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Introduction: Apolipoprotein E (APOE) ε4 allele status is associated with amyloid and tau-related pathological changes related to Alzheimer's disease (AD). However, it is unknown whether brain network changes are related to amyloid beta (Aβ) and/or tau-related pathology in cognitively normal APOE ε4 carriers with subthreshold Aβ accumulation., Methods: Resting state functional connectivity measures of network integrity were evaluated in cognitively normal individuals (n = 121, mean age 76.6 ± 7.8 years, 15% APOE ε4 carriers, 65% female) with minimal Aβ per cerebrospinal fluid (CSF) or amyloid positron emission tomography., Results: APOE ε4 carriers had increased lateralized connections relative to callosal connections within the default-mode, memory, and salience networks (P = .02), with significant weighting on linear regression toward CSF total tau (P = .03) and CSF phosphorylated tau at codon 181 (P = .03), but not CSF Aβ 42 ., Discussion: Cognitively normal APOE ε4 carriers with subthreshold amyloid accumulation may have network reorganization associated with tau., (© 2021 the Alzheimer's Association.)

Objective: To determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals., Methods: Cross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar β-amyloid (Aβ) with PET using the [ 11 C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers., Results: Accelerated changes in CSF Aβ 1-42 (Aβ 42 ) occurred at 48.28 years of age and in Aβ 42 /Aβ 40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aβ 42 and Aβ 42 /Aβ 40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other., Conclusions: Our findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline., (© 2020 American Academy of Neurology.)

Development of tau-based therapies for Alzheimer's disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer's disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.

Introduction: Cerebrospinal fluid (CSF) biomarkers can identify individuals with Alzheimer's disease (AD) pathology (eg, amyloid plaques, neurofibrillary tangles), but defined analyte cut-points using high-throughput automated assays are necessary for general clinical use., Methods: CSF amyloid β42 peptide (Aβ42), t-tau, and t-tau/Aβ42 were quantified by the Lumipulse platform in two test cohorts (A/B: Eisai BAN2401-201/MISSION AD E2609-301/302, n = 138; C: Knight Alzheimer's Disease Research Center (ADRC), n = 198), and receiver operating characteristic (ROC) curve analyses defined cut-points corresponding best to amyloid determinations using positron emission tomography (PET) imaging. The best-performing cut-point was then validated as a predictor of amyloid status in an independent cohort (D: MISSION AD E2609-301/302, n = 240)., Results: Virtually identical t-tau/Aβ42 cut-points (∼0.54) performed best in both test cohorts and with similar accuracy (areas under ROC curve [AUCs] [A/B: 0.95; C: 0.94]). The cut-point yielded an overall percent agreement with amyloid PET of 85.0% in validation cohort D., Discussion: Lumipulse CSF biomarker measures with validated cut-points have clinical utility in identifying AD pathology., (© 2020 the Alzheimer's Association.)

Importance: The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease., Objectives: To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging., Design, Setting, and Participants: This cohort study was set in tertiary research clinics. Each participant was a member of a pedigree with a known mutation for dominantly inherited Alzheimer disease. Participants were divided into 3 groups on the basis of the presence of a mutation and their Clinical Dementia Rating score. Data analysis was performed in June 2019., Main Outcomes and Measures: Rates of change of CSF tTau and pTau181 levels and their association with the rate of change of brain volume., Results: Data from 465 participants (283 mutation carriers and 182 noncarriers) were analyzed. The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3%) were women. The mean (SD) follow-up duration was 2.7 (1.5) years. Two or more longitudinal CSF and magnetic resonance imaging assessments were available for 160 and 247 participants, respectively. Sixty-five percent of mutation carriers (183) did not have symptoms at baseline (Clinical Dementia Rating score, 0). For mutation carriers, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 approximately 10 years before the estimated year of onset (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and 15 years before onset (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively. The rate of change of pTau181 was positive and increased at the early stages of the disease, showing a positive rate of change starting at 15 estimated years before onset until 5 estimated years before onset (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE], 0.1 [0.3]) and then negative rates of change at 5 years (mean [SE], -0.3 [0.4]) and 10 years (mean [SE], -0.6 [0.6]) after symptom onset. In individuals without symptoms (Clinical Dementia Rating score, 0), the rates of change of CSF tTau and pTau181 were negatively associated with brain atrophy (high rates of change in CSF measures were associated with low rates of change in brain volume in asymptomatic stages). After symptom onset (Clinical Dementia Rating score, >0), an increased rate of brain atrophy was not associated with rates of change of levels of both CSF tTau and pTau181., Conclusions and Relevance: These findings suggest that CSF tTau and pTau181 may have different associations with brain atrophy across the disease time course. These results have implications for understanding the dynamics of disease pathobiology and interpreting neuronal injury biomarker concentrations in response to Alzheimer disease progression and disease-modifying therapies.

Introduction: Vascular factors increase the risk of Alzheimer's disease (AD). We investigated the associations between such factors, longitudinal AD cerebrospinal fluid biomarkers, and cognition., Methods: 433 cognitively normal participants were classified into four biomarker groups using their baseline amyloid (A+/-) and tau status (T+/-). 184 participants had undergone serial cerebrospinal fluid collection. Frequencies of risk factors and the Framingham Risk Score (FRS) were compared, and we tested the influence of risk factors on change in biomarker concentrations and cognition., Results: The absence of obesity, presence of hypertension, and a high FRS were associated with an increase in tau levels, particularly in A+T+ individuals. Risk factors were not associated with amyloid. Depression was associated with higher cognitive scores, whereas high FRS was associated with lower scores and a faster decline., Discussion: Our results demonstrate that vascular risk factors may enhance neurodegeneration but not amyloid accumulation in preclinical AD., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct amyloid/tau/neurodegeneration (ATN) profiles., Methods: Pooling data across 4 cohort studies, 814 cognitively normal participants (mean baseline age = 59.6 years) were classified into 8 ATN groups using baseline CSF levels of β-amyloid 1-42 as a measure of amyloid (A), phosphorylated tau 181 as a measure of tau (T), and total tau as a measure of neurodegeneration (N). Cognitive performance was measured using a previously validated global factor score and with the Mini-Mental State Examination. We compared the cognitive trajectories across groups using growth curve models (mean follow-up time = 7 years)., Results: Using different model formulations and cut points for determining biomarker abnormality, only the group with abnormal levels of amyloid, tau, and neurodegeneration (A+T+N+) showed consistently greater cognitive decline than the group with normal levels of all biomarkers (A-T-N-). Replicating prior findings using the 2011 National Institute on Aging-Alzheimer's Association/suspected non-Alzheimer disease pathophysiology schema, only individuals with abnormal levels of both amyloid and phosphorylated tau 181 or total tau (stage 2) showed greater cognitive decline than those with normal biomarker levels (stage 0)., Conclusion: The results are consistent with the hypothesis that both elevated brain amyloid and neurofibrillary tangles are necessary to observe accelerated neurodegeneration, which in turn leads to cognitive decline., (© 2019 American Academy of Neurology.)

