In fact, low CSF Aβ42 (< 500 pg/mL) correlates with reduced hippocampal volumes over 1 year of follow-up114114. Fjell AM, Walhovd KB, Fennema-Notestine C, McEvoy LK, Hagler DJ, Holland D, et al. CSF biomarkers in prediction of cerebral and clinical change in mild cognitive impairment and Alzheimer's disease. J Neurosci. 2010;30:2088-101. and is associated with cognitive decline over time in older adults who were cognitively normal at baseline, predicting cognitive deterioration.115115. Morris JC, Roe CM, Grant EA, Head D, Storandt M, Goate AM, et al. Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch Neurol. 2009;66:1469-75. In addition, brain deposits of amyloid as demonstrated by PiB scans were shown to be significantly correlated with CSF Tau and Tau/Aβ42 ratio, and increased CSF concentrations of Tau have been shown to be associated with reduced brain volumes in mild AD but not in cognitively normal elders.105105. Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, et al. Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease. EMBO Mol Med. 2009;1:371-80. Both increased PiB binding and diminished CSF levels of Aβ42 are influenced by increasing age and the presence of the APOE*E4 genotype.116116. Fagan AM, Younkin LH, Morris JC, Fryer JD, Cole TG, Younkin SG, et al. Differences in the Abeta40/Abeta42 ratio associated with cerebrospinal fluid lipoproteins as a function of apolipoprotein E genotype. Ann Neurol. 2000;48:201-10.,117117. Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol. 2010;67:122-31. Decreased Aβ42 and increased Tau levels in the CSF are also present in pre-symptomatic familial-AD mutation carriers and in individuals with strong, positive family histories of late-onset AD.118118. Kauwe JS, Jacquart S, Chakraverty S, Wang J, Mayo K, Fagan AM, et al. Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer's disease presenilin 1 mutation. Ann Neurol. 2007;61:446-53.

There seems to be a specific temporal trend in the evolution of AD-related biomarkers.119119. Caroli A, Frisoni GB, Alzheimer's disease neuroimaging I. The dynamics of Alzheimer's disease biomarkers in the Alzheimer's disease neuroimaging initiative cohort. Neurobiol Aging. 2010;31:1263-74. Amyloid-related biomarkers (CSF Aβ42 and in vivo Aβ42 imaging) become altered very early in the disease process, as demonstrated by the presence of NP in elderly subjects without cognitive decline (postmortem studies), the evidence that reductions in CSF Aβ42 precedes cognitive complaints and decline in healthy elderly subjects, and the evidence of high retention of in vivo Aβ42 markers in cognitively unimpaired elderly subjects with no significant brain structural changes. Changes in neurodegenerative-related biomarkers follow the changes observed in amyloid-related biomarkers, with changes in CSF Tau (total and phosphorylated) and in brain metabolism (as measured by FDG-PET) being the first to take place, followed by atrophy in the hippocampus and other brain regions. Hippocampal atrophy, despite occurring later in the temporal dynamics of AD biomarkers, has a closer relationship with the severity of memory deficits and with the progression from MCI to AD. Finally, the subject develops cognitive impairment that is severe enough to significantly impair activities of daily living, warranting the clinical diagnosis of AD.1717. Jack CR Jr., Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9:119-28.

Nonetheless, given that changes in AD-related biomarkers may begin decades prior to the first dementia symptoms, long-term longitudinal studies are needed to depict the full pathologic cascades of events that lead to dementia.120120. Jack CR Jr., Lowe VJ, Weigand SD, Wiste HJ, Senjem ML, Knopman DS, et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain. 2009;132:1355-65. In a recent study, Bateman et al.121121. Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012;367:795-804. addressed this issue by estimating the temporal pattern of changes in AD-related biomarkers in carriers of dominantly inherited early-onset AD as a function of parental age of onset of dementia. They showed that changes in CSF Aβ concentrations appear to decline around 25 years prior to the expected date of dementia onset. This is followed by increased Aβ deposition, as assessed by PiB-PET imaging, increased CSF Tau concentration and brain atrophy 15 years before clinical dementia. Finally, reduced brain metabolism and mild episodic memory impairment take place 10 years before expected symptom onset and global cognitive impairment starts 5 years before expected symptom onset in AD mutation carriers.

