Adjudicating Mild Cognitive Impairment Due to Alzheimer's Disease as a Novel Endpoint Event in the TOMMORROW Prevention Clinical Trial.

BACKGROUND: The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer's disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. METHODS: The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant's clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages - independent review, collaborative review, and full committee review - requiring a unanimous decision and ratification by the chair. RESULTS: Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators' clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80-90% for the remainder of the study. CONCLUSIONS: The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

Blast-related disinhibition and risk seeking in mice and combat Veterans: Potential role for dysfunctional phasic dopamine release.

Mild traumatic brain injury (mTBI) caused by exposure to high explosives has been called the "signature injury" of the wars in Iraq and Afghanistan. There is a wide array of chronic neurological and behavioral symptoms associated with blast-induced mTBI. However, the underlying mechanisms are not well understood. Here we used a battlefield-relevant mouse model of blast-induced mTBI and in vivo fast-scan cyclic voltammetry (FSCV) to investigate whether the mesolimbic dopamine system contributes to the mechanisms underlying blast-induced behavioral dysfunction. In mice, blast exposure increased novelty seeking, a behavior closely associated with disinhibition and risk for subsequent maladaptive behaviors. In keeping with this, we found that veterans with blast-related mTBI reported greater disinhibition and risk taking on the Frontal Systems Behavior Scale (FrSBe). In addition, in mice we report that blast exposure causes potentiation of evoked phasic dopamine release in the nucleus accumbens. Taken together these findings suggest that blast-induced changes in the dopaminergic system may mediate aspects of the complex array of behavioral dysfunctions reported in blast-exposed veterans.

Blast exposure causes dynamic microglial/macrophage responses and microdomains of brain microvessel dysfunction.

Exposure to blast overpressure (BOP) is associated with behavioral, cognitive, and neuroimaging abnormalities. We investigated the dynamic responses of cortical vasculature and its relation to microglia/macrophage activation in mice using intravital two-photon microscopy following mild blast exposure. We found that blast caused vascular dysfunction evidenced by microdomains of aberrant vascular permeability. Microglial/macrophage activation was specifically associated with these restricted microdomains, as evidenced by rapid microglial process retraction, increased ameboid morphology, and escape of blood-borne Q-dot tracers that were internalized in microglial/macrophage cell bodies and phagosome-like compartments. Microdomains of cortical vascular disruption and microglial/macrophage activation were also associated with aberrant tight junction morphology that was more prominent after repetitive (3×) blast exposure. Repetitive, but not single, BOPs also caused TNFα elevation two weeks post-blast. In addition, following a single BOP we found that aberrantly phosphorylated tau rapidly accumulated in perivascular domains, but cleared within four hours, suggesting it was removed from the perivascular area, degraded, and/or dephosphorylated. Taken together these findings argue that mild blast exposure causes an evolving CNS insult that is initiated by discrete disturbances of vascular function, thereby setting the stage for more protracted and more widespread neuroinflammatory responses.

ABCB1 genotype and CSF beta-amyloid in Alzheimer disease.

The ABCB1 gene, coding for the efflux transporter P-glycoprotein (PGP), is a candidate gene for Alzheimer disease (AD). P-glycoprotein is heavily expressed at the blood-brain barrier, where it mediates the efflux of ß-amyloid (Aß) from the brain. In this study, we investigated a possible association between 2 common ABCB1 polymorphisms, G2677T/A (Ala893Ser/Thr) and C3435T, AD, and cerebrospinal fluid (CSF) levels of Aß. No strong evidence for association was found.

Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer's disease.

The aim of this exploratory investigation was to determine if genetic variation within amyloid precursor protein (APP) or its processing enzymes correlates with APP cleavage product levels: APPα, APPß or Aß42, in cerebrospinal fluid (CSF) of cognitively normal subjects or Alzheimer's disease (AD) patients. Cognitively normal control subjects (n = 170) and AD patients (n = 92) were genotyped for 19 putative regulatory tagging SNPs within 9 genes (APP, ADAM10, BACE1, BACE2, PSEN1, PSEN2, PEN2, NCSTN and APH1B) involved in the APP processing pathway. SNP genotypes were tested for their association with CSF APPα, APPß, and Aß42, AD risk and age-at-onset while taking into account age, gender, race and APOE ε4. After adjusting for multiple comparisons, a significant association was found between ADAM10 SNP rs514049 and APPα levels. In controls, the rs514049 CC genotype had higher APPα levels than the CA, AA collapsed genotype, whereas the opposite effect was seen in AD patients. These results suggest that genetic variation within ADAM10, an APP processing gene, influences CSF APPα levels in an AD specific manner.

Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease.

A number of distinct beta-amyloid (Abeta) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Abeta-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Abeta and amyloidogenic non-Abeta species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of Abeta and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Abeta1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Abeta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Abeta toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Abeta the monkeys developed high titers not only against Abeta peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Abeta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.

Safety of lumbar puncture procedures in patients with Alzheimer's disease.

Changes in cerebrospinal fluid (CSF) biomarkers are representative of biochemical changes in the brain. Collection of CSF by lumbar puncture (LP) is essential for biomarker analysis, which is important for research in neurodegenerative disorders. However, LP for research purposes has been controversial due to a reported high incidence of severe LP headache when using standard 18g or 20g Quincke needles with a beveled cutting tip. A procedural safety analysis was performed using the database of a multicenter, 13-week study of CSF cholinesterase activity. A 24g Sprotte atraumatic needle was used to collect CSF at baseline and at Week 13 from 63 older patients with mild to moderate Alzheimer's disease. There was a < 2% LP headache incidence, and a favorable safety profile was reported. In conclusion, LP performed with a 24g Sprotte atraumatic needle (blunt, "bullet" tip) was a well tolerated procedure, with good acceptability.

Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease.

BACKGROUND: Treatment with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors ("statins") has been associated in some epidemiologic studies with reduced risk of Alzheimer disease (AD). However, direct evidence of statin effects on neuropathologic markers of AD is lacking. We investigated whether antecedent statin exposure is associated with neuritic plaque (NP) or neurofibrillary tangle (NFT) burden in a population-based sample of human subjects. METHODS: Brain autopsies were performed on 110 subjects, ages 65 to 79 years, who were cognitively normal at enrollment into the Adult Changes in Thought Study. Neuropathologic findings were compared between statin users with > or =3 prescriptions of > or =15 pills of simvastatin, pravastatin, lovastatin, or atorvastatin vs nonusers, based on pharmacy dispensing records. RESULTS: After controlling for age at death, gender, cognitive function at study entry, brain weight, and presence of cerebral microvascular lesions, the odds ratio (OR) for each unit increase in Braak NFT stage in statin users vs nonusers was 0.44 (95% CI: 0.20 to 0.95). The OR for each unit increase in Consortium to Establish a Registry for Alzheimer's Disease (CERAD) staging of NPs did not deviate significantly from unity (OR 0.69; 95% CI: 0.32 to 1.52). However, the risk for typical AD pathology (Braak stage > or = IV and CERAD rating > or = moderate) was reduced in statin users (OR 0.20; 95% CI: 0.05 to 0.86). CONCLUSIONS: These findings demonstrate an association between antecedent statin use and neurofibrillary tangle burden at autopsy. Additional study is needed to examine whether statin use may be causally related to decreased development of Alzheimer disease-related neuropathologic changes.

CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study.

BACKGROUND: Processes of Alzheimer disease (AD) likely begin years prior to the onset of cognitive impairment (latent AD), progress though a prodromal phase of mild cognitive impairment (MCI), and culminate in dementia. While many studies have evaluated CSF tau and Abeta(42) as biomarkers of the dementia or prodromal stages of AD, we are unaware of any study to evaluate these potential CSF biomarkers of latent AD. METHODS: We determined the ratio of CSF tau/Abeta(42) (T/Abeta) using Luminex reagents in 129 control individuals that spanned from 21 to 100 years of age; for comparison we included patients with MCI (n = 12), probable AD (n = 21), or other neurodegenerative diseases (n = 12). RESULTS: We identified 16% of the control group with abnormally elevated CSF T/Abeta; all were 53 years or older. Using age-matched controls with normal CSF T/Abeta we showed that the high CSF T/Abeta subgroup of controls had significantly increased frequency of the epsilon4 allele of the apolipoprotein E gene and significantly increased risk of conversion to MCI during follow-up of up to 42 months suggesting that they had latent AD at the time of lumbar puncture. CONCLUSIONS: These generally applicable methods establish cutoff values to identify control individuals at increased risk of conversion to mild cognitive impairment which may be useful to people weighing the risk-benefit ratio of new preventive therapeutics and to researchers striving to enrich clinical trial populations with people with latent Alzheimer disease.

Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: evidence of compensatory changes.

