Advancing Diversity in Aging and Alzheimer's Disease Research and Clinical Care: Lessons Learned from Educational and Career Trajectories of Recent Mentorship Program Graduates.

Underrepresented minorities (URMs) are disproportionately affected with aging-related conditions and have inadequate representation in gerontology and geriatrics professions. The Mentorship for Advancing Undergraduate Research on Aging (MADURA) Program aims to increase inclusion of URMs by improving undergraduate retention and success, increasing rates of graduate/medical school applications, and increasing entry into aging research/clinical employment. MADURA provides cohorts with faculty and peer mentorship, research skills training, paid research lab experiences and professional development opportunities. About 87% of the 2023 MADURA cohort intends to take 1+ year after receiving a Bachelor's degree, to prepare for graduate education. Planned activities include gaining work experience, preparing for standardized tests, and obtaining formal training to strengthen graduate/medical school applications. In addition to immediate graduate program acceptances, other student outcomes should be assessed. Longitudinal research on the effectiveness of various post-graduation pathways could assist Mentorship programs in supporting their graduates' longer term educational and career goal attainment.

TDP-43 Pathology Exacerbates Cognitive Decline in Primary Age-Related Tauopathy.

OBJECTIVE: Primary age-related tauopathy (PART) refers to tau neurofibrillary tangles restricted largely to the medial temporal lobe in the absence of significant beta-amyloid plaques. PART has been associated with cognitive impairment, but contributions from concomitant limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) are underappreciated. METHODS: We compare prevalence of LATE-NC and vascular copathologies in age- and Braak-matched patients with PART (n = 45, Braak stage I-IV, Thal phase 0-2) or early stage Alzheimer disease neuropathologic change (ADNC; n = 51, Braak I-IV, Thal 3-5), and examine their influence on clinical and cognitive decline. RESULTS: Concomitant LATE-NC and vascular pathology were equally common, and cognition was equally impaired, in PART (Mini-Mental State Examination [MMSE] = 24.8 ± 6.9) and ADNC (MMSE = 24.2 ± 6.0). Patients with LATE-NC were more impaired than those without LATE-NC on the MMSE (by 5.8 points, 95% confidence interval [CI] = 3.0-8.6), Mattis Dementia Rating Scale (DRS; 17.5 points, 95% CI = 7.1-27.9), Clinical Dementia Rating, sum of boxes scale (CDR-sob; 5.2 points, 95% CI = 2.1-8.2), memory composite (0.8 standard deviations [SD], 95% CI = 0.1-1.6), and language composite (1.1 SD, 95% CI = 0.2-2.0), and more likely to receive a dementia diagnosis (odds ratio = 4.8, 95% CI = 1.5-18.0). Those with vascular pathology performed worse than those without on the DRS (by 10.2 points, 95% CI = 0.1-20.3) and executive composite (1.3 SD, 95% CI = 0.3-2.3). Cognition declined similarly in PART and ADNC over the 5 years preceding death; however, LATE-NC was associated with more rapid decline on the MMSE (ß = 1.9, 95% CI = 0.9-3.0), DRS (ß = 7.8, 95% CI = 3.4-12.7), CDR-sob (ß = 1.9, 95% CI = 0.4-3.7), language composite (ß = 0.5 SD, 95% CI = 0.1-0.8), and vascular pathology with more rapid decline on the DRS (ß = 5.2, 95% CI = 0.6-10.2). INTERPRETATION: LATE-NC, and to a lesser extent vascular copathology, exacerbate cognitive impairment and decline in PART and early stage ADNC. ANN NEUROL 2022;92:425-438.

Sex differences in plasma p-tau181 associations with Alzheimer's disease biomarkers, cognitive decline, and clinical progression.

