Skip to main content Accessibility help

Developing new treatments for Alzheimer's disease: the who, what, when, and how of biomarker-guided therapies

  • Constantine G. Lyketsos (a1), Christine A. Szekely (a2), Michelle M. Mielke (a3), Paul B. Rosenberg (a3) and Peter P. Zandi (a4)...


This synthetic review presents an approach to the use of biomarkers for the development of new treatments for Alzheimer's disease (AD). After reviewing the process of translation as applied to AD, the paper provides a general update on what is known about the biology of the disease, and highlights currently available treatments. This is followed by a discussion of future drug development for AD emphasizing the roles that biomarkers are likely to play in this process: (1) define patients who are going to progress rapidly for the purpose of trial enrichment; (2) differentiate disease and therapeutically relevant AD subtypes; (3) assess the potential activity of specific therapies in vivo or ex vivo; and (4) measure the underlying disease state, so as to (a) detect disease and assess drug response in asymptomatic patients, (b) serve as a secondary outcome measure in clinical trials of symptomatic patients, and (c) decide if further development of a treatment should be stopped if not likely to be effective. Several examples are used to illustrate each biomarker utility in the AD context.


Corresponding author

Correspondence should be addressed to: Constantine G. Lyketsos, MD, MHS, The Elizabeth Plank Althouse Professor, Chair, Department of Psychiatry, Johns Hopkins Bayview, 5300 Alpha Commons Drive, 4th floor, Baltimore, Maryland, 21224, U.S.A. Phone: +1 410 550 0062; Fax: +1 410 550 1407. Email:


Hide All
Akiyama, H. et al. (2000). Inflammation and Alzheimer's disease. Neurobiology of Aging, 21, 383421.
Alberts, M. J. et al. (1995). ApoE genotype and survival from intracerebral haemorrhage. Lancet, 346, 575.
Banati, R. B. (2003). Neuropathological imaging: in vivo detection of glial activation as a measure of disease and adaptive change in the brain. British Medical Bulletin, 65, 121131.
Bard, F. et al. (2000). Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Medicine, 6, 916919.
Bennett, D. A., Schneider, J. A., Bienias, J. L., Evans, D. A. and Wilson, R. S. (2005). Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions. Neurology, 64, 834841.
Black, S. E. et al. (2005). A placebo-controlled, double-blind trial of the selective Abeta42-lowering agent Flurizan in patients with mild to moderate Alzheimer's disease: efficacy, safety, and follow-on results. Program No. 585.6. Society for Neuroscience Abstracts.
Blacker, D. et al. (1997). ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative. Neurology, 48, 139147.
Brookmeyer, R. and Gray, S. (2000). Methods for projecting the incidence and prevalence of chronic diseases in aging populations: application to Alzheimer's disease. Statistics in Medicine, 19, 14811493.
Brookmeyer, R., Gray, S. and Kawas, C. (1998). Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. American Journal of Public Health, 88, 13371342.
Brookmeyer, R., Corrada, M. M., Curriero, F. C. and Kawas, C. (2002). Survival following a diagnosis of Alzheimer disease. Archives of Neurology, 59, 17641767.
Cagnin, A. et al. (2001). In-vivo measurement of activated microglia in dementia. Lancet, 358, 461467.
Carroll, K. A. L., Rosenberg, P. B., Lyketsos, C. and Kaplin, A. (2007). IL-6 Release by Peripheral Blood Mononuclear Cells as a Potential Biomarker for Alzheimer's Disease. Paper presented at the American Association of Geriatric Psychiatry annual meeting, New Orleans LA.
Caselli, R. J. et al. (2004). Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology, 62, 19901995.
Crowe, M., Andel, R., Pedersen, N. L., Johansson, B. and Gatz, M. (2003). Does participation in leisure activities lead to reduced risk of Alzheimer's disease? A prospective study of Swedish twins. Journal of Gerontology Series B, Psychological Sciences and Social Sciences, 58, 249255.
de Leon, M. J. et al. (2004). MRI and CSF studies in the early diagnosis of Alzheimer's disease. Journal of Internal Medicine, 256, 205223.
de Leon, M. J. et al. (2006). Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment. Neurobiology of Aging, 27, 394401.
Eikelenboom, P. and Van Gool, W. A. (2004). Neuroinflammatory perspectives on the two faces of Alzheimer's disease. Journal of Neural Transmission, 111, 281294.
Eriksen, J. L. et al. (2003). NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. Journal of Clinical Investigation, 112, 440449.
Evans, D. A. et al. (1997)). Education and other measures of socioeconomic status and risk of incident Alzheimer disease in a defined population of older persons. Archives of Neurology, 54, 13991405.
Ferri, C. P. et al. (2005). Global prevalence of dementia: a Delphi consensus study. Lancet, 366, 21122117.
Fitzpatrick, A. L., Kuller, L. H., Lopez, O. L., Kawas, C. H. and Jagust, W. (2005). Survival following dementia onset: Alzheimer's disease and vascular dementia. Journal of Neurological Science, 229–230, 43–49.
Folstein, M. F., Folstein, S. E. and McHugh, P. R. (1975). “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189198.
Fox, N. C. et al. (2005). Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology, 64, 15631572.
Fritsch, T., Smyth, K. A., Debanne, S. M., Petot, G. J. and Friedland, R. P. (2005). Participation in novelty-seeking leisure activities and Alzheimer's disease. Journal of Geriatric Psychiatry and Neurology, 18, 134141.
Gao, S., Hendrie, H. C., Hall, K. S. and Hui, S. (1998). The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis. Archives of General Psychiatry, 55, 809815.
Gauthier, S. et al. (2006). Mild cognitive impairment. Lancet, 367, 12621270.
Gilman, S. et al. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64, 15531562.
Gitter, B. D. et al. (2004)). Stereoselective inhibition of amyloid beta peptide secretion by LY450139 dihydrate, a novel functional gamma secretase inhibitor. Neurobiology of Aging, 25, S571.
Gleason, C. E. et al. (2001). Effects of raloxifene on verbal memory in women with Alzheimer's disease. Program No. 546.17. Society for Neuroscience Abstracts.
Green, R. C. et al. (2003). Depression as a risk factor for Alzheimer disease: the MIRAGE Study. Archives of Neurology, 60, 753759.
Hendrie, H. C. (1998). Epidemiology of dementia and Alzheimer's disease. American Journal of Geriatric Psychiatry, 6, S318.
Honig, L. S. et al. (2003). Stroke and the risk of Alzheimer disease. Archives of Neurology, 60, 17071712.
Horsburgh, K., McCarron, M. O., White, F. and Nicoll, J. A. (2000). The role of apolipoprotein E in Alzheimer's disease, acute brain injury and cerebrovascular disease: evidence of common mechanisms and utility of animal models. Neurobiology of Aging, 21, 245255.
in ‘t Veld, B. A. et al. (2001). Nonsteroidal anti-inflammatory drugs and the risk of Alzheimer's disease. New England Journal of Medicine, 345, 1515–21.
JackC. R., Jr. C. R., Jr. et al. (2003). MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD. Neurology, 60, 253260.