In Alzheimer's disease (AD) there is a significant loss of locus coeruleus (LC) noradrenergic neurons. However, recent work has shown the surviving noradrenergic neurons to display many compensatory changes, including axonal sprouting to the hippocampus. The prefrontal cortex (PFC) is a forebrain region that is affected in dementia, and receives innervation from the LC noradrenergic neurons. Reduced PFC function can reduce cognition and disrupt behavior. Because the PFC is an important area in AD, we determined if noradrenergic innervation from the LC noradrenergic neurons is maintained and if adrenoreceptors are altered postsynaptically. Presynaptic PFC alpha2-adrenoreceptor (AR) binding site density, as determined by 3H-RX821002, suggests that axons from surviving noradrenergic neurons in the LC are sprouting to the PFC of subjects with dementia. Changes in postsynaptic alpha1-AR in the PFC of subjects with dementia indicate normal to elevated levels of binding sites. Expression of alpha1-AR subtypes (alpha1A- and alpha1D-AR) and alpha2C-AR subtype mRNA in the PFC of subjects with dementia is similar to what was observed in the hippocampus with one exception, the expression of alpha1A-AR mRNA. The expression of the alpha1A-AR mRNA subtype is significantly reduced in specific layers of the PFC in subjects with dementia. The loss of alpha1A-, alpha1D- and alpha2C-AR mRNA subtype expression in the PFC may be attributed to neuronal loss observed in dementia. These changes in postsynaptic AR would suggest a reduced function of the PFC. Consequence of this reduced function of the PFC in dementia is still unknown but it may affect memory and behavior.

Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men.

BACKGROUND: It has been suggested that cognitive changes in response to T supplementation may occur within an ideal range. The objective of this study was to compare the cognitive responses of older, eugonadal men in whom moderate or large increases in serum testosterone levels was induced by exogenous testosterone supplementation. DESIGN: Randomized, double-blind, placebo-controlled study with subsequent grouping of participants according to average increase in circulating T from baseline. SETTING: Community dwelling participants. PARTICIPANTS: Fifty-seven healthy, eugonadal, community dwelling male volunteers, mean age 67 years (+/-11 years). INTERVENTIONS: Participants were randomized to receive weekly intramuscular (i.m.) injections of either 50, 100 or 300 mg T enanthate or placebo (saline) injection for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, weeks 3 and 6 of treatment and after 6 weeks of wash-out. MAIN OUTCOME MEASURES: Performance on cognitive tests of verbal and spatial memory. RESULTS: Men with moderate increases in serum T and/or its metabolites demonstrated significant improvements in verbal and spatial memory. In contrast, men with large or low increases in circulating T levels, failed to demonstrate significant changes in memory. CONCLUSION: These results suggest that in healthy older men, beneficial changes in cognitive function induced by T supplementation are most evident with moderate changes in cognition from moderate to high T supplementation increases in T levels. Large or no to low increases in T levels do not appear to appreciably effect cognition.

Identification of potential CSF biomarkers in ALS.

BACKGROUND: The clinical diagnosis of ALS is based entirely on clinical features. Identification of biomarkers for ALS would be important for diagnosis and might also provide clues to pathogenesis. OBJECTIVE: To determine if there is a specific protein profile in the CSF that distinguishes patients with ALS from those with purely motor peripheral neuropathy (PN) and healthy control subjects. METHODS: CSF obtained from patients with ALS, disease controls (patients with other neurologic disorders), and normal controls were analyzed using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry proteomics technique. Biomarker sensitivity and specificity was calculated with receiver operating characteristic curve methodology. ALS biomarkers were purified and sequence identified by mass spectrometry-directed peptide sequencing. RESULTS: In initial proteomic discovery studies, three protein species (4.8-, 6.7-, and 13.4-kDa) that were significantly lower in concentration in the CSF from patients with ALS (n = 36) than in normal controls (n = 21) were identified. A combination of three protein species (the "three-protein" model) correctly identified patients with ALS with 95% accuracy, 91% sensitivity, and 97% specificity from the controls. Independent validation studies using separate cohorts of ALS (n = 13), healthy control (n = 25), and PN (n = 7) subjects confirmed the ability of the three CSF protein species to separate patients with ALS from other diseases. Protein sequence analysis identified the 13.4-kDa protein species as cystatin C and the 4.8-kDa protein species as a peptic fragment of the neurosecretory protein VGF. CONCLUSION: Additional application of a "three-protein" biomarker model to current diagnostic criteria may provide an objective biomarker pattern to help identify patients with ALS.

Serum cholesterol and risk of Alzheimer disease: a community-based cohort study.