Studies have shown that women on the Alzheimer's disease (AD) continuum have more pathological tau in the brain and cerebrospinal fluid (CSF), than men. Some studies have found that higher levels of tau biomarkers are more strongly associated with clinical AD, cognitive decline and neurodegeneration in women than in men. Despite major developments in the use of plasma tau phosphorylated at threonine 181 (p-tau181) as an AD biomarker, it is unknown whether these sex differences apply to plasma p-tau181. In 1060 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (47% women, 73.8 ± 7.6 years old), we examined sex differences in plasma p-tau181 levels and their association with other biomarkers, cognitive decline and incident AD. Linear regressions tested for an effect of sex on plasma p-tau181 levels and for plasma p-tau181 × sex interactions on CSF p-tau181, as well as entorhinal cortex tau, cortical amyloid-ß (Aß) deposition, and brain glucose metabolism, quantified using PET imaging. Linear mixed effects models tested for a sex × baseline plasma p-tau181 interaction on change in cognition over time. Finally, Cox models tested for a sex × plasma p-tau181 interaction on the risk of AD dementia in participants who were free of dementia at baseline. Despite similar plasma p-tau181 levels between sexes, women had lower brain glucose metabolism, greater brain Aß and entorhinal cortex tau deposition, higher CSF p-tau181 and faster cognitive decline in relation to higher baseline plasma p-tau181 levels compared with men. Among Aß positive, dementia-free participants, women had higher rates of incident AD dementia associated with increasing baseline plasma p-tau181 levels, relative to men. Our results suggest that sex may impact the clinical interpretation of plasma p-tau181 concentrations. If replicated, these findings could have important implications for the use of plasma p-tau181 as an accessible AD biomarker and screening tool for preventive and therapeutic clinical trials.

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment.

The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-ß42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-ß42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression.

Mid- and later-life risk factors for predicting neuropathological brain changes associated with Alzheimer's and vascular dementia: The Honolulu Asia Aging Study and the Age, Gene/Environment Susceptibility-Reykjavik Study.

INTRODUCTION: Dementia prediction models are necessary to inform the development of dementia risk reduction strategies. Here, we examine the utility of neuropathological-based risk scores to predict clinical dementia. METHODS: Models were developed for predicting Alzheimer's disease (AD) and non-AD neuropathologies using the Honolulu Asia Aging neuropathological sub-study (HAAS; n = 852). Model accuracy for predicting clinical dementia, over 30 years, was tested in the non-autopsied HAAS sample (n = 2960) and the Age, Gene/Environment Susceptibility-Reykjavik Study (n = 4614). RESULTS: Different models were identified for predicting neurodegenerative and vascular neuropathology (c-statistic range: 0.62 to 0.72). These typically included age, APOE, and a blood pressure-related measure. The neurofibrillary tangle and micro-vascular lesion models showed good accuracy for predicting clinical vascular dementia. DISCUSSION: There may be shared risk factors across dementia-related lesions, suggesting common pathways. Strategies targeting these models may reduce risk or postpone clinical symptoms of dementia as well as reduce neuropathological burden associated with AD and vascular lesions.

A simple genetic stratification method for lower cost, more expedient clinical trials in early Alzheimer's disease: A preliminary study of tau PET and cognitive outcomes.

INTRODUCTION: Identifying individuals who are most likely to accumulate tau and exhibit cognitive decline is critical for Alzheimer's disease (AD) clinical trials. METHODS: Participants (N = 235) who were cognitively normal or with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative were stratified by a cutoff on the polygenic hazard score (PHS) at 65th percentile (above as high-risk group and below as low-risk group). We evaluated the associations between the PHS risk groups and tau positron emission tomography and cognitive decline, respectively. Power analyses estimated the sample size needed for clinical trials to detect differences in tau accumulation or cognitive change. RESULTS: The high-risk group showed faster tau accumulation and cognitive decline. Clinical trials using the high-risk group would require a fraction of the sample size as trials without this inclusion criterion. DISCUSSION: Incorporating a PHS inclusion criterion represents a low-cost and accessible way to identify potential participants for AD clinical trials.

Committee on High-quality Alzheimer's Disease Studies (CHADS) consensus report.

BACKGROUND: Consensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials. METHODS: An ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations. RESULTS: Consensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement to disseminate and/or publish trial results even if the study is negative. CONCLUSIONS: This consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public.

Shortening heparan sulfate chains prolongs survival and reduces parenchymal plaques in prion disease caused by mobile, ADAM10-cleaved prions.

Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1+/-) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.

The CAIDE Dementia Risk Score and the Honolulu-Asia Aging Study.