Importance: Racial differences in molecular biomarkers for Alzheimer disease may suggest race-dependent biological mechanisms., Objective: To ascertain whether there are racial disparities in molecular biomarkers for Alzheimer disease., Design, Setting, and Participants: A total of 1255 participants (173 African Americans) were enrolled from January 1, 2004, through December 31, 2015, in longitudinal studies at the Knight Alzheimer Disease Research Center at Washington University and completed a magnetic resonance imaging study of the brain and/or positron emission tomography of the brain with Pittsburgh compound B (radioligand for aggregated amyloid-β) and/or cerebrospinal fluid (CSF) assays for the concentrations of amyloid-β42, total tau, and phosphorylated tau181. Independent cross-sectional analyses were conducted from April 22, 2016, to August 27, 2018, for each biomarker modality with an analysis of variance or analysis of covariance including age, sex, educational level, race, apolipoprotein E (APOE) ε4 allele status, and clinical status (normal cognition or dementia). All biomarker assessments were conducted without knowledge of the clinical status of the participants., Main Outcomes and Measures: The primary outcomes were hippocampal volumes adjusted for differences in intracranial volumes, global cerebral amyloid burden as transformed into standardized uptake value ratios (partial volume corrected), and CSF concentrations of amyloid-β42, total tau, and phosphorylated tau181., Results: Of the 1255 participants (707 women and 548 men; mean [SD] age, 70.8 [9.9] years), 116 of 173 African American participants (67.1%) and 724 of 1082 non-Hispanic white participants (66.9%) had normal cognition. There were no racial differences in the frequency of cerebral ischemic lesions noted on results of brain magnetic resonance imaging, mean cortical standardized uptake value ratios for Pittsburgh compound B, or for amyloid-β42 concentrations in CSF. However, in individuals with a reported family history of dementia, mean (SE) total hippocampal volumes were lower for African American participants than for white participants (6418.26 [138.97] vs 6990.50 [44.10] mm3). Mean (SE) CSF concentrations of total tau were lower in African American participants than in white participants (293.65 [34.61] vs 443.28 [18.20] pg/mL; P < .001), as were mean (SE) concentrations of phosphorylated tau181 (53.18 [4.91] vs 70.73 [2.46] pg/mL; P < .001). There was a significant race by APOE ε4 interaction for both CSF total tau and phosphorylated tau181 such that only APOE ε4-positive participants showed the racial differences., Conclusions and Relevance: The results of this study suggest that analyses of molecular biomarkers of Alzheimer disease should adjust for race. The lower CSF concentrations of total tau and phosphorylated tau181 in African American individuals appear to reflect a significant race by APOE ε4 interaction, suggesting a differential effect of this Alzheimer risk variant in African American individuals compared with white individuals.

In Alzheimer's disease (AD), deposition of insoluble amyloid-β (Aβ) is followed by intracellular aggregation of tau in the neocortex and subsequent neuronal cell loss, synaptic loss, brain atrophy, and cognitive impairment. By the time even the earliest clinical symptoms are detectable, Aβ accumulation is close to reaching its peak and neocortical tau pathology is frequently already present. The period in which AD pathology is accumulating in the absence of cognitive symptoms represents a clinically relevant time window for therapeutic intervention. Sleep is increasingly recognized as a potential marker for AD pathology and future risk of cognitive impairment. Previous studies in animal models and humans have associated decreased non-rapid eye movement (NREM) sleep slow wave activity (SWA) with Aβ deposition. In this study, we analyzed cognitive performance, brain imaging, and cerebrospinal fluid (CSF) AD biomarkers in participants enrolled in longitudinal studies of aging. In addition, we monitored their sleep using a single-channel electroencephalography (EEG) device worn on the forehead. After adjusting for multiple covariates such as age and sex, we found that NREM SWA showed an inverse relationship with AD pathology, particularly tauopathy, and that this association was most evident at the lowest frequencies of NREM SWA. Given that our study participants were predominantly cognitively normal, this suggested that changes in NREM SWA, especially at 1 to 2 Hz, might be able to discriminate tau pathology and cognitive impairment either before or at the earliest stages of symptomatic AD., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau 181 , and whether these increases are associated with accelerated brain volume loss and memory decline., Methods: A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network., Results: In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau 181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical β-amyloid accumulation or change in CSF Aβ 42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical β-amyloid accumulation, or change in any CSF measures of tau, ptau 181 , and CSF Aβ 42 ., Interpretation: As in sporadic AD, the deleterious effects of β-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018;84:424-435., (© 2018 American Neurological Association.)

Objective: To assess the relationships between fluid and imaging biomarkers of tau pathology and compare their diagnostic utility in a clinically heterogeneous sample., Methods: Fifty-three patients (28 with clinical Alzheimer disease [AD] and 25 with non-AD clinical neurodegenerative diagnoses) underwent β-amyloid (Aβ) and tau ([ 18 F]AV1451) PET and lumbar puncture. CSF biomarkers (Aβ 42 , total tau [t-tau], and phosphorylated tau [p-tau]) were measured by multianalyte immunoassay (AlzBio3). Receiver operator characteristic analyses were performed to compare discrimination of Aβ-positive AD from non-AD conditions across biomarkers. Correlations between CSF biomarkers and PET standardized uptake value ratios (SUVR) were assessed using skipped Pearson correlation coefficients. Voxelwise analyses were run to assess regional CSF-PET associations., Results: [ 18 F]AV1451-PET cortical SUVR and p-tau showed excellent discrimination between Aβ-positive AD and non-AD conditions (area under the curve 0.92-0.94; ≤0.83 for other CSF measures), and reached 83% classification agreement. In the full sample, cortical [ 18 F]AV1451 was associated with all CSF biomarkers, most strongly with p-tau ( r = 0.75 vs 0.57 for t-tau and -0.49 for Aβ 42 ). When restricted to Aβ-positive patients with AD, [ 18 F]AV1451 SUVR correlated modestly with p-tau and t-tau (both r = 0.46) but not Aβ 42 ( r = 0.02). On voxelwise analysis, [ 18 F]AV1451 correlated with CSF p-tau in temporoparietal cortices and with t-tau in medial prefrontal regions. Within AD, Mini-Mental State Examination scores were associated with [ 18 F]AV1451-PET, but not CSF biomarkers., Conclusion: [ 18 F]AV1451-PET and CSF p-tau had comparable value for differential diagnosis. Correlations were robust in a heterogeneous clinical group but attenuated (although significant) in AD, suggesting that fluid and imaging biomarkers capture different aspects of tau pathology., Classification of Evidence: This study provides Class III evidence that, in a clinical sample of patients with a variety of suspected neurodegenerative diseases, both CSF p-tau and [ 18 F]AV1451 distinguish AD from non-AD conditions., (Copyright © 2017 American Academy of Neurology.)

