Research Findings

Biomarker Findings

  • We identified more than 1,500 proteins in cerebrospinal fluid. Out of those proteins, 136 were uniquely associated with Alzheimer's disease, 72 were associated with Parkinson's disease, and 101 were associated with dementia with Lewy Bodies.19 Learn more about biomarkers here.
  • Dr. Elaine Peskind, Associate Director of the UW ADRC, pioneered techniques to improve the safety and comfort of patients during research lumbar punctures.20
  • A comparison of spinal fluid tau and ptau (181) concentrations may indicate subtle nerve changes in brain regions vulnerable to Alzheimer's disease. A longitudinal assessment of spinal fluid and position emission tomography (PET) brain imaging biomarkers is needed to determine whether these changes predict cognitive impairment and the initial onset of Alzheimer's disease.21

Treatment Findings

  • We found that regularly exercising may reduce the risk for incident dementia.22
  • Taking additional vitamin C and/or vitamin E supplements does not affect a person's risk for Alzheimer's disease.23
  • The medication prazosin improved some behavioral symptoms of people with Alzheimer's disease who had agitation and aggression. This medication was well tolerated and showed few worrisome side effects.24 We are currently conducting additional studies of this medication treatment; click here for further information.
  • In a community-based study, we confirmed earlier findings that statin therapy in early old age, but not in late age, may be associated with a lower risk of Alzheimer's disease. The relationship between statin use and Alzheimer's was consistent across APOE genotypes.25 We are currently looking at the role of statins as a potential prevention strategy for Alzheimer's disease; find out more here.

Genetic Findings

  • We found clues contributing to the identification of the Presenilin 1 (PSEN1) genetic mutations on chromosome 14, which cause early onset Alzheimer's Disease.1
  • We identified the Presenilin 2 (PSEN2) genetic mutation on chromosome 1, which causes Alzheimer's Disease. This genetic mutation was discovered in a few families of Volga German background.2, 3, 4, 5, 6 There is no evidence that Alzheimer's disease is more common generally in Germans from Russia.
  • We determined that other genes, not yet identified, may contribute to late onset Alzheimer's disease.7
  • We identified genetic mutations in the tau gene, which cause frontotemporal dementia.8, 9, 10
  • We have contributed extensively to the knowledge base regarding mutations in the progranulin gene underlying frontotemporal dementia.11, 12, 13
  • We have done the largest study of families in which both spouses have Alzheimer's disease (conjugal AD), to better understand the risk of Alzheimer's in their adult children.14
  • We are one of the collaborators in the largest genome-wide association study identifying new genes contributing to Alzheimer's disease.15, 16
  • We have done an extensive clinical and pathological study of identical twins with Alzheimer's disease.17
  • We published the earliest information concerning social and emotional responses in asymptomatic persons undergoing genetic testing for mutations in PSEN1, PSEN2, and tau.18

Other Significant Findings

  • We confirmed that tremors, decreased bodily movements, rigidity, and difficulties with balance, which are collectively known as parkinsonism, and hallucinations are predictive of Lewy bodies in brain tissue.26
  • We developed the Mini-Cog test, which detects clinically significant cognitive impairment in multiethnic elderly individuals with as much accuracy and reliability—and often better accuracy and reliability—as the Mini-Mental State Examination (MMSE) in multiethnic elderly individuals. The Mini-Cog is also easier to administer to non-English speakers and is less biased by education and literacy differences.27
  • A landmark study of 184 healthy volunteers suggested that amyloid plaques may begin forming in the brain when people are between the ages of 50 and 60, which is much earlier than scientists previously assumed. These plaques are important traits of Alzheimer's disease.28

Citations:

  1. Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, White JA, Bonnycastle L, Weber JL, Alonso E, Potter H, Heston LL, Martin GM.  Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14.  Science  258: 668-671, 1992.
  2. Bird TD, Lampe TH, Nemens EJ, Miner GD, Sumi SM, Schellenberg GD.  Familial Alzheimer’s disease in American descendants of the Volga Germans:  probable genetic founder effect.  Ann Neurol 23: 25-31, 1988.
  3. Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KAB, Weber JL, Bird TD, Schellenberg GD. familial Alzheimer’s disease locus on chromosome 1.  Science 269: 970-973, 1995.
  4. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu C, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu Y-H, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE.  Candidate gene for the chromosome 1 familial Alzheimer’s disease locus.  Science 269: 973-977, 1995.
  5. Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu C-E, Bird TD.  Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2.  Brain 133: 1143-1154, 2010.
  6. Reiswig, Gary.  The Thousand Mile Stare:  One Family’s Journey through the Struggle and Science of Alzheimer’s.  Nicholas Brealey Publishing, 2010.
  7. Wijsman EM, Warwick Daw E, Yu C-E, Payami H, Steinbart EJ, Nochlin D, Conlon EM, Bird TD, Schellenberg GD.  Evidence for a novel late-onset Alzheimer disease locus on chromosome 19p13.2.  Am J Hum Genet 75: 398-409, 2004.
  8. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD.  Tau is a candidate gene for chromosome 17 frontotemporal dementia.  Ann Neurol 43: 815-825, 1998.
  9. Bird TD, Nochlin D, Poorkaj P, Cherrier M, Kaye J Payami H, Peskind E, Lampe TH, Nemens E, Boyer PJ, Schellenberg GD.  A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L).  Brain 122: 741-756, 1999.
  10. Poorkaj P, Grossman M, Steinbart E, Payami H, Sadovnick A, Nochlin D, Tabira T, Trojanowski JQ, Borson S, Galasko D, Reich S, Quinn B, Schellenberg G, Bird TD.  Frequency of tau gene mutations in familial and sporadic cases on non-Alzheimer dementia.  Arch Neurol 58:383-387, 2001.
  11. Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, Spina S, Coppola G, Karydas AM, Stewart H, Johnson N, Hsiung G-Y, Kelley B, Kuntz K, Steinbart E, McCarty Wood E, Yu C-E, Josephs K, Sorenson E, Womack KB, Weintraub S, Pickering-Brown SM, Schofield PR, Brooks WS, Van Deerlin VM, Snowden J, Clark CM, Kertesz A, Boylan K, Ghetti B, Neary D, Schellenberg GD, Beach TG, Mesulam M, Mann D, Grafman J, Mackenzie IR, Feldman H, Bird T, Petersen R, Knopman D, Boeve B, Geschwind DH, Miller B, Wszolek Z, Lippa C, Bigio EH, Dickson D, Graff-Radford N, Hutton M.  Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-T (Arg493X) mutation:  an international initiative.  Lancet Neurol 6:857-868, 2007.
  12. Leverenz JB, Y C-E, Montine TJ, Steinbart E, Bekris LM, Zabetian C, Kwong LK, Lee V M-Y, Schellenberg GD, Bird TD.  A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology.  Brain 130:1360-1374, 2007.
  13. Yu C-E, Bird TD, Bekris LM, Montine TJ, Leverenz JB, Steinbart E, Galloway NM, Feldman H, Woltjer R, Miller CA, McCarty Wood E, Grossman M, McCluskey L, Clark CM, Neumann M, Danek A, Galasko DR, Arnold SE, Chen-Plotkin A, Karadas A, Miller BL, Trojanowski JQ, Lee VM-Y, Schellenberg GD, Van Deerlin VM.  The spectrum of mutations in progranulin:  A collaborative study screening 545 cases of neurodegeneration.  Arch Neurol 67(2):161-170, 2010
  14. Jayadev S, Steinbart EJ, Chi Y-Y, Kukull WA, Schellenberg GD, Bird TD. Conjugal Alzheimer disease:  Risk in children when both parents have Alzheimer disease.  Arch Neurol 65(3):373-378, 2008.