INTRODUCTION: The CAIDE (Cardiovascular Risk Factors, Aging, and Incidence of Dementia) dementia risk score is based on demographic, genetic, and modifiable risk factors in midlife and has been shown to be predictive of later-life dementia. OBJECTIVE: To test the predictive capacity of the CAIDE dementia risk score among a cohort of Japanese-American men. METHODS: Midlife measures were obtained from a sample of 3,582 Japanese-American men in the Honolulu Heart Program (1965-1968, average age = 53.1 years). A follow-up exam in 1991 (average age = 77.8 years) assessed cognitive impairment using the Cognitive Abilities Screening Instrument (CASI). Severe cognitive impairment was defined as a CASI score <60. RESULTS: In this cohort, the CAIDE dementia risk score demonstrates significant association with later-life severe cognitive impairment (OR = 1.477, 95% CI: 1.39-1.58). However, the area under the receiver-operating characteristic curve c-statistics suggests poor predictive ability (c = 0.645, 95% CI: 0.62-0.67). Using a score cut-point of 10, the accuracy is acceptable (0.82), but the sensitivity is low (0.50). CONCLUSION: While the CAIDE dementia risk score at midlife is associated with later development of cognitive impairment in Japanese-American men, its predictive capacity in this population is weak.

MCI-to-normal reversion using neuropsychological criteria in the Alzheimer's Disease Neuroimaging Initiative.

INTRODUCTION: The low mild cognitive impairment (MCI) to cognitively normal (CN) reversion rate in the Alzheimer's Disease Neuroimaging Initiative (2-3%) suggests the need to examine reversion by other means. We applied comprehensive neuropsychological criteria (NP criteria) to determine the resulting MCI to CN reversion rate. METHODS: Participants with CN (n = 641) or MCI (n = 569) were classified at baseline and year 1 using NP criteria. Demographic, neuropsychological, and Alzheimer's disease biomarker variables as well as progression to dementia were examined across stable CN, reversion, and stable MCI groups. RESULTS: NP criteria produced a one-year reversion rate of 15.8%. Reverters had demographics, Alzheimer's disease biomarkers, and risk-of-progression most similar to the stable CN group and showed the most improvement on neuropsychological measures from baseline to year 1. DISCUSSION: NP criteria produced a reversion rate that is consistent with, albeit modestly improved from, reversion rates in meta-analyses. Reverters' biomarker profiles and progression rates suggest that NP criteria accurately tracked with underlying pathophysiologic status.

Artificially low mild cognitive impairment to normal reversion rate in the Alzheimer's Disease Neuroimaging Initiative.

INTRODUCTION: We examined reasons for low mild cognitive impairment (MCI)-to-cognitively normal (CN) reversion rates in the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: CN and MCI participants were identified as remaining stable, progressing, or reverting at 1-year of follow-up (Year 1). Application of ADNI's MCI criteria at Year 1 in addition to Alzheimer's disease biomarkers by group were examined. RESULTS: The MCI-to-CN reversion rate was 3.0%. When specific components were examined, 22.5% of stable MCI participants had normal memory performance at Year 1 and their Alzheimer's disease biomarkers were consistent with the stable CN group. At Year 1, when all MCI criteria were not met, the more subjective Clinical Dementia Rating rather than objective memory measure appeared to drive continuation of the MCI diagnosis. DISCUSSION: Results demonstrate an artificially low 1-year MCI-to-CN reversion rate in ADNI-diagnosed participants. If the Logical Memory cutoffs had been consistently applied, the reversion rate would have been at least 21.8%.

Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need.

Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

Neuropsychological Criteria for Mild Cognitive Impairment in the Framingham Heart Study's Old-Old.

BACKGROUND/AIMS: Mild cognitive impairment (MCI) lacks a "gold standard" operational definition. The Jak/Bondi actuarial neuropsychological criteria for MCI are associated with improved diagnostic stability and prediction of progression to dementia compared to conventional MCI diagnostic approaches, although its utility in diagnosing MCI in old-old individuals (age 75+) is unknown. Therefore, we investigated the applicability of neuropsychological MCI criteria among old-old from the Framingham Heart Study. METHODS: A total of 347 adults (ages 79-102) were classified as cognitively normal or MCI via Jak/Bondi and conventional Petersen/Winblad criteria, which differ on cutoffs for cognitive impairment and number of impaired scores required for a diagnosis. Cox models examined MCI status in predicting risk of progression to dementia. RESULTS: MCI diagnosed by both the Jak/Bondi and Petersen/Winblad criteria was associated with incident dementia; however, when both criteria were included in the regression model together, only the Jak/Bondi criteria remained statistically significant. At follow-up, the Jak/Bondi criteria had a lower MCI-to-normal reversion rate than the Petersen/Winblad criteria. CONCLUSIONS: Our findings are consistent with previous research on the Jak/Bondi criteria and support the use of a comprehensive neuropsychological diagnostic approach for MCI among old-old individuals.