Karp, A., Kareholt, I., Qiu, C., Bellander, T., Winblad, B. and Fratiglioni, L. (2004). Relation of education and occupation-based socioeconomic status to incident Alzheimer's disease. American Journal of Epidemiology, 159, 175183.
Khachaturian, A. S., Corcoran, C. D., Mayer, L. S., Zandi, P. P. and Breitner, J. C. (2004). Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: the Cache County Study. Archives of General Psychiatry, 61, 518524.
Klunk, W. E. et al. (2004). Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Annals of Neurology, 55, 306319.
Leoni, V., Masterman, T., Patel, P., Meaney, S., Diczfalusy, U. and Bjorkhem, I. (2003). Side chain oxidized oxysterols in cerebrospinal fluid and the integrity of blood-brain and blood-cerebrospinal fluid barriers. Journal of Lipid Research, 44, 793799.
Luchsinger, J. A. and Mayeux, R. (2004). Cardiovascular risk factors and Alzheimer's disease. Current Atherosclerosis Reports, 6, 261266.
Lutjohann, D. and von Bergmann, K. (2003). 24S-hydroxycholesterol: a marker of brain cholesterol metabolism. Pharmacopsychiatry, 36 (Suppl.2), S102S106.
Lyketsos, C. G. et al. . (2006). Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia due to Alzheimer's disease. American Journal of Geriatric Psychiatry, 14, 561572.
May, P. C., Yang, Z., Li, W., Hyslop, P. A., Siemers, E. R. and Boggs, L. N. (2004). Multi-compartmental pharmaco-dynamic assessment of the functional gamma-secretase inhibitor LY450139 dihydrate in PDAPP transgenic mice and non-transgenic mice. Neurobiology of Aging, 25, S65.
McGeer, E. G. and McGeer, P. L. (2003). Inflammatory processes in Alzheimer's disease. Progress in Neuropsychopharmacology and Biological Psychiatry, 27, 741749.
Meyer, M. R. et al. (1998). APOE genotype predicts when – not whether – one is predisposed to develop Alzheimer disease. Nature Genetics, 19, 321322.
Mielke, M. M. et al. (2006). Low serum potassium in mid life associated with decreased cerebrospinal fluid Abeta42 in late life. Alzheimer Disease and Associated Disorders, 20, 3036.
Mielke, M. M., Haughy, N., Bandaru, V. V. R., Carlson, M. C., Rabins, P. V. and Lyketsos, C. (2007a). Development of blood-based lipid biomarkers for Alzheimer's disease prevention. Paper presented at the American Association for Geriatric Psychiatry annual meeting, New Orleans LA.
Mielke, M. M., Haughy, N., Bandaru, V. V. R., Rabins, P. V., Lyketsos, C. G. and Carlson, M. C. (2007b). Serum sphingomyelins and ceramides predict development of memory impairment in a population-based longitudinal study. Paper presented at the International College of Geriatric Psychoneuropharmacology (ICGP) conference, San Diego CA.
Mielke, M. M. et al. (2007c). Vascular factors predict rate of progression in Alzheimer disease. Neurology, 69, 1850–1858.
Mielke, M. M. et al. (2008). Regionally specific diffusion tensor imaging measures in Alzheimer's disease, MCI, and controls. Paper presented at the International Conference on Prevention of Dementia, Washington DC.
Montine, T. J., Montine, K. S., McMahan, W., Markesbery, W. R., Quinn, J. F. and Morrow, J. D. (2005). F2-isoprostanes in Alzheimer and other neurodegenerative diseases. Antioxidants and Redox Signaling, 7, 269275.
Moreira, P. I. et al. (2005). Oxidative stress: the old enemy in Alzheimer's disease pathophysiology. Current Alzheimer Research, 2, 403408.
Morris, M. C. et al. (2002). Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA, 287, 32303237.
Mortimer, J. A., Borenstein, A. R., Gosche, K. M. and Snowdon, D. A. (2005). Very early detection of Alzheimer neuropathology and the role of brain reserve in modifying its clinical expression. Journal of Geriatric Psychiatry and Neurology, 18, 218223.
Nakada, T., Matsuzawa, H., Igarashi, H., Fujii, Y. and Kwee, I. L. (2008). In vivo visualization of senile plaque like pathology in Alzheimer's disease patients by MR microscopy on a 7T system. Journal of Neuroimaging, doi:10.1111/j.1552-6569.2007.00179.x.
Nemetz, P. N. et al. (1999). Traumatic brain injury and time to onset of Alzheimer's disease: a population-based study. American Journal of Epidemiology, 149, 3240.
NIH Office of Science Policy Analysis (2006). Alzheimer's Disease and Other Dementias: Summary of Methods and Data for Estimates of Costs of Illness. Accessed at Last accessed 17 July 2006.
Orgogozo, J. M. et al. (2003). Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology, 61, 4654.
Panza, F. et al. (2004). Mediterranean diet and cognitive decline. Public Health Nutrition, 7, 959963.
Petersen, R. C. et al. (2005). Vitamin E and donepezil for the treatment of mild cognitive impairment. New England Journal of Medicine, 352, 23792388.
Petersen, R. C. et al. (2006). Neuropathologic features of amnestic mild cognitive impairment. Archives of Neurology, 63, 665672.
Podewils, L. J. et al. (2005). Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. American Journal of Epidemiology, 161, 639651.
Pratico, D. et al. (1998). IPF2alpha-I: an index of lipid peroxidation in humans. Proceedings of the National Academy of Sciences of the United States of America, 95, 34493454.
Price, D. L. and Sisodia, S. S. (1994). Cellular and molecular biology of Alzheimer's disease and animal models. Annual Review of Medicine, 45, 435446.
Price, J. C. et al. (2005). Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B. Journal of Cerebral Blood Flow and Metabolism, 25, 15281547.