Background: The Caribbean vervet monkey ( Chlorocebus aethiops sabaeus ) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood., Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aβ 1-40 , Aβ 1-42 , total tau, and p-tau 181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits., Results: Aβ 1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau 181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aβ 1-40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak., Conclusions: Overall, these results support the vervet as a non-human primate model of amyloid-related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aβ 1-40 and p-tau 181 as potentially valuable biomarkers of these processes.

Background: There exists a need for more sensitive measures capable of detecting subtle cognitive decline due to Alzheimer's disease., Objective: To advance the literature in Alzheimer's disease by demonstrating that performance on a cued-Stroop task is impacted by preclinical Alzheimer's disease neuropathology., Method: Twenty-nine cognitively asymptomatic older adults completed a computerized, cued-Stroop task in which accuracy rates and intraindividual variability in reaction times were the outcomes of interest. Cerebrospinal fluid biomarkers of Aβ42 and tau were measured and participants were then grouped according to a published p-tau/Aβ42 cutoff reflecting risk for Alzheimer's disease (preclinical Alzheimer's disease = 14; control = 15)., Results: ANOVAs indicated that accuracy rates did not differ between the groups but 4-second delay incongruent color-naming Stroop coefficient of variation reaction times were higher in the preclinical Alzheimer's disease group compared to the control group, reflecting increased within-person variability. Moreover, partial correlations showed no relationships between cerebrospinal fluid biomarkers and accuracy rates. However, increases in coefficient of variation reaction times correlated with decreased Aβ42 and increases in p-tau and the p-tau/Aβ42 ratio., Conclusion: Results supported the ability of the computerized, cued-Stroop task to detect subtle Alzheimer's disease neuropathology using a small cohort of cognitively asymptomatic older adults. The ongoing measurement of cued-Stroop coefficient of variation reaction times has both scientific and clinical utility in preclinical Alzheimer's disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: The objective of this study was to evaluate the relationship between self-reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers., Methods: In 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self-reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aβ 42, and CSF tau levels was evaluated using linear regression., Results: No differences in brain amyloid load, CSF Aβ 42 , or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels., Discussion: Our findings indicate a relationship exists between self-reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.

Objective: To examine potential disease-modifying effects of statin drugs, we conducted a 12-month randomized, placebo-controlled clinical trial of simvastatin in cognitively normal adults using change in CSF Alzheimer disease biomarkers as primary outcome measure., Methods: Participants were 45-64 years old and statin-naive with normal cognition and normal or mildly elevated cholesterol. Forty-six participants completed the 1-year study per protocol (25 in the simvastatin and 21 in the placebo group). Simvastatin was titrated to 40 mg/d. CSF Aβ 42 , total tau, and p-tau 181 were measured at baseline and after 12 months of treatment using the INNO-BIA AlzBio3 assay. We used analysis of covariance to assess differences in biomarker change from baseline between treatment groups, adjusting for age, sex, and APOE ε4 status., Results: Changes from baseline did not differ significantly between treatment groups for any CSF biomarker, with p values of 0.53, 0.36, and 0.25 for CSF Aβ 42 , total tau, and p-tau 181 , respectively. There was no significant modifying effect of sex, APOE ε4, or baseline high-density lipoprotein or triglycerides on treatment group for any of the biomarkers (all p > 0.18). However, a significant interaction between treatment group and baseline low-density lipoprotein (LDL) was observed for p-tau 181 ( p = 0.003), where greater decreases from baseline in CSF p-tau 181 concentrations were associated with higher baseline LDL level for the simvastatin group., Conclusions: Simvastatin-related reductions in CSF p-tau 181 concentrations may be modulated by LDL cholesterol. The potential disease-modifying effects of simvastatin on CSF phospho-tau should be further investigated in persons with hypercholesterolemia., (© 2017 American Academy of Neurology.)

To assess stages of Alzheimer's disease (AD) pathogenesis and the efficacy of drugs during clinical trials, there has been immense interest in the field to establish baseline cerebrospinal fluid (CSF) concentrations for potential AD biomarkers such as amyloid-β (Aβ) and tau. Significant within-person variations in CSF Aβ concentrations over time found that this variation followed the sleep-wake cycle. A recent paper in Molecular Neurodegeneration reported the absence of diurnal variations in multiple classical and candidate AD biomarkers, such as soluble APP, Aβ, tau, p-tau, YKL-40, VILIP-1, or apolipoprotein E. This commentary addresses these apparently discordant results regarding the diurnal variability of APP and Aβ compared with the literature. Despite our concerns, we appreciate the authors' interest in this important topic and contribution to improve our knowledge about the factors influencing Aβ diurnal variation.

More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ 42 ), tau, and phosphorylated tau (ptau 181 ) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau 181 , including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ 42 near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10 -8 ) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10 -8 ) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10 -2 ), disease progression (GLIS1: β = 0.277, P = 1.92 × 10 -2 ), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10 -3 ). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ 42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau 181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.

We examined whether neuropsychiatric symptoms (NPS) interact with cerebrospinal fluid (CSF) biomarkers (amyloid-β42 [Aβ42], tau, phosphorylated tau181 [ptau181], tau/Aβ42, and ptau181/Aβ42) of Alzheimer's disease pathology to predict driving decline among cognitively-normal older adults (N = 116) aged ≥65. Cox proportional hazards models examined time to receiving a rating of marginal or fail on the driving test. Age, education, and gender were adjusted in the models. Participants with more abnormal CSF (Aβ42, tau/Aβ42, ptau181/Aβ42) and NPS were faster to receive a marginal/fail on the road test compared to those without NPS. NPS interact with abnormal CSF biomarkers to impact driving performance among cognitively-normal older adults.