The MoCA-Memory Index Score: An Efficient Alternative to Paragraph Recall for the Detection of Amnestic Mild Cognitive Impairment.

OBJECTIVE: To compare ability of 2 measures of delayed memory (word list, story paragraph) to discriminate Normal Control (NC) subjects from those with amnestic mild cognitive impairment (aMCI). METHODS: Demographic, neuropsychological, and diagnostic data contributed by 34 Alzheimer's Disease Centers to the National Alzheimer's Coordinating Center characterized 2717 individuals with a diagnosis of either NC (n=2205) or aMCI (n=512). The Montreal Cognitive Assessment-Memory Index Score (MoCA-MIS) assessed delayed word recall, and the Craft Story 21, delayed story recall. Logistic regression and receiver operator characteristic curves controlling for age, sex, and education assessed the ability of each test to differentiate NCs from subjects with aMCI. RESULTS: The MoCA-MIS had significantly better sensitivity and specificity (area under the receiver operator characteristic curve 0.83 vs. 0.80, P=0.004). At sensitivity 80%, the specificity of the MoCA-MIS was 69.1%, compared with 62.8% for the Craft Story. CONCLUSIONS: These data suggest that the MoCA-MIS, a recall score from items within the MoCA, is better at discriminating NCs from subjects with aMCI than the Craft Story. Word recall may be an efficient alternative to paragraph recall for diagnostic screening within clinical practice and research settings.

Smoking prevalence in urban and rural populations: findings from California between 2001 and 2012.

BACKGROUND: Tobacco smoking and related health problems are still major public health concerns in the United States despite the declining smoking prevalence. OBJECTIVES: This study explored differences in smoking prevalence between urban and rural areas potentially relevant to tobacco control efforts in California. METHODS: Public use adult smoking data from the California Health Interview Survey (CHIS) between 2001 and 2011-2012 were analyzed. A total of 282 931 adults were surveyed across the six CHIS cycles. A ZIP code-based geographic classification (Urban, Second-City, Suburban, and Town/Rural) was used to examine the association between smoking prevalence and area of residency. RESULTS: The overall smoking prevalence in California decreased from 17.0% in 2001 to 13.8% in 2011-2012. Within each CHIS cycle, the Town/Rural areas had the highest smoking prevalence, followed by Urban and Second-City areas, and Suburban areas had the lowest. Pooled data from all CHIS cycles showed a similar pattern, with rates in Urban, Second-City, Suburban and Town/Rural areas being 15.2%, 15.2%, 13.1% and 17.3%, respectively. Weighted multivariate logistic regression analysis indicated significantly higher odds of smoking in Urban, Second-City and Town/Rural areas compared to Suburban areas (all adjusted odds ratios > 1.10), although this trend varied by race/ethnicity, being present in non-Hispanic Whites and not present in Hispanics. CONCLUSIONS: Town/Rural and Urban populations of California are consistently at higher risk of smoking than Suburban populations. These results indicate a need for population-specific tobacco control approaches that address the lifestyle, behavior, and education of disparate populations within the same state or region.

Smokers who report smoking but do not consider themselves smokers: a phenomenon in need of further attention.

