James Levy

Cerebrospinal fluid β-amyloid1–42 and tau in control subjects at risk for Alzheimer’s disease: The effect of APOE ε4 allele

Background Cerebrospinal fluid (CSF) measures of β-amyloid 1–42 and tau are linked with the known neuropathology of Alzheimers disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE e4 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 e4 allele as a predictive variable in the search for possible prognostic biomarkers of AD. Methods We assessed the levels of β-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. Results When divided according to the absence or presence of the APOE e4 allele, the control subjects with at least one e4 allele had significantly lower CSF β-amyloid 1–42 but not tau levels than control subjects without an APOE e4 allele ( p 1–42 and higher CSF tau levels than the normal control group ( p Conclusions The association of APOE e4 allele and lower, more AD-like levels of CSF β-amyloid 1–42 in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with e4 carriers and suggests that CSF β-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.

Longitudinal stability of CSF tau levels in Alzheimer patients

BACKGROUND Antemortem levels of tau in the cerebrospinal fluid (CSF) of Alzheimers disease (AD) patients have repeatedly been demonstrated to be elevated when compared to controls. Although CSF tau has been reported to be elevated even in very mild AD, it is unknown how tau levels change during the course of the disease. METHODS We have followed 29 mild-to-moderately affected AD subjects over 2 years with repeated CSF taps. Clinical measures of dementia severity (Clinical Dementia Rating Scale, Global Deterioration Scale and Mini-Mental Status Examination) were obtained at the start and conclusion of the observation period, and CSF tau was measured with a standard enzyme-linked immunoabsorbent assay (ELISA) using two monoclonal antibodies. RESULTS Despite significant changes in the clinical measures consistent with progression of the disease, no significant overall change in CSF tau levels (548 +/- 355 vs. 557 +/- 275 pg/mL, NS) was observed. None of the clinical variables was significantly correlated with either baseline measures of CSF tau or delta CSF tau (last-first). Similarly, CSF tau at baseline and changes over time were not significantly related to Apolipoprotein E (APO E) phenotype. CONCLUSIONS These data suggest that CSF tau levels are stable over extended periods of time in a group of mild-to-moderately demented AD subjects and that CSF tau levels do not predict the severity or rate of progression of AD, at least not during the middle stages of the illness.

Interleukin-6 is not altered in cerebrospinal fluid of first-degree relatives and patients with Alzheimer's disease

We investigated interleukin-6 (IL-6) levels in cerebrospinal fluid (CSF) of 25 patients with clinically diagnosed sporadic Alzheimers disease (AD) and 19 healthy control subjects (HC). For comparison 19 clinically healthy subjects with at least one first-degree relative with clinical or autopsy confirmed AD (CF/AD) were examined. CSF levels of IL-6 did not show statistically significant differences between AD patients, CF/AD and HC subjects. There was no correlation between age, gender, age of onset, degree of cognitive impairment, blood-brain barrier dysfunction and IL-6 values. We could not demonstrate altered CSF concentrations of IL-6 that may indicate an inflammatory response or capability to support neuronal survival in the central nervous system (CNS) of first-degree relatives and patients with AD. We suggest that combined measurement of all parameters of the IL-6-receptor complex could yield more insight in a probably altered IL-6 function.

Decreased soluble interleukin-6 receptor in cerebrospinal fluid of patients with Alzheimer's disease.

The function of the cytokine interleukin-6 (IL-6) is augmented by soluble IL-6 receptors (sIL-6R). We investigated cerebrospinal fluid sIL-6R concentrations in patients with Alzheimers disease (AD) compared to age-matched healthy subjects and individuals with at least one first degree relative with AD. We found a statistically significant decrease in sIL-6R levels in the AD group compared to controls. Complete analysis of the IL-6R complex seems crucial to better understand the impact of IL-6 in AD pathophysiology.

Context-specific memory and apolipoprotein E (ApoE) [varepsilon]4: Cognitive evidence from the NIMH prospective study of risk for Alzheimer's disease

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 Alzheimers 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 Alzheimers 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.

Scaling of visuospatial attention undergoes differential longitudinal change as a function of APOE genotype prior to old age : Results from the NIMH BIOCARD study

The effect of apolipoprotein E (APOE) genotype on longitudinal cognitive decline in midlife was investigated with attentional scaling. Healthy individuals (mean age 59.6 years) genotyped for APOE were tested at 3 12-month intervals on a cued visual search task. A random effects model revealed significant interaction in effect of precue size on search speed between APOE-epsilon4 gene dose and assessment, with longitudinal increases in noncarriers and heterozygotes but longitudinal decreases in homozygotes. Association of APOE-epsilon4 with cognitive decline in midlife is consistent with an Alzheimers disease (AD) prodrome, albeit a decade or more before average age of AD diagnosis. However, cognitive decline in midlife associated with a gene modulating neuronal response to insult argues that the concept of an AD prodrome includes factors that allow as well as cause AD.