OBJECTIVES: To examine the association of serum total cholesterol (TC) and high density lipoprotein (HDL) levels and subsequent incidence of dementia and Alzheimer disease (AD) in a population-based cohort study. METHODS: A cohort of cognitively intact persons, aged 65 and older, was randomly selected from Group Health Cooperative (GHC), a large health maintenance organization, and was assessed biennially for dementia. Premorbid levels of TC and HDL were obtained from a computerized clinical laboratory database at GHC. Cox proportional hazards regression was used to calculate hazard ratios (HR, 95% CI) for dementia and AD associated with quartiles of TC and HDL levels. RESULTS: Of the 2,356 eligible participants, 2,141 had at least one serum TC measure prior to the initial enrollment. Using the lowest TC quartiles as the reference group, the HR in the highest TC quartiles was not significantly elevated for dementia (1.16, 0.81 to 1.67) or for AD (1.00, 0.61 to 1.62) after adjusting for age, sex, education, baseline cognition, vascular comorbidities, body mass index, and lipid-lowering agent use. Serum HDL showed a similar lack of significant association with risk of dementia or AD. Models that included the presence of one or more APOE-epsilon4 alleles showed a typical association of epsilon4 with AD risk. This association was not materially modified by inclusion of TC level. CONCLUSION: The data do not support an association between serum total cholesterol or high density lipoprotein in late life and subsequent risk of dementia or Alzheimer disease (AD). The increased risk of AD with APOE-epsilon4 is probably not mediated by serum total cholesterol levels.

Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment.

OBJECTIVE: To determine the efficacy of testosterone (T) supplementation on cognition in a sample of men with Alzheimer disease (AD) or mild cognitive impairment (MCI). METHODS: Fifteen patients with AD and 17 patients with MCI aged 63 to 85 years completed a randomized, double-blind, placebo-controlled study. Nineteen participants received weekly intramuscular (IM) injections of 100 mg T enanthate and 13 participants received weekly injections of placebo (saline) for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, week 3, and week 6 of treatment and again after 6 weeks of washout. RESULTS: Peak serum total T levels were raised from baseline an average of 295% in the active treatment group. Improvements in spatial memory (p < 0.05) and constructional abilities (p < 0.05) and verbal memory were evident in the T group. No changes were noted for selective and divided attention or language. Prostate specific antigen did not significantly change during this brief treatment. CONCLUSION: Testosterone supplementation may benefit selective cognitive functions in men with Alzheimer disease and mild cognitive impairment.

The role of aromatization in testosterone supplementation: effects on cognition in older men.

OBJECTIVE: To determine the contribution of conversion of testosterone (T) to estradiol on cognitive processing in a population of healthy older men who received T supplementation. METHODS: Sixty healthy, community-dwelling volunteers aged 50 to 90 years completed a randomized, double-blind, placebo-controlled study. Participants were randomized to receive weekly IM injections of 100 mg T enanthate plus daily oral placebo pill (T group, n = 20), 100 mg testosterone enanthate plus 1 mg daily of anastrozole, an aromatase inhibitor (oral pill), to block the conversion of T to estradiol (AT group, n = 19), or saline injection and placebo pill (placebo group, n = 21) for 6 weeks. Cognitive evaluations using a battery of neuropsychological tests were conducted at baseline, week 3 and week 6 of treatment, and after 6 weeks of washout. RESULTS: Circulating total T was increased from baseline an average of 238% in the T and AT treatment groups. Estradiol increased an average of 81% in the T group and decreased 50% in the AT group during treatment. Significant improvements in spatial memory were evident in the AT and T treatment groups. However, only the group with elevated estradiol levels (T group) demonstrated significant verbal memory improvement. CONCLUSION: In healthy older men, improvement in verbal memory induced by testosterone administration depends on aromatization of testosterone to estradiol, whereas improvement in spatial memory occurs in the absence of increases in estradiol.

Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study.

