Clinical Experience with Cerebrospinal Fluid Aβ42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia

Giuseppe Tosto, MD, PhD	Richard Mayeux, MD, MSc

While autopsy remains the "gold standard" for a definitive diagnosis of Alzheimer's disease (AD), elevated levels of total tau (tTau), 181-phosphorylated phosphorylated tau (pTau), and decreasing levels of amyloid-β42 (Aβ42) in antemortem lumbar cerebrospinal fluid (CSF) have been associated with AD and correlated with postmortem amyloid plaque load. In 2014, a consensus was reached by the Alzheimer’s Biomarkers Standardization Initiative (ABSI) that lumbar puncture CSF biomarker analysis should be considered as a routine clinical test in patients referred for memory complaints or admitted to hospitals for cognitive impairment and complex differential diagnoses of dementia. However, most published studies on these CSF biomarkers in the diagnosis of AD have been from research settings that compared AD patients to healthy controls.

Figure: Receiver operation curve (ROC). Alzheimer's disease compared to overall population of the cohort. Alzheimer's disease (n = 264) was compared to the overall population of the cohort (n = 752). Aβ42 (red), tTau (green), pTau (blue), and ATI (black) CSF biomarker ROC curves are reported here. AUC analyses fully reported in the text.

Thus, in the present study, Drs. Richard Mayeux, Giuseppe Tosto, Larry Honig, Andy Teich, and colleagues sought to provide a realistic and unbiased evaluation of these CSF biomarkers in a non-research setting, by assessing the sensitivity, specificity, and area under the curve (see figure) of CSF Aβ42, tTau, pTau, and the Aβ42/total tau index (ATI) from the medical records of 1,016 patients that had CSF studies for dementia over a 12-year period at NewYork-Presbyterian/Columbia University Irving Medical. As published in the Journal of Alzheimer's Disease, their results indicate that, individually, CSF biomarkers Aβ42, tTau, pTau, and the computed ATI provide excellent sensitivity but moderate to low specificity for clinically diagnosed AD compared to patients with other diseases or other forms of dementia in routine practice. The use of CSF biomarkers in the diagnosis of patients meeting the clinical criteria listed by ABSI needs to be state of the art in identifying AD; the findings presented here indicate that further work needs to be done to improve their specificity and overall accuracy.

Giuseppe Tosto, MD, PhD
Postdoctoral Research Scientist (in the Taub Institute and the Gertrude H. Sergievsky Center)
gt2260@cumc.columbia.edu

Richard Mayeux, MD, MSc
Gertrude H. Sergievsky Professor of Neurology, Psychiatry and Epidemiology (in the Gertrude H. Sergievsky Center and in the Taub Institute)
rpm2@cumc.columbia.edu

Evaluation of TDP-43 Proteinopathy and Hippocampal Sclerosis in Relation to APOE ε4 Haplotype Status: A Community-Based Cohort Study

Philip De Jager, MD, PhD, MMSc

Transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy in older adults frequently coexists with Alzheimer's disease pathology and hippocampal sclerosis. It is unclear whether there is a link between APOEε4 and TDP-43 proteinopathy, and the role of APOEε4 in the association of TDP-43 proteinopathy with hippocampal sclerosis remains to be examined. According to a new study by Dr. Philip De Jager and colleagues, genetic association studies can provide a unique opportunity to examine the relationship between different post-mortem neuropathologies by assessing shared genetic associations between two pathologies.

As published in The Lancet Neurology, Dr. De Jager and colleagues leveraged the largest TDP-43 proteinopathy dataset reported, to date, to investigate the relationships among Alzheimer's disease, TDP-43 proteinopathy, and hippocampal sclerosis through a shared genetic risk factor, APOE ε4. In this study of more than 1000 well-characterized older adults from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP) community-based cohorts, they found that APOE ε4 is a strong genetic predictor of the presence and severity of TDP-43 proteinopathy, and this effect, in turn, was associated with higher odds of hippocampal sclerosis, a pathology potentially downstream of TDP-43 proteinopathy.. This association was not fully explained or significantly moderated by other APOE ε4-related proteinopathies. The authors conclude that TDP-43 proteinopathy contributes to the detrimental effect of APOE ε4 on late-life cognition through mechanisms independent of Alzheimer's disease pathology, and future research should consider that TDP-43 proteinopathy might be an integral component of APOE-related neurodegeneration.

Philip De Jager, MD, PhD, MMSc
Weil-Granat Professor of Neurology (in the Taub Institute, the Precision Medicine Initiative, and the Center for Translational and Computational Neuro-immunology)
pld2115@cumc.columbia.edu