Background The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer’s disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer’s Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program. Methods The program is open for laboratories using commercially available kits for Aβ, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Molndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples. Results Forty laboratories participated. Twenty-six used INNOTESTenzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Aβ-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN-42, AβN-40, and AβN-38) or T-tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories. Conclusions Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.

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The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics.

Background The cerebrospinal fluid (CSF) biomarkers amyloid beta 1–42, total tau, and phosphorylated tau are used increasingly for Alzheimer’s disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. Methods Data from the first nine rounds of the Alzheimer’s Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. Results A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1–42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). Conclusions The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.

Alzheimer's disease (AD) is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms, mostly affecting medial temporal lobe and associative neocortical structures. Neuritic plaques and neurofibrillary tangles represent the pathological hallmarks of AD, and are respectively related to the accumulation of the amyloid-beta peptide (Aβ) in brain tissues, and to cytoskeletal changes that arise from the hyperphosphorylation of microtubule-associated Tau protein in neurons. According to the amyloid hypothesis of AD, the overproduction of Aβ is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein (APP). Genetic, age-related and environmental factors contribute to a metabolic shift favoring the amyloidogenic processing of APP in detriment of the physiological, secretory pathway. Aβ peptides are generated by the successive cleavage of APP by beta-secretase (BACE-1) and gamma-secretase, which has been recently characterized as part of the presenilin complex. Among several beta-amyloid isoforms that bear subtle differences depending on the number of C-terminal amino acids, Aβ (1-42) plays a pivotal role in the pathogenesis of AD. The neurotoxic potential of the Aβ peptide results from its biochemical properties that favor aggregation into insoluble oligomers and protofibrils. These further originate fibrillary Aβ species that accumulate into senile and neuritic plaques. These processes, along with a reduction of Aβ clearance from the brain, leads to the extracellular accumulation of Aβ, and the subsequent activation of neurotoxic cascades that ultimately lead to cytoskeletal changes, neuronal dysfunction and cellular death. Intracerebral amyloidosis develops in AD patients in an age-dependent manner, but recent evidence indicate that it may be observed in some subjects as early as in the third or fourth decades of life, with increasing magnitude in late middle age, and highest estimates in old age. According to recent propositions, three clinical phases of Alzheimer's disease may be defined: (i) pre-symptomatic (or pre-clinical) AD, which may last for several years or decades until the overproduction and accumulation of Aβ in the brain reaches a critical level that triggers the amyloid cascade; (ii) pre-dementia phase of AD (compatible with the definition of progressive, amnestic mild cognitive impairment), in which early-stage pathology is present, ranging from mild neuronal dystrophy to early-stage Braak pathology, and may last for several years according to individual resilience and brain reserve; (iii) clinically defined dementia phase of AD, in which cognitive and functional impairment is severe enough to surmount the dementia threshold; at this stage there is significant accumulation of neuritic plaques and neurofibrillary tangles in affected brain areas, bearing relationship with the magnitude of global impairment. New technologies based on structural and functional neuroimaging, and on the bi...