Objectives: To evaluate whether cerebrospinal fluid (CSF) and PET Pittsburgh Compound B (PiB) biomarkers of underlying Alzheimer disease (AD) pathology (β-amyloid 42 [Aβ 42 ], tau, phosphorylated tau 181 [ptau 181 ], tau/Aβ 42 , ptau 181 /Aβ 42 and mean cortical binding potential [MCBP] for PET-PiB) predict changes in mood in cognitively normal older adults., Setting: Knight Alzheimer's Disease Research Center (ADRC) at Washington University (WU)., Participants: Participants, 65 years of age or older, were enrolled from longitudinal studies at the WU Knight ADRC., Measurements: CSF, PET-PiB biomarkers, Clinical Dementia Rating (CDR), Mini-Mental State Examination (MMSE), Profile of Mood States-Short Form (POMS-SF), the Geriatric Depression Scale (GDS), and Neuropsychiatric Inventory Questionnaire (NPI-Q)., Results: Data from 118 participants at baseline and 66 participants at one-year follow-up were analyzed. CSF and PET biomarkers were not associated cross-sectionally with any mood disturbances at baseline (p > 0.05). Changes in mood as indicated by the total mood disturbance score on the POMS-SF, selected POMS-SF subscales, GDS, and NPI-Q scores from baseline to one-year follow-up were associated with (p < 0.05) CSF and PET-PiB biomarkers. There was no statistically significant decline in cognitive functioning., Conclusions: Generally, higher values of CSF and PET-PiB biomarkers are associated with more changes in mood in cognitively normal older adults. Further work is needed to understand the temporal development of mood changes over several years during the phase of preclinical AD. Evaluating mood as a noncognitive outcome may provide further insight into the development of preclinical AD in cognitively normal older adults., (Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer's disease., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: Preclinical Alzheimer disease (AD) can be staged using a 2-factor model denoting the presence or absence of β-amyloid (Aβ+/-) and neurodegeneration (ND+/-). The association of these stages with longitudinal biomarker outcomes is unknown., Objective: To examine whether longitudinal Aβ accumulation and hippocampal atrophy differ based on initial preclinical staging., Design, Setting, and Participants: This longitudinal population-based cohort study used data collected at the Knight Alzheimer Disease Research Center, Washington University, St Louis, Missouri, from December 1, 2006, to June 31, 2015. Cognitively normal older adults (n = 174) were recruited from the longitudinal Adult Children Study and Healthy Aging and Senile Dementia Study at the Knight Alzheimer Disease Research Center. At baseline, all participants had magnetic resonance imaging (MRI) scans, positron emission tomography (PET) scans with carbon 11-labeled Pittsburgh Compound B (PiB), and cerebrospinal fluid assays of tau and phosphorylated tau (ptau) acquired within 12 months. Using the baseline biomarkers, individuals were classified into preclinical stage 0 (Aβ-/ND-), 1 (Aβ+/ND-), or 2+ (Aβ+/ND+) or suspected non-AD pathophysiology (SNAP; Aβ-/ND+)., Main Outcomes and Measures: Subsequent longitudinal accumulation of Aβ assessed with PiB PET and loss of hippocampal volume assessed with MRI in each group., Results: Among the 174 participants (81 men [46.6%]; 93 women [53.4%]; mean [SD] age, 65.7 [8.9] years), a proportion (14%-17%) of individuals with neurodegeneration alone (SNAP) later demonstrated Aβ+. The rates of Aβ accumulation and loss of hippocampal volume in individuals with SNAP were indistinguishable from those without any pathologic features at baseline (for Aβ accumulation: when hippocampal volume was used to define ND, t = 0.00 [P > .99]; when tau and ptau were used to define ND, t = -0.02 [P = .98]; for loss of hippocampal volume: when hippocampal volume was used to define ND, t = -1.34 [P = .18]; when tau and ptau were used to define ND, t = 0.84 [P = .40]). Later preclinical stages (stages 1 and 2+) had elevated Aβ accumulation. Using hippocampal volume to define ND, individuals with stage 1 had accelerated Aβ accumulation relative to stage 0 (t = 11.06; P < .001), stage 2+ (t = 2.10; P = .04), and SNAP (t = 9.32; P < .001), and those with stage 2+ had accelerated Aβ accumulation relative to stage 0 (t = 4.38; P < .001) and SNAP (t = 4.08; P < .001). When ND was defined using tau and ptau, individuals with stage 2+ had accelerated Aβ accumulation relative to stage 0 (t = 4.96) and SNAP (t = 4.06), and those with stage 1 had accelerated Aβ accumulation relative to stage 0 (t = 8.44) and SNAP (t = 6.61) (P < .001 for all comparisons). When ND was defined using cerebrospinal fluid biomarkers, individuals with stage 2+ had accelerated hippocampal atrophy relative to stage 0 (t = -3.41; P < .001), stage 1 (t = -2.48; P = .03), and SNAP (t = -2.26; P = .03)., Conclusions and Relevance: More advanced preclinical stages of AD have greater longitudinal Aβ accumulation. SNAP appears most likely to capture inherent individual variability in brain structure or to represent comorbid pathologic features rather than early emerging AD. Low hippocampal volumes or elevated levels of tau or ptau in isolation may not accurately represent ongoing neurodegenerative processes., Competing Interests: Disclosures: No other disclosures were reported.

Importance: In vivo tau imaging may become a diagnostic marker for Alzheimer disease (AD) and provides insights into the pathophysiology of AD., Objective: To evaluate the usefulness of [18F]-AV-1451 positron emission tomography (PET) imaging to stage AD and assess the associations among β-amyloid (Aβ), tau, and volume loss., Design, Setting, and Participants: An imaging study conducted at Knight Alzheimer Disease Research Center at Washington University in St Louis, Missouri. A total of 59 participants who were cognitively normal (CN) (Clinical Dementia Rating [CDR] score, 0) or had AD dementia (CDR score, >0) were included., Main Outcomes and Measures: Standardized uptake value ratio (SUVR) of [18F]-AV-1451 in the hippocampus and a priori-defined AD cortical signature regions, cerebrospinal fluid Aβ42, hippocampal volume, and AD signature cortical thickness., Results: Of the 59 participants, 38 (64%) were male; mean (SD) age was 74 (6) years. The [18F]-AV-1451 SUVR in the hippocampus and AD cortical signature regions distinguished AD from CN participants (area under the receiver operating characteristic curve range [95% CI], 0.89 [0.73-1.00] to 0.98 [0.92-1.00]). An [18F]-AV-1451 SUVR cutoff value of 1.19 (sensitivity, 100%; specificity, 86%) from AD cortical signature regions best separated cerebrospinal fluid Aβ42-positive (Aβ+) AD from cerebrospinal fluid Aβ42-negative (Aβ-) CN participants. This same cutoff also divided Aβ+ CN participants into low vs high tau groups. Moreover, the presence of Aβ+ was associated with an elevated [18F]-AV-1451 SUVR in AD cortical signature regions (Aβ+ participants: mean [SD], 1.3 [0.3]; Aβ- participants: 1.1 [0.1]; F = 4.3, P = .04) but not in the hippocampus. The presence of Aβ+ alone was not related to hippocampal volume or AD signature cortical thickness. An elevated [18F]-AV-1451 SUVR was associated with volumetric loss in both the hippocampus and AD cortical signature regions. The observed [18F]-AV-1451 SUVR volumetric association was modified by Aβ status in the hippocampus but not in AD cortical signature regions. An inverse association between hippocampal [18F]-AV-1451 SUVR and volume was seen in Aβ+ participants (R2 = 0.55; P < .001) but not Aβ- (R2 = 0; P = .97) participants., Conclusions and Relevance: Use of [18F]-AV-1451 has a potential for staging of the preclinical and clinical phases of AD. β-Amyloid interacts with hippocampal and cortical tauopathy to affect neurodegeneration. In the absence of Aβ, hippocampal tau deposition may be insufficient for the neurodegenerative process that leads to AD., Competing Interests: Disclosures: Dr Fagan is a member of the scientific advisory boards of IBL International and Roche and is a consultant for AbbVie, Novartis, and DiamiR. Drs Benzinger and Morris and are currently participating in a clinical trial of antidementia drugs: A4 (The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease) trial. Dr Benzinger also participates in the Dominantly Inherited Alzheimer Network Trials Unit and in clinical trials sponsored by Eli Lilly/Avid Radiopharmaceuticals. Dr Morris has served as a consultant for Lilly USA and Takeda Pharmaceuticals. Drs Benzinger and Morris receive research support from Eli Lilly/Avid Radiopharmaceuticals. Dr McConathy has served as a consultant for Eli Lilly/Avid Radiopharmaceuticals, GE Healthcare, and Siemens Healthcare. No other disclosures were reported.