OBJECTIVE: To assess the association between statin therapy and risk of Alzheimer disease (AD) in a prospective cohort study with documented statin exposure and incident dementia. METHODS: This is a prospective, cohort study of statin use and incident dementia and probable AD. A cohort of 2,356 cognitively intact persons, aged 65 and older, were randomly selected from a health maintenance organization (HMO), and were assessed biennially for dementia. Statin use was identified using the HMO pharmacy database. A proportional hazards model with statin use as a time-dependent covariate was used to assess the statin-dementia/AD association. RESULTS: Among 312 participants with incident dementia, 168 had probable AD. The unadjusted hazard ratios (HRs) with statin use were 1.33 (95% CI 0.95 to 1.85) for all-cause dementia and 0.90 (CI 0.54 to 1.51) for probable AD. Adjusted corresponding HRs were 1.19 (CI 0.82 to 1.75) and 0.82 (CI 0.46 to 1.46). A subgroup analysis of participants with at least one APOE-epsilon4 allele who entered the study before age 80 produced an adjusted HR of 0.33 (CI 0.10 to 1.04). CONCLUSION: Employing time-dependent proportional hazards modeling, the authors found no significant association between statin use and incident dementia or probable AD. In contrast, when the data were analyzed, inappropriately, as a case-control study, the authors found an OR of 0.55 for probable AD, falsely indicating a protective effect of statins. Study design and analytic methods may explain the discrepancy between the current null findings and earlier findings.

Chronic cortisol suppresses pituitary and hypothalamic peptide message expression in pigtailed macaques.

The effects of chronic elevations in circulating glucocorticoids on the expression of peptides and peptide receptors of the hypothalamic-pituitary-adrenal (HPA) axis have been studied extensively in rodents, but they have not been examined in primates. To determine the responses of the HPA axis in primates to elevated cortisol, hypothalamic and pituitary tissue from normal older pigtailed macaques (Macaca nemestrina) that had received daily oral administration of cortisol or placebo for 1 year were studied. Pro-opiomelanocortin in the anterior pituitary and corticotropin-releasing factor (CRF) mRNA expression in the hypothalamic paraventricular nucleus (PVN) were significantly reduced in cortisol-treated monkeys in comparison with controls. CRF receptor 1 (CRF-R1) expression in the anterior pituitary and arginine vasopressin mRNA expression in the PVN were unchanged by chronic cortisol administration. Sustained elevation of circulating glucocorticoids results in suppression of HPA peptide and peptide receptor expression in the PVN and anterior pituitary similar to those found in rodents. Chronic therapeutic administration of glucocorticoids in humans may have unintended consequences for hypothalamic and pituitary function.

Relationship between testosterone supplementation and insulin-like growth factor-I levels and cognition in healthy older men.

BACKGROUND: Our laboratory has previously reported that testosterone (T) administration to older men significantly improves cognitive function. This study examined potential changes in insulin-like growth factor (IGF) IGF-I, IGF-II and IGF-related binding proteins in response to T administration in older men and their relationship to cognitive functioning. METHODS: Twenty-five healthy community dwelling volunteers, ranging in age from 50-80 years were randomized to receive weekly intra-muscular (i.m.) injections of either 100 mg T enanthate or placebo (saline) for 6 weeks. Serum hormone levels and cognitive functioning was assessed at baseline and twice during treatment. RESULTS: Significant positive associations between IGF-I and IGF-II and spatial memory, spatial reasoning, and verbal fluency were observed after 6 weeks of T administration. Increased serum T levels from treatment were positively associated with improvement in spatial reasoning performance, whereas estradiol was associated with a decline in divided attention performance. Serum IGF-I, IGF-II and IGFBPs did not change in response to T treatment. CONCLUSIONS: Our results suggest that T, estradiol and IGF-I may have independent and selective effects on cognitive functioning. Positive associations between T levels and cognition are consistent with an effect of androgen treatment, whereas positive associations between IGF-I levels and cognition are reflective of a relationship between endogenous IGF-I levels and cognition.

Insulin increases CSF Abeta42 levels in normal older adults.

BACKGROUND: Abnormal insulin metabolism may contribute to the clinical symptoms and pathophysiology of AD. In vitro studies show that insulin enhances the release of beta-amyloid protein (Abeta) or inhibits its degradation, either of which might increase amyloid burden. METHODS: On separate mornings, 16 healthy older adults (10 women, 6 men; mean age 68.7 years, SD 8.6 years) each underwent two infusions consisting of either saline (placebo) or insulin (1.0 mU x kg(-1) x min(-1)) plus dextrose to maintain euglycemia. After 120 minutes of infusion, blood, CSF, and cognitive measures were acquired. RESULTS: As expected, insulin infusion produced an increase in CSF insulin concentration. Insulin infusion also led to an increase in CSF Abeta42 levels, most notably in older subjects. As has been observed previously, insulin infusion facilitated declarative memory, but such facilitation was attenuated in the subjects with the greatest increase in CSF Abeta42 levels. CONCLUSIONS: These findings are consistent with recent in vitro studies of insulin effects on Abeta and support the notion that insulin may modulate Abeta42 levels acutely in humans.