It is important to note that the progression of changes in distinct AD biomarkers may be nonlinear and have significant overlap between each other.1717. Jack CR Jr., Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9:119-28. These aspects render the presentation of biomarker changes in individual patients heterogeneous. In addition, the pattern of progression of these biomarkers (and the emergence of significant clinical symptoms) might be influenced by other factors, such as alterations in neurotrophic, inflammatory, and oxidative stress cascades and genetic and epigenetic alterations, at any stage of disease progression.122. Cunningham C, Campion S, Lunnon K, Murray CL, Woods JF, Deacon RM, et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry. 2009;65:304-12. 123. Swerdlow RH. Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? Neurobiol Aging. 2007;28:1465-80. 122-124124. Swerdlow RH, Burns JM, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis. J Alzheimers Dis. 2010;20:S265-79. Thus, several factors beyond changes in biomarkers at specific disease stages alone have a significant influence on the relationship between biomarker patterns, disease progression, and clinical phenomena in AD.

Redefining AD

The extent to which available AD biomarkers (and those to be presented in the future) will represent definitive indications of the presence of disease in the absence of clinical symptoms is an important issue to be discussed. The revised NINCDS-ADRDA diagnostic criteria for AD proposed by Dubois et al.125125. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6:734-46. anticipate the etiological diagnosis in the presence of evidence of episodic memory impairment plus one or more supportive features provided by validated biomarkers. This is a requirement for the next generation of research into AD, particularly with respect to the selection of patient samples for clinical trials.126126. Hampel H, Wilcock G, Andrieu S, Aisen P, Blennow K, Broich K, et al. Biomarkers for Alzheimer's disease therapeutic trials. Prog Neurobiol. 2011;95:579-93.

A recent working group from the U.S. National Institute on Aging (NIA) and the Alzheimer's Association proposed new diagnostic criteria for AD and its prodromal and preclinical stages. These criteria incorporate the assessment of AD-related biomarkers at all diagnostic levels, either to confirm the diagnosis of dementia in AD or to provide information on the underlying pathophysiologic process and increase the degree of certainty of the diagnosis in the prodromal and preclinical stages of AD.5. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:270-9. 6. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:280-92. 5-77. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Jr., Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:263-9. Three levels of certainty of the presence of AD pathology have been defined for suspected cases, namely: dementia probably, possibly, or unlikely due to AD. Within these categories, three levels of evidence were considered: a) positive biomarker possibility due to AD etiology; b) identification by PET of amyloid-β deposition in brain tissues, corroborated by Aβ42 changes in CSF; and c) evidence of neuronal injury indicated by disturbances of Tau in CSF, as well as by FDG-PET and MRI changes.5. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:270-9. 6. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:280-92. 5-77. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Jr., Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:263-9.

There is a high probability of diagnosis of AD (i.e., probable AD) when the core clinical features of dementia are supported by persistent and progressive decline of episodic memory, with amnestic syndrome being the most common cognitive manifestation. Cognitive decline is accompanied by impairment in activities of daily living. Even in early dementia, neuropsychiatric symptoms can emerge and may be considered. In addition, diagnosis of probable AD is highly likely when pathophysiological biomarkers of AD, such as brain amyloid-β deposition evidenced by PET, reduced concentrations of Aβ42 peptide in CSF, occurrence of neuronal injury indicated by increased phosphorylated Tau in CSF, reduction of brain metabolism on FDG-PET, and brain atrophy documented by MRI are present. Diagnosis of possible AD comprises an atypical clinical course of dementia with an etiologically mixed presentation characterized by unavailable, conflicting or indeterminate amyloid-β biomarkers, and markers of neuronal injury. Concomitant cerebral disease or symptoms and signs suggesting other neuropsychiatric disorders, as well as intake of medications with an unfavorable impact on cognition, may create uncertainty as to a more precise and reliable diagnosis. Dementia unlikely due to AD should be considered when the clinical course provides sufficient support for another condition requiring distinct diagnostic approaches, or when additional investigation is negative for biomarkers indicative of brain amyloid-β deposition, neuronal injury, and brain atrophy.