The two primary molecular pathologies in Alzheimer's disease are amyloid-β plaques and tau-immunoreactive neurofibrillary tangles. Investigations into these pathologies have been restricted to cerebrospinal fluid assays, and positron emission tomography tracers that can image amyloid-β plaques. Tau tracers have recently been introduced into the field, although the utility of the tracer and its relationship to other Alzheimer biomarkers are still unknown. Here we examined tau deposition in 41 cognitively normal and 11 cognitively impaired older adults using the radioactive tau ligand (18)F-AV-1451 (previously known as T807) who also underwent a lumbar puncture to assess cerebrospinal fluid levels of total tau (t-tau), phosphorylated tau181 (p-tau181) and amyloid-β42 Voxel-wise statistical analyses examined spatial patterns of tau deposition associated with cognitive impairment. We then related the amount of tau tracer uptake to levels of cerebrospinal fluid biomarkers. All analyses controlled for age and gender and, when appropriate, the time between imaging and lumbar puncture assessments. Symptomatic individuals (Clinical Dementia Rating > 0) demonstrated markedly increased levels of tau tracer uptake. This elevation was most prominent in the temporal lobe and temporoparietal junction, but extended more broadly into parietal and frontal cortices. In the entire cohort, there were significant relationships among all cerebrospinal fluid biomarkers and tracer uptake, notably for tau-related cerebrospinal fluid markers. After controlling for levels of amyloid-β42, the correlations with tau uptake were r = 0.490 (P < 0.001) for t-tau and r = 0.492 (P < 0.001) for p-tau181 Within the cognitively normal cohort, levels of amyloid-β42, but not t-tau or p-tau181, were associated with elevated tracer binding that was confined primarily to the medial temporal lobe and adjacent neocortical regions. AV-1451 tau binding in the medial temporal, parietal, and frontal cortices is correlated with tau-related cerebrospinal fluid measures. In preclinical Alzheimer's disease, there is focal tauopathy in the medial temporal lobes and adjacent cortices., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD., Methods: The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO., Results: Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset., Interpretation: Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease. Ann Neurol 2016;79:929-939., (© 2016 American Neurological Association.)

Alzheimer's disease (AD) is characterized by two molecular pathologies: cerebral β-amyloidosis in the form of β-amyloid (Aβ) plaques and tauopathy in the form of neurofibrillary tangles, neuritic plaques, and neuropil threads. Until recently, only Aβ could be studied in humans using positron emission tomography (PET) imaging owing to a lack of tau PET imaging agents. Clinical pathological studies have linked tau pathology closely to the onset and progression of cognitive symptoms in patients with AD. We report PET imaging of tau and Aβ in a cohort of cognitively normal older adults and those with mild AD. Multivariate analyses identified unique disease-related stereotypical spatial patterns (topographies) for deposition of tau and Aβ. These PET imaging tau and Aβ topographies were spatially distinct but correlated with disease progression. Cerebrospinal fluid measures of tau, often used to stage preclinical AD, correlated with tau deposition in the temporal lobe. Tau deposition in the temporal lobe more closely tracked dementia status and was a better predictor of cognitive performance than Aβ deposition in any region of the brain. These data support models of AD where tau pathology closely tracks changes in brain function that are responsible for the onset of early symptoms in AD., (Copyright © 2016, American Association for the Advancement of Science.)

Background: The influence of reserve variables and Alzheimer's disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on "non-cognitive" outcomes, including functional abilities and mood., Objective: We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior., Methods: Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants., Results: Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers., Conclusions: The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD.

Importance: Measures of neuronal loss are likely good surrogates for clinical and radiological disease progression in Alzheimer disease (AD). Cerebrospinal fluid (CSF) markers of neuronal injury or neurodegeneration may offer usefulness in predicting disease progression and guiding outcome assessments and prognostic decisions in clinical trials of disease-modifying therapies. Visinin-like protein 1 (VILIP-1) has demonstrated potential usefulness as a marker of neuronal injury in AD., Objective: To investigate the usefulness of CSF VILIP-1, tau, p-tau181, and Aβ42 levels in predicting rates of whole-brain and regional atrophy in early AD and cognitively normal control subjects over time., Design, Setting, and Participants: Longitudinal observational study of brain atrophy in participants with early AD and cognitively normal controls. Study participants had baseline CSF biomarker measurements and longitudinal magnetic resonance imaging assessments for a mean follow-up period of 2 to 3 years. Mixed linear models assessed the ability of standardized baseline CSF biomarker measures to predict rates of whole-brain and regional atrophy over the follow-up period. The setting was The Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St Louis. Participants (mean age, 72.6 years) were individuals with a clinical diagnosis of very mild AD (n = 23) and cognitively normal controls (n = 64) who were enrolled in longitudinal studies of healthy aging and dementia. The study dates were 2000 to 2010., Main Outcomes and Measures: Correlations between baseline CSF biomarker measures and rates of whole-brain or regional atrophy in the AD and control cohorts over the follow-up period., Results: Baseline CSF VILIP-1, tau, and p-tau181 levels (but not Aβ42 levels) predicted rates of whole-brain and regional atrophy in AD over the follow-up period. Baseline CSF VILIP-1 levels predicted whole-brain (P = .006), hippocampal (P = .01), and entorhinal (P = .001) atrophy rates at least as well as tau and p-tau181 in early AD. Cognitively normal controls whose CSF VILIP-1, tau, or p-tau181 levels were in the upper tercile had higher rates of whole-brain (P = .02, P = .003, and P = .02, respectively), hippocampal (P = .001, P = .01, and P = .02, respectively), and entorhinal (P = .007, P = .01, and P = .01, respectively) atrophy compared with those whose levels were in the lower 2 terciles., Conclusions and Relevance: Cerebrospinal fluid VILIP-1 levels predict rates of whole-brain and regional atrophy similarly to tau and p-tau181 and may provide a useful CSF biomarker surrogate for neurodegeneration in early symptomatic and preclinical AD.

