Accumulating evidence suggests that Alzheimer's disease (AD) pathology, such as plaques and tangles, begins 10-20 years prior to the earliest signs and symptoms of cognitive decline. This period, during which pathology is developing but individuals remain cognitively normal, has been referred to as 'pre-clinical AD'. One pathological feature that appears to distinguish individuals with pre-clinical AD from those with very early AD (very mildly demented with plaques and tangles) is that the earliest clinical symptoms coincide with neuronal and synaptic loss and/or dysfunction in certain brain regions. Given this observation and that promising disease-modifying treatments are on the horizon, it will be critically important to have biomarkers that: 1) correlate with the presence of AD pathology in the brain regardless of clinical status;2) predict with high likelihood the development of cognitive decline in individuals who are still cognitively normal but developing AD pathology (antecedent biomarkers);and 3) differentiate those individuals with very mild or uncertain dementia (mild cognitive impairment) who are most likely to experience cognitive decline. Over the last five years, we have found that: 1) low CSF A(342 is very sensitive and specific for determining the presence or absence of amyloid in the brain as assessed by imaging with Pittsburgh Compound B (PIB), regardless of clinical status;2) ratios of CSF tau/A(342 and ptau181/A(342 are highly predictive of progression from CDR 0 to CDR >0.5 over an average 3-4 year period;and 3) new potential biomarkers for AD (ATIII, ZAG, CNDP1, ACT) can be identified in CSF by unbiased proteomic techniques. We hypothesize that an assessment of the CSFand plasma proteome, including markers such as A042, tau, ptau181, and other proteins, can be combined to develop an accurate determination of dementia risk in cognitively normal elderly individuals. To test this hypothesis, we propose the following aims:
Aim 1 :To determine the ability of CSF AB42, tau, ptaul81, ATIII, ACT, ZAG, and CNDP1, both alone and in combination, to predict clinical progression from CDR 0 to CDR >0 and progression from CDR 0.5 (very mild dementia) to CDR 1 (mild dementia);
Aim 2 : To determine whether CSF levels of Ap42, tau, ptaul81, ATIII, ACT, ZAG, and CNDP1, both alone and in combination, correlate with brain amyloid load as measured with PiB, brain volume as assessed by structural MRI, and neuropsychological test scores;
Aim 3 : To determine, in collaboration with the Wyss-Coray lab, whether a group of 18 plasma signaling proteins that was recently shown to classify AD vs. control subjects correlates with CSF biomarkers of AD studied in Aims 1 and 2, as well as whether these 18 proteins predict progression from CDR 0 to CDR >0 or from CDR 0.5 to CDR 1;
and Aim 4 : To identify novel CSF biomarkers of AD utilizing a new quantitative and highly sensitive proteomic technique called targeted label free LC-MS/MS analysis.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Saint Louis
United States
Zip Code
Blaiotta, Claudia; Freund, Patrick; Cardoso, M Jorge et al. (2018) Generative diffeomorphic modelling of large MRI data sets for probabilistic template construction. Neuroimage 166:117-134
Schindler, Suzanne E; Sutphen, Courtney L; Teunissen, Charlotte et al. (2018) Upward drift in cerebrospinal fluid amyloid ? 42 assay values for more than 10 years. Alzheimers Dement 14:62-70
Gabel, Matthew; Gooblar, Jonathan; Roe, Catherine M et al. (2018) Political Ideology, Confidence in Science, and Participation in Alzheimer Disease Research Studies. Alzheimer Dis Assoc Disord 32:179-184
Blue, Elizabeth E; Bis, Joshua C; Dorschner, Michael O et al. (2018) Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project. Dement Geriatr Cogn Disord 45:1-17
Roe, Catherine M; Babulal, Ganesh M; Mishra, Shruti et al. (2018) Tau and Amyloid Positron Emission Tomography Imaging Predict Driving Performance Among Older Adults with and without Preclinical Alzheimer's Disease. J Alzheimers Dis 61:509-513
Rao, Shuquan; Ghani, Mahdi; Guo, Zhiyun et al. (2018) An APOE-independent cis-eSNP on chromosome 19q13.32 influences tau levels and late-onset Alzheimer's disease risk. Neurobiol Aging 66:178.e1-178.e8
Laurido-Soto, Osvaldo; Brier, Matthew R; Simon, Laura E et al. (2018) Patient characteristics and outcome associations in AMPA receptor encephalitis. J Neurol :
Peloso, Gina M; van der Lee, Sven J; International Genomics of Alzheimer's Project (IGAP) et al. (2018) Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease. Alzheimers Dement (Amst) 10:595-598
Armstrong, Richard A; McKee, Ann C; Stein, Thor D et al. (2018) Cortical degeneration in chronic traumatic encephalopathy and Alzheimer's disease neuropathologic change. Neurol Sci :
Sato, Chihiro; Barthélemy, Nicolas R; Mawuenyega, Kwasi G et al. (2018) Tau Kinetics in Neurons and the Human Central Nervous System. Neuron 98:861-864

Showing the most recent 10 out of 911 publications