Profenno, L. A., Jakimovich, L., Holt, C. J., Porsteinsson, A. and Tariot, P. N. (2005). A randomized, double-blind, placebo-controlled pilot trial of safety and tolerability of two doses of divalproex sodium in outpatients with probable Alzheimer's disease. Current Alzheimer Research, 2, 553558.
Rabins, P. V., Lyketsos, C. G. and Steele, C. D. (2006). Practical Dementia Care. New York: Oxford Press.
Reiman, E. M. et al. (1996). Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. New England Journal of Medicine, 334, 752758.
Rogers, J. et al. (1993). Clinical trial of indomethacin in Alzheimer's disease. Neurology, 43, 16091611.
Rosen, W. G., Mohs, R. C. and Davis, K. L. (1984). A new rating scale for Alzheimer's disease. American Journal of Psychiatry, 141, 13561364.
Rosenberg, P. B. (2005a). Clinical aspects of inflammation in Alzheimer's disease. International Review of Psychiatry, 17, 503514.
Rosenberg, R. N. (2005b). Translational research on the way to effective therapy for Alzheimer disease. Archives of General Psychiatry, 62, 11861192.
Rosenberg, R. N. (2006). Time will be of the essence in treating Alzheimer disease. JAMA, 296, 327329.
Rosenberg, P. B. (2007). Inflammatory biomarkers for treatment development in Alzheimer's disease. Paper presented at American College of Neuropsychopharmacology annual meeting, Boca Raton, FL.
Rosenberg, P. B., Mielke, M. M., Xue, Q. L. and Carlson, M. C. (2007). Depression and MCI in WHAS-II. Paper presented at the International Conference on Prevention of Dementia, Washington DC.
Rovio, S. et al. (2005). Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurology, 4, 705711.
Sano, M. et al. (1997). A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. New England Journal of Medicine, 336, 12161222.
Sastre, M., Klockgether, T. and Heneka, M. T. (2006). Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms. International Journal of Developmental Neuroscience, 24, 167176.
Scarmeas, N., Stern, Y., Tang, M. X., Mayeux, R. and Luchsinger, J. A. (2006). Mediterranean diet and risk for Alzheimer's disease. Annals of Neurology, 59, 912921.
Schenk, D. et al. (1999). Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 400, 173177.
Schofield, P. W. et al. (1997). Alzheimer's disease after remote head injury: an incidence study. Journal of Neurology, Neurosurgery, and Psychiatry, 62, 119124.
Schulte, P. A. (2005). The use of biomarkers in surveillance, medical screening, and intervention. Mutation Research, 592, 155163.
Selkoe, D. J. (1996). Amyloid beta-protein and the genetics of Alzheimer's disease. The Journal of Biological Chemistry, 271, 1829518298.
Selkoe, D. J. (2001). Alzheimer's disease: genes, proteins, and therapy. Physiological Reviews, 81, 741766.
Selkoe, D. J. (2004). Alzheimer disease: mechanistic understanding predicts novel therapies. Annals of Internal Medicine, 140, 627638.
Shumaker, S. A. et al. (2003). Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA, 289, 26512662.
Snowdon, D. A., Kemper, S. J., Mortimer, J. A., Greiner, L. H., Wekstein, D. R. and Markesbery, W. R. (1996). Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study. JAMA, 275, 528532.
Sparks, D. L. et al. (2005). Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Archives of Neurology, 62, 753757.
Stewart, W. F., Kawas, C., Corrada, M. and Metter, E. J. (1997). Risk of Alzheimer's disease and duration of NSAID use. Neurology, 48, 626–32.
Sullivan, E. V. and Pfefferbaum, A. (2003). Diffusion tensor imaging in normal aging and neuropsychiatric disorders. European Journal of Radiology, 45, 244255.
Szekely, C. A. et al. (2004). Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review. Neuroepidemiology, 23, 159169.
Teasdale, G. M., Nicoll, J. A., Murray, G. and Fiddes, M. (1997). Association of apolipoprotein E polymorphism with outcome after head injury. Lancet, 350, 10691071.
Watson, G. S. and Craft, S. (2003). The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs, 17, 2745.
Wilson, R. S. et al. (2002). Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA, 287, 742748.
Wilson, R. S., Arnold, S. E., Schneider, J. A., Kelly, J. F., Tang, Y. and Bennett, D. A. (2006). Chronic psychological distress and risk of Alzheimer's disease in old age. Neuroepidemiology, 27, 143153.
Wyss-Coray, T. and Mucke, L. (2002). Inflammation in neurodegenerative disease–a double-edged sword. Neuron, 35, 419432.
Yaffe, K. et al. (2004). The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA, 292, 22372242.
Yaffe, K. et al. (2005). Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. American Journal of Psychiatry, 162, 683690.
Zandi, P. P., Anthony, J. C., Hayden, K. M., Mehta, K., Mayer, L. and Breitner, J. C. (2002). Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology, 59, 880886.
Zandi, P. P. et al. (2004). Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Archives of Neurology, 61, 8288.
Zarit, S. H., Reever, K. E. and Bach-Peterson, J. (1980). Relatives of the impaired elderly: correlates of feelings of burden. The Gerontologist, 20, 649655.
Zhang, Y. et al. (2007). Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease. Neurology, 68, 1319.

Related content

Powered by UNSILO

Developing new treatments for Alzheimer's disease: the who, what, when, and how of biomarker-guided therapies

  • Constantine G. Lyketsos (a1), Christine A. Szekely (a2), Michelle M. Mielke (a3), Paul B. Rosenberg (a3) and Peter P. Zandi (a4)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.