Objectives: To determine whether an MRI-based Alzheimer disease (AD) signature biomarker can detect tau-related neurodegeneration in preclinical AD, and to assess whether AD signature cortical thinning is associated with cognitive changes in cognitively normal (CN) older individuals., Methods: In a large cohort of CN individuals (n = 188), we measured the hippocampal volume and cortical thickness within independently defined AD signature regions. We cross-sectionally assessed the associations between AD signature cortical thinning or hippocampal atrophy with CSF biomarkers of tau (increased tau) and β-amyloid (Aβ) (decreased Aβ42). We also examined the impact of AD signature cortical thinning or other biomarker changes (i.e., hippocampal atrophy, reduced CSF Aβ42, or increased CSF tau) on cognitive performance in CN individuals., Results: Elevated CSF tau was associated with AD signature cortical thinning but not hippocampal atrophy. In contrast, decreased CSF Aβ42 was associated with hippocampal loss but not AD signature cortical thinning. In addition, AD signature cortical thinning was associated with lower visuospatial performance. Reduced CSF Aβ42 was related to poorer performance on episodic memory., Conclusions: Spatially distinct neurodegeneration is associated with Aβ and tau pathology in preclinical AD. Aβ deposition and AD signature cortical atrophy independently affect cognition in CN older individuals., (© 2015 American Academy of Neurology.)

Several potential disease-modifying drugs for Alzheimer's disease (AD) have failed to show any effect on disease progression in clinical trials, conceivably because the AD subjects are already too advanced to derive clinical benefit from treatment and because diagnosis based on clinical criteria alone introduces a high misdiagnosis rate. Thus, well-validated biomarkers for early detection and accurate diagnosis are crucial. Low cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ1-42) peptide, in combination with high total tau and phosphorylated tau, are sensitive and specific biomarkers highly predictive of progression to AD dementia in patients with mild cognitive impairment. However, interlaboratory variations in the results seen with currently available immunoassays are of concern. Recent worldwide standardization efforts and quality control programs include standard operating procedures for both preanalytical (e.g., lumbar puncture and sample handling) and analytical (e.g., preparation of calibration curve) procedures. Efforts are also ongoing to develop highly reproducible assays on fully automated instruments. These global standardization and harmonization measures will provide the basis for the generalized international application of CSF biomarkers for both clinical trials and routine clinical diagnosis of AD., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome., Methods: A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aβ42 was used as a continuous trait in these analyses., Results: The ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aβ42) compared with elderly control subjects with no pathology (low ptau181, high Aβ42). The FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD., Conclusions: Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: To test whether CSF Alzheimer disease biomarkers (β-amyloid 42 [Aβ42], tau, phosphorylated tau at threonine 181 [ptau181], tau/Aβ42, and ptau181/Aβ42) predict future decline in noncognitive outcomes among individuals cognitively normal at baseline., Methods: Longitudinal data from participants (N = 430) who donated CSF within 1 year of a clinical assessment indicating normal cognition and were aged 50 years or older were analyzed. Mixed linear models were used to test whether baseline biomarker values predicted future decline in function (instrumental activities of daily living), weight, behavior, and mood. Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination scores were also examined., Results: Abnormal levels of each biomarker were related to greater impairment with time in behavior (p < 0.035) and mood (p < 0.012) symptoms, and more difficulties with independent activities of daily living (p < 0.012). However, biomarker levels were unrelated to weight change with time (p > 0.115). As expected, abnormal biomarker values also predicted more rapidly changing Mini-Mental State Examination (p < 0.041) and Clinical Dementia Rating Sum of Boxes (p < 0.001) scores compared with normal values., Conclusions: CSF biomarkers among cognitively normal individuals are associated with future decline in some, but not all, noncognitive Alzheimer disease symptoms studied. Additional work is needed to determine the extent to which these findings generalize to other samples.

Importance: Resting-state functional connectivity magnetic resonance imaging has great potential for characterizing pathophysiological changes during the preclinical phase of Alzheimer disease., Objective: To assess the relationship between default mode network integrity and cerebrospinal fluid biomarkers of Alzheimer disease pathology in cognitively normal older individuals., Design, Setting, and Participants: Cross-sectional cohort study at The Charles F. and Joanne Knight Alzheimer's Disease Research Center at Washington University in St Louis, St Louis, Missouri, among 207 older adults with normal cognition (Clinical Dementia Rating, 0)., Main Outcomes and Measures: Resting-state functional connectivity magnetic resonance imaging measures of default mode network integrity., Results: Decreased cerebrospinal fluid Aβ42 and increased cerebrospinal fluid phosphorylated tau181 were independently associated with reduced default mode network integrity, with the most prominent decreases in functional connectivity observed between the posterior cingulate and medial temporal regions. Observed reductions in functional connectivity were unattributable to age or structural atrophy in the posterior cingulate and medial temporal areas. Similar resting-state functional connectivity magnetic resonance imaging findings in relation to cerebrospinal fluid biomarkers were obtained using region-of-interest analyses and voxelwise correlation mapping., Conclusions and Relevance: Both Aβ and tau pathology affect default mode network integrity before clinical onset of Alzheimer disease.

Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ₄₂ are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10⁻⁹ for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10⁻⁸ and p = 3.22 × 10⁻⁹ for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10⁻⁸ for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10⁻⁴, 0.039, 4.86 × 10⁻⁵, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Biomarkers are needed to improve the sensitivity and accuracy of diagnosis, and also prognosis, in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau protein levels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of the Alzheimer type., Design: A single CSF sample and longitudinal magnetic resonance scans were collected. The CSF samples were assayed for tau, phosphorylated tau181 (p-tau181), Aβ1-42, and Aβ1-40 using an enzyme-linked immunosorbent assay. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference., Patients or Other Participants: Thirteen participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0)., Intervention: None., Main Outcome Measures: Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum, and CA2-4+DG cellular subfields, and their correlations with initial CSF measures., Results: Lower CSF Αβ1-42 levels and higher tau/Αβ1-42 and p-tau181/Αβ1-42 ratios were strongly correlated with decreases in hippocampal volume and measures of progressive inward deformations of the CA1 subfield in participants with early AD, but not in cognitively normal participants., Conclusions: Despite the small sample size, we found that Αβ1-42 related and tau-related CSF measures were associated with hippocampal degeneration in individuals with clinically diagnosed early AD and may reflect an association with a common underlying disease mechanism.