Using the same approach, biomarker information has also been incorporated in the diagnostic workup of MCI due to AD.5. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:270-9. 6. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:280-92. 5-77. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Jr., Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:263-9. The probability that clinically defined MCI be in fact considered a case of pre-dementia AD will be high in the presence of core AD biomarkers, such as evidence of intracerebral accumulation of amyloid-β (as identified by molecular imaging with PET), reduced CSF concentrations of Aβ42, increased phosphorylated Tau in CSF, and brain atrophy as shown by MRI scans. Conversely, the diagnostic certainty of MCI due to AD is lower when investigation of these biomarkers is not available or provides indeterminate, conflicting or negative results. Longitudinal and periodic assessments could improve diagnostic accuracy.

The characterization of preclinical AD5. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:270-9. 6. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:280-92. 5-77. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Jr., Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:263-9. is hindered by several important challenges, such as the lack of definitive knowledge concerning specific roles of amyloid-β species as etiological agents of sporadic, late-onset disease. Moreover, disturbances of this protein can be associated with other pathophysiological processes. To date, the impact of brain amyloid-β deposition on neurodegenerative mechanisms remains to be elucidated. Ethical and clinical aspects are another important question for discussion. Nevertheless, biomarkers should also be incorporated in preclinical diagnosis of AD because of the prolonged nature of the preclinical phase, which could represent a crucial opportunity to change the disease course. If investigations of biomarkers reveal cerebral amyloidosis, neuronal injury, and subtle cognitive, functional or behavioral decline, the possibility of preclinical AD is high. This possibility is lower when biomarkers are uninformative or conflicting.

There are several challenges to the widespread application of biomarkers for the diagnosis of AD in clinical practice. To date, there is no consensus about the best biomarker combination and when to start the diagnostic assessment. Furthermore, standardized laboratory methods and well-validated, population-based, reference values for discriminating pathological vs. non-pathological biomarker patterns, which are mandatory to their implementation in clinical practice, are still unavailable.4646. Mattsson N, Andreasson U, Persson S, Arai H, Batish SD, Bernardini S, et al. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement. 2011;7:386-95 e6.,127127. Lewczuk P, Beck G, Ganslandt O, Esselmann H, Deisenhammer F, Regeniter A, et al. International quality control survey of neurochemical dementia diagnostics. Neurosci Lett. 2006;409:1-4. Finally, there are important clinical and ethical implications of the identification (or misidentification) of cases in the prodromal and preclinical stages of the disease in view of the absence of approved or well-established treatments to prevent or slow the progression of AD to its full-blown dementia stage.

Biomarkers and impact on treatment

The search for treatments with disease-preventing or modifying properties is the Holy Grail of AD research. Despite great efforts toward the achievement of this goal, either with well-established drugs for the treatment of AD (e.g., cholinesterase inhibitors)128. Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, et al. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurol. 2007;6:501-12. 129. Winblad B, Gauthier S, Scinto L, Feldman H, Wilcock GK, Truyen L, et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology. 2008;70:2024-35. 130. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379-88. 128-131131. Diniz BS, Pinto JA Jr., Gonzaga ML, Guimaraes FM, Gattaz WF, Forlenza OV. To treat or not to treat? A meta-analysis of the use of cholinesterase inhibitors in mild cognitive impairment for delaying progression to Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci. 2009;259:248-56. or with newly developed agents (e.g., amyloid-β aggregation inhibitors, gamma-secretase modulators, active and passive immunization),132132. Citron M. Alzheimer's disease: strategies for disease modification. Nat Rev Drug Discov. 2010;9:387-98. interventions tested thus far have demonstrated little or no clinical benefit in the prevention of progression from MCI to AD.133. Aisen PS, Saumier D, Briand R, Laurin J, Gervais F, Tremblay P, et al. A Phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease. Neurology. 2006;67:1757-63. 134. Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011;198:351-6. 135. Gómez-Isla T, Blesa R, Boada M, Clarimón J, Del Ser T, Domenech G, et al. A randomized, double-blind, placebo controlled-trial of triflusal in mild cognitive impairment: the TRIMCI study. Alzheimer Dis Assoc Disord. 2008;22:21-9. 136. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, et al. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008;372:216-23. 133-137137. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061-70.

