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Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42) and tau are linked with the known neuropathology of Alzheimer's disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE epsilon4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE epsilon4 allele as a predictive variable in the search for possible prognostic biomarkers of AD.We assessed the levels of beta-amyloid(1-42) and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing.When divided according to the absence or presence of the APOE epsilon4 allele, the control subjects with at least one epsilon4 allele had significantly lower CSF beta-amyloid(1-42) but not tau levels than control subjects without an APOE epsilon4 allele (p.01). As expected, the AD patients had lower levels of CSF beta-amyloid(1-42) and higher CSF tau levels than the normal control group (p.01).The association of APOE epsilon4 allele and lower, more AD-like levels of CSF beta-amyloid(1-42) in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with epsilon4 carriers and suggests that CSF beta-amyloid(1-42) decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.

ContextAlzheimer disease (AD) is characterized by pathological results at autopsy of amyloid plaques and tau-associated neurofibrillary tangles, but the clinical diagnosis of AD is determined on the basis of medical history, cognitive symptoms, and exclusionary criteria. The search for antemortem biomarkers is intense and has focused on cerebrospinal fluid (CSF) β-amyloid1-42 and tau proteins.ObjectivesTo compare CSF β-amyloid and tau levels in a new population of AD patients and controls. To perform a meta-analysis of studies of CSF β-amyloid and tau levels in AD patients and controls.DesignCross-sectional study of the comparison of baseline CSF β-amyloid1-42 and tau levels in AD patients and controls. Meta-analysis involved 17 studies of CSF β-amyloid and 34 studies of CSF tau.SettingClinical research unit of the National Institute of Mental Health, Bethesda, Md.PatientsThe Geriatric Psychiatry Branch evaluated AD patients as inpatients at the National Institutes of Health Clinical Center between May 1985 and January 2001. A total of 203 patients participated in this study (131 with AD and 72 controls). None had other serious illnesses, and 31 of 131 AD cases had AD confirmed at autopsy. Meta-analysis provided an additional 3133 AD patients and 1481 controls.Main Outcome MeasuresLevels of CSF β-amyloid1-42 were measured by a sandwich enzyme-linked immunoabsorbent assay with a polyclonal capture antibody and a monoclonal detection antibody. Levels of CSF tau were measured with a standard commercial immunoassay.ResultsLevels of CSF β-amyloid1-42 were significantly lower in the AD patients vs controls (mean [SD], 183 [121] pg/mL vs 491 [245] pg/mL; P

The aim of the study was to determine whether the epsilon 4 allele of the apolipoprotein E (ApoE) gene was associated primarily with context-specific memory among individuals at genetic risk for developing Alzheimer's disease. The effect of ApoE status on comprehensive neuropsychological results was examined in 176 healthy adults during baseline cognitive testing in the NIMH Prospective Study of Biomarkers for Older Controls at Risk for Alzheimer's Disease (NIMH Prospective BIOCARD Study). The presence of the epsilon 4 allele was associated with significantly lower total scores on the Logical Memory II subtest of the Wechsler Memory Scale-Revised and percent of information retained after delay. Further analysis indicated the prose recall and retention effect was partially explained by a small subgroup of epsilon 4 homozygotes, suggesting a gradually progressive process that may be presaged with specific cognitive measures. The current results may represent an epsilon 4-associated breakdown between gist-related information and context-bound veridical recall. This relative disconnection may be understood in light of putative epsilon 4-related preclinical accumulation of Alzheimer pathology (tangles and plaques) in the entorhinal cortex (EC) and among frontal networks, as well as the possibility of less-efficient compensatory strategies.

Analysis of CSF is an important component of clinical and research studies involving illnesses such as AD. In fact, longitudinal analysis of CSF may be vital to identify and track potential biological markers in people at risk for developing AD. However, recruiting initial and long-term participation of research subjects in lumbar puncture (LP)-based studies can be challenging, especially because the incidence of post-LP headaches (post-LPHAs) with traditional methods often exceeds 30%.1 Reduction of post-LPHAs through the use of small-diameter spinal needles is well documented,2 presumably due to reduced leakage of CSF from the smaller hole produced when the spinal needle traverses the dura.3-5⇓⇓ There is relatively little experience obtaining large quantities of fluid from small-diameter Whitacre spinal needles compared with the traditional 20-guage, Quincke needles. Therefore, we sought to determine whether research quantities of CSF could be withdrawn using small, atraumatic needles and negative pressure techniques without causing a significant increase in the rate of …