To investigate the ability of cerebrospinal fluid (CSF) and plasma measures to discriminate early-stage Alzheimer disease (AD) (defined by clinical criteria and presence/absence of brain amyloid) from nondemented aging and to assess whether these biomarkers can predict future dementia in cognitively normal individuals. Design: Evaluation of CSF ␤-amyloid 40 (A␤ 40), A␤ 42 , tau, phosphorylated tau 181 , and plasma A␤ 40 and A␤ 42 and longitudinal clinical follow-up (from 1 to 8 years). Setting: Longitudinal studies of healthy aging and dementia through an AD research center. Participants: Community-dwelling volunteers (n=139) aged 60 to 91 years and clinically judged as cognitively normal (Clinical Dementia Rating [CDR], 0) or having very mild (CDR, 0.5) or mild (CDR, 1) AD dementia. Results: Individuals with very mild or mild AD have reduced mean levels of CSF A␤ 42 and increased levels of CSF tau and phosphorylated tau 181. Cerebrospinal fluid A␤ 42 level completely corresponds with the presence or absence of brain amyloid (imaged with Pittsburgh Compound B) in demented and nondemented individuals. The CSF tau/A␤ 42 ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau 181 /A␤ 42 ratio (adjusted hazard ratio, 4.39; 95% confidence interval, 1.62-11.86) predict conversion from a CDR of 0 to a CDR greater than 0. Conclusions: The very mildest symptomatic stage of AD exhibits the same CSF biomarker phenotype as more advanced AD. In addition, levels of CSF A␤ 42 , when combined with amyloid imaging, augment clinical methods for identifying in individuals with brain amyloid deposits whether dementia is present or not. Importantly, CSF tau/A␤ 42 ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.

Objective-To examine interactions of Apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer's disease (AD) in cognitively normal aging.Methods-Two hundred and 41 cognitively normal individuals, age 45 to 88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta 42 (Aβ 42 ), tau, and phosphorylated tau (ptau 181 ). All individuals were genotyped for APOE.Results-The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Aβ 42 appear to begin earlier (18.2% of those age 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There is a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Aβ 42 with increased numbers of APOE4 alleles. Individuals with an APOE2 have no increase in MCBP with age and have higher CSF Aβ 42 levels than individuals without an APOE2 allele. There is no APOE4 or APOE2 effect on CSF tau or ptau 181 . NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptInterpretation-Increasing cerebral Aβ deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Aβ deposition may first be lowered CSF Aβ 42 , followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.Keywords preclinical Alzheimer's disease; Alzheimer's biomarkers; Aβ; amyloid imaging (PIB); APOE The concept of preclinical Alzheimer's disease (AD) postulates that AD lesions accumulate in the brain for years prior to the appearance of cognitive deficits or symptoms of dementia. 1 This concept developed from observations that densities of senile plaques (SPs) and neurofibrillary tangles (NFTs), sufficient to meet histopathologic criteria for AD, frequently are present in brains of individuals whose cognition at death was normal 2 -9 or stable.10 , 11 Preclinical AD assumes that AD neuropathology in cognitively normal individuals results in progressive neuronal deterioration and eventually will culminate in the clinical syndrome of dementia of the Alzheimer type (DAT), although the time to DAT may be influenced by variables such as an individual's degree of cognitive and brain "reserve".12 -14 To date, however, it is not known whether DAT is inevitable in preclinical AD. It remains possible that certain individuals with presumptive preclinical AD may never develop DAT, no matter how long they live. These biomarkers for AD may identify nondemented individuals at risk for developing DAT. In persons with mild cognitive impairment (MCI),28 progression to a clinical diagnosis of DAT is predicted by CSF Aβ 42 and tau levels and PIB findings.29 -31 Limited studies in cognitively normal older adults show that reduced levels of CSF Aβ 42...

Objective-To determine the frequency and possible cognitive effect of histological Alzheimer's disease (AD) in autopsied older nondemented individuals.Design-Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer's Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions. Setting-Washington University Alzheimer's Disease Research Center.Participants-Ninety-seven nondemented participants who were age 60 years or older at death (mean = 84 years).Results-About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs.Conclusions-Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80-85 years, many nondemented older adults have substantial AD pathology.

The AD8 is a brief, sensitive measure that reliably differentiates between nondemented and demented individuals. Use of the AD8 in conjunction with a brief assessment of the participant could improve diagnostic accuracy in general practice.

Background Disease-modifying therapies for Alzheimer’s disease (AD) would be most beneficial if applied during the ‘preclinical’ stage (pathology present with cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that can detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design. Methods 2D–difference gel electrophoresis and liquid chromatography tandem mass spectrometry were used to measure AD-associated changes in cerebrospinal fluid (CSF). Concentrations of CSF YKL-40 were further evaluated by enzyme-linked immunosorbent assay in the discovery cohort (N=47), an independent sample set (N=292) with paired plasma samples (N=237), frontotemporal lobar degeneration (N=9), and progressive supranuclear palsy (PSP, N=6). Human AD brain was studied immunohistochemically to identify potential source(s) of YKL-40. Results In the discovery and validation cohorts, mean CSF YKL-40 was higher in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) vs. controls (CDR 0) and PSP. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 vs. CDR 0 groups, and correlated with CSF levels. YKL-40 immunoreactivity was observed within astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition. Conclusions These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD, and that, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.