Therapeutic strategies for patients with AD tend to be tailored to the clinical stage of the disease, underlying mechanisms of disease, and putative clinical and biological markers.133. Aisen PS, Saumier D, Briand R, Laurin J, Gervais F, Tremblay P, et al. A Phase II study targeting amyloid-beta with 3APS in mild-to-moderate Alzheimer disease. Neurology. 2006;67:1757-63. 134. Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011;198:351-6. 135. Gómez-Isla T, Blesa R, Boada M, Clarimón J, Del Ser T, Domenech G, et al. A randomized, double-blind, placebo controlled-trial of triflusal in mild cognitive impairment: the TRIMCI study. Alzheimer Dis Assoc Disord. 2008;22:21-9. 136. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, et al. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008;372:216-23. 133-137137. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061-70. The first phase of the disease process should be considered as the preclinical stage of AD, which probably occurs decades before the onset of symptoms. Although patients have no clinical manifestations at this stage, they exhibit amyloid-β accumulation within the brain, as demonstrated by molecular neuroimaging with PET, and autosomal dominant mutation involving genetic components affecting the APP or presenilin (PS) genes (PS1 and PS2). Potential therapeutic strategies at this stage will comprise a broad intervention spectrum, including the well-established strategy of cognitive reserve improvement by complex intellectual stimulation, appropriate lifestyle modifications such as regular physical exercise, adequate nutrition, and stress reduction, reduction of risk factors for cardiovascular diseases, and management of comorbidities. Despite insufficient evidence, anti-amyloid therapies are forthcoming, based on anti-Aβ immunotherapy, modulation of beta- and gamma-secretase, antifibrillization agents, and chelators. Several drugs have been designed to interrupt potential therapeutic targets along the disease course. These outcomes are expected to be achieved in the prodromal clinical stage as well.

The prodromal stage of AD encompasses features of the disease process that are detectable at its pre-dementia phases. Diagnosis in the prodromal stage should capture the earliest clinical manifestations before the occurrence of functional impairment severe enough to be consistent with the diagnosis of dementia. These clinical markers include episodic memory impairment consistent with amnestic MCI. Specific biomarkers can support diagnosis of prodromal AD, including reduced concentrations of Aβ42 in the CSF and molecular imaging with PET showing amyloid-β deposition in brain tissues. The presence of an autosomal dominant mutation involving specific genes such as APP and PS1 or 2 could reinforce the underlying AD pathology. Another way to understand the prodromal stage of AD is via neurodegenerative processes associated with Tau-related pathology, which is characterized by elevated concentrations of phosphorylated Tau in CSF, medial temporal lobe atrophy on MRI, and diminished brain metabolism on FDG-PET. Pharmacological intervention approaches targeting this stage are also forthcoming, and should encompass neuroprotective strategies (antioxidants and anti-inflammatory drugs) and neurorestorative agents (stem cells, BDNF, and nerve growth factor). Tau-related therapies involving pharmacological interventions with GSK inhibitors and lithium134134. Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011;198:351-6. could constitute promising strategies. Clinically, patients tend to exhibit multiple-domain amnestic MCI with subtle impairment of episodic memory and other cognitive functions, but no impairment in functional activities. A healthy lifestyle including appropriate nutrition, regular aerobic exercise, psychosocial engagement, and cognitive stimulation remains an important resource for improving brain and cognitive reserve, and contributes to delaying disease progression.