  15. Jun G, Naj AC, Beecham GW, Wang L-S, Buros J, Gallins PJ, Buxbaum JD, Ertekin-Taner J, Fallin MD, Friedland R, Inzelberg R, Kramer P, Rogaeva R, St.George-Hyslop P, Alzheimer’s Disease Genetics Consortium, Cantwell LB, Dombroski BA, Saykin AJ, Reiman EM, Bennett DA, Morris JC, Lunetta KL, Martin ER, Montine TJ, Goate AM, Blacker D, Tsuang DW, Beekly D, Cupples LA, Hakonarson H, Kukull W, Foroud TM, Haines J, Mayeux R, Farrer LA, Pericak-Vance MA, Schellenberg GD.  Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals Interactions with APOE genotypes.  Arch Neurol. Published online August 9, 2010.
  16. Wijsman EM, Pankratz N, Choi Y, Rothstein JH, Faber K, Cheng R, Lee JH, Bird TD, Bennett D, Diaz-Arrastia R, Goate A, Farlow M, Sweet R, Foroud T, Mayeux R, for the NIA-LOAD/NCRAD Family Study Group.  Genome wide association of familial late onset Alzheimer’s disease replicates BIN1 and CLU, and nominates CUGBP2 interaction with APOE.  PLoS Genetics in press.
  17. Brickell KL, Leverenz JB, Steinbart EJ, Rumbaugh M, Schellenberg GD, Nochlin D, Lampe TH, Holm IE, Van Deerlin V, Yuan W, Bird TD.  Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer’s disease.  J Neurol Neurosurg Psychiatry 78:1050-55, 2007.
  18. Steinbart EJ, Smith CO, Poorkaj P, Bird TD.  Impact of DNA testing for early-onset familial Alzheimer disease and frontotemporal dementia.  Arch Neurol 58:1828-1831, 2001.
  19. Zhang J, Keene CD, Pan C, Montine KS, Montine TJ. Proteomics of human neurodegenerative diseases. J Neuropathol Exp Neurol 67 (10): 923-32, 2008.
  20. Peskind ER, Riekse R, Quinn JF, Kaye J, Clark CM, Farlow MR, Decarli C, Chabal C, Vavrek D, Raskind MA, Galasko D. Safety and acceptability of the research lumbar puncture. Alzheimer Dis Assoc Disord 19 (4): 220-5, 2005.
  21. Petrie EC, Cross DJ, Galasko D, Schellenberg GD, Raskind MA, Peskind ER, Minoshima S. Preclinical evidence of Alzheimer changes: convergent cerebrospinal fluid biomarker and fluorodeoxyglucose positron emission tomography findings. Arch Neurol 66(5):632-7, 2009.
  22. Larson EB, Wang L, Bowen JB, McCormick WC, Teri L, Crane P, Kukull W. Exercise is associated with reduced risk for incident dementia among persons 65 years of age or older. Ann Intern Med 144 (2): 73-81, 2006.
  23. Gray SL, Anderson ML, Crane PK, Breitner JC, McCormick W, Bowen JD, Teri L, Larson E. Antioxidant vitamin supplement use and risk of dementia or Alzheimer’s disease in older adults. JAGS 56 (2): 291-5, 2008.
  24. Wang LY, Shofer JB, Rohde K, Hart KL, Hoff DJ, McFall YH, Raskind MA, Peskind ER. Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. Am J Geriatr Psychiatry 17 (9): 744-51, 2009.
  25. Li G, Shofer JB, Rhew IC, Kukull WA, Peskind ER, McCormick W, Bowen JD, Schellenberg GD, Crane PK, Breitner JC, Larson EB. Age-varying association between statin use and incident Alzheimer's disease. J Am Geriatr Soc 58 (7): 1311-7, 2010.
  26. Tsuang D, Simpson K, Larson EB, Peskind E, Kukull W, Bowen JB, McCormick W, Teri L, Montine T, Thompson ML, Leverenz JB. Predicting Lewy body pathology in a community-based sample with clinical diagnosis of Alzheimer’s disease. J Geriatr Psychiatry Neurol 19 (4): 195-201, 2006.
  27. Borson S, Scanlan JM, Watanabe J, Tu SP, Lessig M. Simplifying detection of cognitive impairment: Comparison of the Mini-Cog and Mini-Mental State Examination in a multiethnic sample. J Am Geriatr Soc 53 (5): 871-4, 2005.
  28. Peskind ER, Li G, Shofer J, Quinn JF, Kaye JA, Clark CM, Farlow MR, DeCarli C, Raskind MA, Schellenberg GD, Lee VM, Galasko DR. Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition. Arch Neurol 63 (7): 936-9, 2006.