Acetylcholine affects the spatial scale of attention: evidence from Alzheimer's disease.

Location precues were used to manipulate the spatial scale of attention in visual search for a target in an array of letters in patients with dementia of the Alzheimer type (DAT) and in age-matched older controls. Cue size varied in the amount of spatial precision conferred. Scopolamine, a muscarinic antagonist, decreased overall arousal and broadened spatial attention after a precise precue (small and valid) to target location for DAT patients but not for controls, suggesting a selective effect for attentional impairment induced by cholinergic blockade. In contrast, physostigmine, a cholinesterase inhibitor, did not alter the distribution of spatial attention relative to no-drug baseline testing for patients. Results support a differential role for cholinergic mechanisms in the modulation of the spatial scale of visual attention.

Effects of Previous Major Depressive Illness on Cognition in Alzheimer Disease Patients

OBJECTIVE Major Depressive Disorder (MDD) may be a risk factor for subsequent development of irreversible dementia; however, the influence of a premorbid history of MDD on the clinical course of patients diagnosed with probable Alzheimer disease (AD) has not been fully explored. METHODS Forty-three AD patients with mild-to-moderate cognitive impairment were screened for a life-long history of MDD with the Clinical Assessment of Depression in Dementia Scale. Twenty-two subjects had a history of MDD before onset of cognitive impairment, but none was suffering from an MDD episode at time of cognitive assessment. RESULTS After controlling for age, education, duration of illness, gender, and medication status, subjects with a history of MDD had significantly lower scores, as a group, on cognitive performance tests, including the Mini-Mental State Exam, WAIS Full-Scale and Verbal Scale I.Q., and the Initiation/Perseveration subscale of the Mattis Dementia Rating Scale. These subjects also developed symptoms of dementia at a significantly earlier age than the subjects who had no premorbid history of MDD. CONCLUSIONS Although previous studies have shown that late-onset MDD may increase risk for subsequent dementia, the current results suggest that premorbid MDD is associated with more severe cognitive deficits during the actual course of dementia.

Stability of CSF β-Amyloid1–42 and Tau Levels by APOE Genotype in Alzheimer Patients

Background: Cerebrospinal fluid (CSF) measures of β-amyloid1–42 and tau differ between patients with Alzheimer’s Disease (AD) and elderly normal controls. The effect of time and APOE genotype on these biomarkers continues to be elucidated. Methods: We assessed CSF β-amyloid1–42 and tau in 20 mild-to-moderate AD patients, 11 APOE Ε4+ and 9 APOE Ε4–, over a mean time of 3.8 years (range 1–11.1 years). Results: Over the period measured, CSF β-amyloid1–42 levels were lower in APOE Ε4+ compared to APOE Ε4– patients, and the levels decreased over time. Tau levels were stable over time and did not show an effect of APOE allele. Conclusions: While this is a limited clinical sample, the further decrease in CSF β-amyloid1–42 (i.e., more abnormal) combined with the CSF tau stability over a mean period of almost 4 years suggests that β-amyloid1–42 and tau maintain their potential usefulness as diagnostic biomarkers over time. These findings should be taken into account if CSF β-amyloid1–42 and tau are used as measures of treatment response.

Apolipoprotein E ?4 allele in association with global cognitive performance and CSF markers in Alzheimer's disease

To better define the influence of apolipoprotein E (ApoE) ϵ4 genotype on the cognitive and biochemical features of Alzheimers disease (AD), cross‐sectional analysis of global cognitive measures and cerebrospinal fluid studies gathered on AD subjects at a tertiary care facility between 1986 and 1997 was carried out. The 112 AD patients examined included 62 women and 50 men with a mean (SD) age of 64·2 (9·2) years. Patient demographics, illness onset age and duration, education level and global cognitive measures were recorded systematically. Genetic analysis for ApoE allele type and biochemical characterization of CSF, including total tau concentration, was performed. Descriptive statistics of demographics, cognitive and CSF measures were performed by chi‐square, ANOVA and Tukeys tests. Overrepresentation of the ϵ4 allele was found, with 45·5% of AD patients heterozygous and 20·5% homozygous for ApoE ϵ4. Overall, ApoE ϵ4 status had no effect on mean onset age of AD (F=1·56; p=0·214), but an earlier mean onset age of AD (F=4·10; p=0·02) was seen in the late‐onset subjects. No differences were found with regard to ApoE ϵ4 status and measures of disease, duration of illness or global cognitive performance. Although CSF tau was elevated in our sample (575·4±290·3 pg/ml), ApoE ϵ4 status did not influence total CSF tau or neurotransmitter metabolite levels. ApoE ϵ4 genotype had no impact on a variety of illness severity, cognitive and CSF examinations in the largest cross‐sectional analysis of AD subjects yet reported. Copyright