Research progress has provided detailed understanding of the molecular pathogenesis of Alzheimer disease (AD). This knowledge has been translated into new drug candidates with putative disease-modifying effects, which are now being tested in clinical trials. The promise of effective therapy has created a great need for biomarkers able to detect AD in the predementia phase, because drugs will probably be effective only if neurodegeneration is not too advanced. In this chapter, cerebrospinal fluid (CSF) and plasma biomarkers are reviewed. The core CSF biomarkers total tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of β-amyloid (Aβ42) reflect AD pathology, and have high diagnostic accuracy to diagnose AD with dementia and prodromal AD in mild cognitive impairment cases. The rationale for the use of CSF biomarkers to identify and monitor the mechanism of action of new drug candidates is also outlined in this chapter.

Background: Cross-sectional studies suggest that the cognitive impact of Alzheimer disease pathology varies depending on education and brain size., Objective: To evaluate the combination of cerebrospinal fluid biomarkers of β-amyloid(42) (Aβ(42)), tau, and phosphorylated tau (ptau(181)) with education and normalized whole-brain volume (nWBV) to predict incident cognitive impairment., Design: Longitudinal cohort study., Setting: Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, St Louis, Missouri., Participants: A convenience sample of 197 individuals 50 years and older with normal cognition (Clinical Dementia Rating of 0) at baseline observed for a mean of 3.3 years., Main Outcome Measure: Time to Clinical Dementia Rating ≥ 0.5., Results: Three-factor interactions among the baseline biomarker values, education, and nWBV were found for Cox proportional hazards regression models testing tau (P = .02) and ptau (P = .008). In those with lower tau values, nWBV (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.31-0.91; P = .02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (P = .01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment in those with higher ptau values (P = .02)., Conclusion: In individuals with normal cognition and higher levels of cerebrospinal fluid tau and ptau at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.

Background: Cerebrospinal fluid (CSF) biomarkers of Alzheimer disease (AD) are currently being considered for inclusion in revised diagnostic criteria for research and/or clinical purposes to increase the certainty of antemortem diagnosis., Objective: To test whether CSF biomarker assays differ in their ability to identify true markers of underlying AD pathology (eg, amyloid plaques and/or neurofibrillary tangles) in living individuals., Design: We compared the performances of the 2 most commonly used platforms, INNOTEST enzyme-linked immunosorbent assay and INNO-BIA AlzBio3, for measurement of CSF β-amyloid (Aβ) and tau proteins to identify the presence of amyloid plaques in a research cohort (n=103). Values obtained for CSF Aβ1-42, total tau, and phosphorylated tau 181 (p-tau(181)) using the 2 assay platforms were compared with brain amyloid load as assessed by positron emission tomography using the amyloid imaging agent Pittsburgh compound B., Setting: The Knight Alzheimer's Disease Research Center at Washington University in St Louis, Missouri., Subjects: Research volunteers who were cognitively normal or had mild to moderate AD dementia., Results: The 2 assay platforms yielded different (approximately 2- to 6-fold) absolute values for the various analytes, but relative values were highly correlated. The CSF Aβ1-42 correlated inversely and tau and p-tau(181) correlated positively with the amount of cortical Pittsburgh compound B binding, albeit to differing degrees. Both assays yielded similar patterns of CSF biomarker correlations with amyloid load. The ratios of total tau to Aβ1-42 and p-tau(181) to Aβ1-42 outperformed any single analyte, including Aβ1-42, in discriminating individuals with vs without cortical amyloid., Conclusions: The INNOTEST and INNO-BIA CSF platforms perform equally well in identifying individuals with underlying amyloid plaque pathology. Differences in absolute values, however, point to the need for assay-specific diagnostic cutoff values.

Alzheimer's Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau(181)) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau(181) levels in two independent CSF series (P(combined) = 1.17 x 10(-05)). We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series (P(combined) = 1.17 x 10(-05)). Our analyses suggest that genetic variants associated with CSF ptau(181) levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aβ(42) levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF Aβ(42) levels. Finally, we believe genome-wide association studies of CSF tau/ptau(181) levels should identify novel genetic variants which will likely influence rate of progression of AD., Competing Interests: The work presented in this report is also the subject of a pending patent filed by Washington University in St. Louis, Missouri, United States of America, in which Drs. C. Cruchaga, A. M. Goate, D. M. Holtzman and A. Fagan are named as inventors. The patent is currently under option to AstraZeneca Pharmaceuticals, LP. Drs. Goate and Holtzman have acted as consultants for AstraZeneca Pharmaceuticals, LP, in 2008/2009.

Objective: In addition to the increasingly recognized role of physical exercise in maintaining cognition, exercise may influence Alzheimer's disease (AD) pathology, as transgenic mouse studies show lowered levels of AD pathology in exercise groups. The objective of this study was to elucidate the association between exercise and AD pathology in humans using Pittsburgh compound-B (PIB), amyloid-beta (Abeta)(42), tau, and phosphorylated tau (ptau)(181) biomarkers., Methods: Sixty-nine older adults (17 males, 52 females) aged 55 to 88 years, were recruited and confirmed to be cognitively normal. A questionnaire on physical exercise levels over the past decade was administered to all. Cerebrospinal fluid samples were collected from 56 participants, and amyloid imaging with PIB was performed on 54 participants., Results: Participants were classified based on biomarker levels. Those with elevated PIB (p = 0.030), tau (p = 0.040), and ptau(181) (p = 0.044) had significantly lower exercise, with a nonsignificant trend for lower Abeta(42) (p = 0.135) to be associated with less exercise. Results were similar for PIB after controlling for covariates; tau (p = 0.115) and ptau(181) (p = 0.123) differences were reduced to nonsignificant trends. Additional analyses also demonstrated that active individuals who met the exercise guidelines set by the American Heart Association had significantly lower PIB binding and higher Abeta(42) levels with and without controlling for covariates (PIB: p = 0.006 and p = 0.001; Abeta(42): p = 0.042 and p = 0.046). Last, the associations between exercise engagement and PIB levels were more prominent in APOE epsilon 4 noncarriers., Interpretation: Collectively, these results are supportive of an association between exercise engagement and AD biomarkers in cognitively normal older adults.