BACKGROUND: Heightened stigma surrounding the action of smoking may decrease the likelihood that individuals who engage in smoking identify with the label 'smoker'. Non-identifying smokers (NIS) may undermine accurate smoking prevalence estimates and can be overlooked by tobacco control efforts. OBJECTIVE: We sought to characterise NIS in a cross-sectional study using a sample representative of the population of adults (>18 years) in California who reported smoking at least 100 cigarettes in their lifetime, smoking at least some days and at least once in the last 30 days (n=1698). Individuals were considered NIS if they met the above criteria and answered 'no' when asked if they 'considered themselves a smoker'. RESULTS: We estimate that 395 928 (SD=54 126) NIS were living in California in 2011 (a prevalence of 12.3% of all smokers in California). The odds of being NIS were higher among non-daily smokers who were previously daily smokers (adjusted OR (AOR)=7.63, 95% CI 2.67 to 21.8) or were never previously daily smokers (AOR=7.14, CI 2.78 to 18.3) compared with daily smokers. The odds of being an NIS were also higher among those who did not believe they were addicted to cigarettes (AOR=3.84, CI 1.68 to 9.22), were older than 65 years (vs less than 45 years) (AOR=3.35, CI 1.16 to 9.75) or were from ethnic minorities including Black and Asian (vs non-Hispanic white) (AOR=3.16, CI 1.19 to 8.49). CONCLUSIONS: Smoking surveillance should restructure selection criteria to more accurately account for NIS in areas with high stigma toward smokers. Targeted interventions may be needed for NIS including educating healthcare providers to enquire more deeply into smoking habits.

Optimal composite scores for longitudinal clinical trials under the linear mixed effects model.

Clinical trials of chronic, progressive conditions use rate of change on continuous measures as the primary outcome measure, with slowing of progression on the measure as evidence of clinical efficacy. For clinical trials with a single prespecified primary endpoint, it is important to choose an endpoint with the best signal-to-noise properties to optimize statistical power to detect a treatment effect. Composite endpoints composed of a linear weighted average of candidate outcome measures have also been proposed. Composites constructed as simple sums or averages of component tests, as well as composites constructed using weights derived from more sophisticated approaches, can be suboptimal, in some cases performing worse than individual outcome measures. We extend recent research on the construction of efficient linearly weighted composites by establishing the often overlooked connection between trial design and composite performance under linear mixed effects model assumptions and derive a formula for calculating composites that are optimal for longitudinal clinical trials of known, arbitrary design. Using data from a completed trial, we provide example calculations showing that the optimally weighted linear combination of scales can improve the efficiency of trials by almost 20% compared with the most efficient of the individual component scales. Additional simulations and analytical results demonstrate the potential losses in efficiency that can result from alternative published approaches to composite construction and explore the impact of weight estimation on composite performance.

Longitudinal plasma amyloid beta in Alzheimer's disease clinical trials.

INTRODUCTION: Little is known about the utility of plasma amyloid beta (Aß) in clinical trials of Alzheimer's disease (AD). METHODS: We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months). RESULTS: Baseline plasma Aß was not related to cognitive or clinical progression. We observed a decrease in plasma Aß40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aß compared with placebo. We found significant storage time effects and considerable plate-to-plate variation. DISCUSSION: We found no support for the utility of plasma Aß as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aß may prove useful in pharmacodynamic studies of antiamyloid drugs.

Early and selective impairments in axonal transport kinetics of synaptic cargoes induced by soluble amyloid ß-protein oligomers.

The downstream targets of amyloid ß (Aß)-oligomers remain elusive. One hypothesis is that Aß-oligomers interrupt axonal transport. Although previous studies have demonstrated Aß-induced transport blockade, early effects of low-n soluble Aß-oligomers on axonal transport remain unclear. Furthermore, the cargo selectivity for such deficits (if any) or the specific effects of Aß on the motility kinetics of transported cargoes are also unknown. Toward this, we visualized axonal transport of vesicles in cultured hippocampal neurons treated with picomolar (pm) levels of cell-derived soluble Aß-oligomers. We examined select cargoes thought to move as distinct organelles and established imaging parameters that allow organelle tracking with consistency and high fidelity - analyzing all data in a blinded fashion. Aß-oligomers induced early and selective diminutions in velocities of synaptic cargoes but had no effect on mitochondrial motility, contrary to previous reports. These changes were N-methyl D-aspartate receptor/glycogen synthase kinase-3ß dependent and reversible upon washout of the oligomers. Cluster-mode analyses reveal selective attenuations in faster-moving synaptic vesicles, suggesting possible decreases in cargo/motor associations, and biochemical experiments implicate tau phosphorylation in the process. Collectively, the data provide a biological basis for Aß-induced axonal transport deficits.