The clinical dementia stage is markedly characterized by the occurrence of NP and NFT in brain tissues. Neuropathology becomes strongly evident with reduced Aβ42 and elevated phosphorylated Tau in CSF; significant atrophy, mainly in temporo-parietal regions, on MRI; strong amyloid-β uptake on molecular imaging with PiB-PET; and hypometabolism on FDG-PET. Clinically, patients present significant decline of episodic memory and other cognitive functions, which cause decline of functional activities, as well as behavioral disturbances. Treatment remains with anti-dementia drugs (cholinesterase inhibitors, memantine), cognitive training, functional rehabilitation as far as possible, and psychoeducation for caregivers.

The adequate selection of patients that would benefit most from these interventions is a major challenge in clinical trial design, and poor patient selection is a common explanation for negative results.138138. Visser PJ, Scheltens P, Verhey FR. Do MCI criteria in drug trials accurately identify subjects with predementia Alzheimer's disease? J Neurol Neurosurg Psychiatry. 2005;76:1348-54. Most trials selected patients based solely on clinical data or the diagnosis of MCI. As reviewed above, this strategy yields a highly heterogeneous sample that decreases study power to identify the potential benefits of interventions. When included in trial designs, biomarkers are usually evaluated for secondary outcome analysis, as proof of concept of drug mechanism of action, or to stratify the sample in secondary analyses. In opposition to this secondary role, biomarkers could be used as primary inclusion criteria, along with clinical diagnosis, in clinical trials. This strategy would enable several methodological advances, as it allows the selection of more homogeneous study samples, consequently increasing the power to detect clinically significant benefits of interventions with disease-modifying properties. Nonetheless, to date, no large, published clinical trial that included biomarkers as criteria for patient inclusion.139139. Vellas B, Andrieu S, Sampaio C, Coley N, Wilcock G, European Task Force G. Endpoints for trials in Alzheimer's disease: a European task force consensus. Lancet Neurol. 2008;7:436-50.,140140. Vellas B, Andrieu S, Sampaio C, Wilcock G, European Task Force g. Disease-modifying trials in Alzheimer's disease: a European task force consensus. Lancet Neurol. 2007;6:56-62.

Conclusion

Knowledge about the pre-dementia stages of AD has progressed substantially in the last decade. AD has a long preclinical phase that can last 10 to 15 years, during which time amyloid plaques accumulate within the brain, but symptoms are absent or minimal and indistinguishable from the cognitive changes that occur in normal aging or in the prodromal phases of other neuropsychiatric conditions that are prevalent in this age group. Although patients with MCI are still a heterogeneous group, MCI is not a benign entity, which renders the precise, early diagnosis of dementing diseases essential to guide clinical and therapeutic decisions. Major developments in the understanding of the early pathophysiological features of AD have allowed the development of biomarkers that could identify such changes in different biological substrates. These clinical-biological insights led to identification of the AD signature in the CSF, which is a very consistent finding. Nevertheless, these developments did not translate into immediate improvement of clinical strategies for the early diagnosis of AD. Urgent needs include definition of the clinical validity and reliability of a panel of biomarkers; the use of such an instrument to detect AD at initial, preclinical stages; testing of this model in proof-of-concept trials with disease-modifying compounds; and, finally, design of AD prevention trials. Major challenges to be faced in the coming years are the integration of developments in preclinical (experimental) and clinical research to enable development of widely available tools for the early diagnosis of AD and selection of patients that would benefit most from therapeutic interventions. This, in turn, would allow a more personalized approach to patient care, improving therapeutic effectiveness and quality of life.

Acknowledgments

This work was supported by grants from the Associação Beneficiente Alzira Denise Hertzog da Silva (ABADHS) and from Fundação de Amparo è Pesquisa do Estado de São Paulo (FAPESP) (projects no. 02/12633-7 and 2009/52825-8).

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Publication Dates

  • Publication in this collection
    Jul-Sep 2013

History

  • Received
    8 Jan 2012
  • Accepted
    8 Sept 2012
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