Objective: To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging., Methods: Two hundred forty-one cognitively normal individuals, aged 45-88 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) (Abeta(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 Abeta(42) appeared to begin earlier (18.2% of those aged 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Abeta(42) with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Abeta(42) levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau(181)., Interpretation: Increasing cerebral Abeta deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Abeta deposition may first be lowered CSF Abeta(42), followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.

Recent large-scale genetic studies of late-onset Alzheimer's disease have identified risk variants in CALHM1, GAB2, and SORL1. The mechanisms by which these genes might modulate risk are not definitively known. CALHM1 and SORL1 may alter amyloid-β (Aβ) levels and GAB2 may influence phosphorylation of the tau protein. In this study we have analyzed disease associated genetic variants in each of these genes for association with cerebrospinal fluid (CSF) Aβ or tau levels in 602 samples from two independent CSF series. We failed to detect association between CSF Aβ42 levels and single nucleotide polymorphisms in SORL1 despite substantial statistical power to detect association. While we also failed to detect association between variants in GAB2 and CSF tau levels, power to detect this association was limited. Finally, our data suggest that the minor allele of rs2986017, in CALHM1, is marginally associated with CSF Aβ42 levels. This association is consistent with previous reports that this non-synonymous coding substitution results in increased Aβ levels in vitro and provides support for an Aβ-related mechanism for modulating risk for Alzheimer's disease.

Background: Cerebrospinal fluid (CSF) levels of Abeta peptide 1-42 (Abeta 42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer disease., Objective: To determine whether Abeta 42, tau, and ptau predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT)., Design: Retrospective analysis of CSF biomarkers and clinical data., Setting: An academic Alzheimer disease research center., Participants: Research volunteers in a longitudinal study of aging and cognition. Participants (n = 49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All the participants had at least 1 follow-up assessment (mean [SD] follow-up, 3.5 [1.8] years)., Main Outcome Measures: Baseline CSF levels of Abeta 42, Abeta 40, tau, and ptau at threonine 181 (ptau181) and the rate of dementia progression as measured using the CDR sum of boxes (CDR-SB) score and psychometric performance., Results: The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Abeta 42 levels, higher tau or ptau181 levels, or high tau: Abeta 42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Abeta 42 values and 0.3 for the highest tertile of Abeta 42 values., Conclusions: In individuals with very mild DAT, lower CSF Abeta 42 levels, high tau or ptau181 levels, or high tau:Abeta 42 ratios quantitatively predict more rapid progression of cognitive deficits and dementia. Biomarkers of CSF may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.

There is substantial evidence that cerebrospinal fluid (CSF) levels of both Abeta42 and tau/ptau are promising biomarkers for Alzheimer's disease (AD). We show that both Abeta and tau exhibit more than 10-fold interindividual variation in CSF levels suggesting that these biomarkers may also be effectively used as endophenotypes for genetic studies of AD. To test the role of common variation in the gene encoding microtubule associated protein tau (MAPT) in influencing CSF tau/ptau levels, we genotyped 21 MAPT single nucleotide polymorphisms (SNPs) in 313 individuals and tested for association with CSF tau/ptau levels. We identified alleles of several SNPs that show association with increased CSF tau/ptau levels. When CSF Abeta42 levels were used to stratify the sample into those with and without likely Abeta deposition in the brain the association was only observed in individuals with evidence of Abeta deposition. This association was replicated in an independent CSF series. When these SNPs were evaluated in a late-onset AD case control series the alleles associated with higher CSF tau/ptau were associated with an earlier age at onset but had no effect on risk for AD. In vivo gene expression studies show that these alleles are associated with increased MAPT mRNA levels in individuals with evidence of brain Abeta deposition. This endophenotype-based approach provides evidence for a gene (MAPT SNPs)-physiological environment (Abeta deposition) interaction that places changes in CSF tau after Abeta deposition and suggest that this interaction predisposes for the development of tauopathy and accelerated disease progression.

Objectives: 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 beta-amyloid(40) (Abeta(40)), Abeta(42), tau, phosphorylated tau(181), and plasma Abeta(40) and Abeta(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 Abeta(42) and increased levels of CSF tau and phosphorylated tau(181). Cerebrospinal fluid Abeta(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/Abeta(42) ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau(181)/Abeta(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 Abeta(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/Abeta(42) ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.

Alzheimer's disease (AD) will likely become the greatest public health crisis in the United States within the next 2-3 decades if left unchecked. There are no proven treatments that delay the onset or prevent the progression of AD, although a few promising candidates are under development. Even the earliest clinical symptoms of AD are accompanied by, and likely due to, neuronal/synaptic dysfunction and/or cell death. Thus, it is critical to identify individuals with "preclinical AD", prior to the development of clinical symptoms and concomitant neuronal loss, so new therapies will have the greatest clinical impact. At present, there are no antecedent biomarkers that will identify individuals with preclinical AD, however ongoing investigations of "at risk" populations, including those with Mild Cognitive Impairment (MCI), presymptomatic individuals harboring known disease-causing familial AD mutations or carriers of the epsilon4 allele of apolipoprotein E are offering insights into possible biomarkers of early disease processes. To discover antecedent biomarkers of AD, a prospective, longitudinal study of middle-aged individuals with positive or negative family history of AD has been initiated at Washington University in St. Louis. The Adult Children Study provides an opportunity to discuss the challenges and goals for investigations of antecedent AD biomarkers.

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.

Vascular contributions to cognitive impairment are increasingly recognized1-5 as shown by neuropathological6,7, neuroimaging4,8-11, and cerebrospinal fluid biomarker4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer's disease (AD)3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)3,11,14, and more recently tau15. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood-brain barrier (BBB) breakdown14-16. Although neurovascular dysfunction3,11 and BBB breakdown develop early in AD1,4,5,8-10,12,13, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-β8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging8-10. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer's Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau.

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values  0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Background:The Caribbean vervet monkey (Chlorocebus aethiops sabaeus) is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood. Methods:To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau, and p-tau181 in 329 members of a multigenerational pedigree. Linkage and genome-wide association were used to elucidate a genetic contribution to these traits. Results:Aβ1-40 concentrations were significantly correlated with age, brain total surface area, and gray matter thickness. Levels of p-tau181 were associated with cerebral volume and brain total surface area. Among the measured analytes, only CSF Aβ1-40 was heritable. No significant linkage (LOD > 3.3) was found, though suggestive linkage was highlighted on chromosomes 4 and 12. Genome-wide association identified a suggestive locus near the chromosome 4 linkage peak. Conclusions:Overall, these results support the vervet as a non-human primate model of amyloid-related neurodegeneration, such as Alzheimer's disease and cerebral amyloid angiopathy, and highlight Aβ1-40 and p-tau181 as potentially valuable biomarkers of these processes.