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IntroductionCognitive composite scales constructed by combining existing neuropsychometric tests are seeing wide application as endpoints for clinical trials and cohort studies of Alzheimer's disease (AD) predementia conditions. Preclinical Alzheimer's Cognitive Composite (PACC) scales are composite scores calculated as the sum of the component test scores weighted by the reciprocal of their standard deviations at the baseline visit. Reciprocal standard deviation is an arbitrary weighting in this context, and may be an inefficient utilization of the data contained in the component measures. Mathematically derived optimal composite weighting is a promising alternative.MethodsSample size projections using standard power calculation formulas were used to describe the relative performance of component measures and their composites when used as endpoints for clinical trials. Power calculations were informed by (n=1,333) amnestic mild cognitive impaired participants in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set.ResultsA composite constructed using PACC reciprocal standard deviation weighting was both less sensitive to change than one of its component measures and less sensitive to change than its optimally weighted counterpart. In standard sample size calculations informed by NACC data, a clinical trial using the PACC weighting would require 38% more subjects than a composite calculated using optimal weighting.DiscussionThese findings illustrate how reciprocal standard deviation weighting can result in inefficient cognitive composites, and underscore the importance of component weights to the performance of composite scales. In the future, optimal weighting parameters informed by accumulating clinical trial data may improve the efficiency of clinical trials in AD.

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-β (Aβ) 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 Aβ 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 Aβ 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.

BackgroundConsensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials.MethodsAn ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations.ResultsConsensus 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.ConclusionsThis 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.

We have previously derived power calculation formulas for cohort studies and clinical trials using the longitudinal mixed effects model with random slopes and intercepts to compare rate of change across groups [Ard & Edland, Power calculations for clinical trials in Alzheimer's disease. J Alzheim Dis 2011;21:369-77]. We here generalize these power formulas to accommodate 1) missing data due to study subject attrition common to longitudinal studies, 2) unequal sample size across groups, and 3) unequal variance parameters across groups. We demonstrate how these formulas can be used to power a future study even when the design of available pilot study data (i.e., number and interval between longitudinal observations) does not match the design of the planned future study. We demonstrate how differences in variance parameters across groups, typically overlooked in power calculations, can have a dramatic effect on statistical power. This is especially relevant to clinical trials, where changes over time in the treatment arm reflect background variability in progression observed in the placebo control arm plus variability in response to treatment, meaning that power calculations based only on the placebo arm covariance structure may be anticonservative. These more general power formulas are a useful resource for understanding the relative influence of these multiple factors on the efficiency of cohort studies and clinical trials, and for designing future trials under the random slopes and intercepts model.

Background and objectivePatients with earlier age at onset of sporadic Alzheimer disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine whether this age-related clinical and cognitive heterogeneity is mediated by different topographic distributions of tau-aggregate neurofibrillary tangles (NFTs) or by variable amounts of concomitant non-AD neuropathology.MethodsThe relative distribution of NFT density in hippocampus and midfrontal neocortex was calculated, and α-synuclein, TAR DNA binding protein 43 (TDP-43), and microvascular copathologies were staged, in patients with severe AD and age at onset of 51-60 (n = 40), 61-70 (n = 41), and >70 (n = 40) years. Regression, mediation, and mixed effects models examined relationships of pathologic findings with clinical features and longitudinal cognitive decline.ResultsPatients with later age at onset of AD were less likely to present with nonmemory complaints (odds ratio [OR] 0.46 per decade, 95% confidence interval [CI] 0.22-0.88), psychiatric symptoms (β = -0.66, 95% CI -1.15 to -0.17), and functional impairment (β = -1.25, 95% CI -2.34 to -0.16). TDP-43 (OR 2.00, 95% CI 1.23-3.35) and microvascular copathology (OR 2.02, 95% CI 1.24-3.40) were more common in later onset AD, and α-synuclein copathology was not related to age at onset. NFT density in midfrontal cortex (β = -0.51, 95% CI -0.72 to -0.31) and midfrontal/hippocampal NFT ratio (β = -0.18, 95% CI -0.26 to -0.10) were lower in those with later age at onset. Executive function (β = 0.48, 95% CI 0.09-0.90) and visuospatial cognitive deficits (β = 0.97, 95% CI 0.46-1.46) were less impaired in patients with later age at onset. Mediation analyses showed that the effect of age at onset on severity of executive function deficits was mediated by midfrontal/hippocampal NFT ratio (β = 0.21, 95% CI 0.08-0.38) and not by concomitant non-AD pathologies. Midfrontal/hippocampal NFT ratio also mediated an association between earlier age at onset and faster decline on tests of global cognition, executive function, and visuospatial abilities.DiscussionWorse executive dysfunction and faster cognitive decline in people with sporadic AD with earlier rather than later age at onset is mediated by greater relative midfrontal neocortical to hippocampal NFT burden and not by concomitant non-AD neuropathology.

The interaction between APOE ɛ4 and vascular risk factors on cognitive function is stronger in women than in men. These effects may be mediated by the amount of tau pathology in the brain. Therefore, we examined whether APOE ɛ4 and sex modify cross-sectional associations between cardiovascular risk and tau deposition in cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative. We calculated the Framingham Heart Study cardiovascular disease risk score for 141 participants (74 women, 47 APOE ɛ4 carriers) with complete medical history data, processed tau-PET data and a Clinical Dementia Rating global score of 0.0 at the time of the tau-PET scan, implying no significant cognitive or functional impairment. We used linear regression models to examine the effects of sex, APOE ɛ4, cardiovascular risk and their interactions on tau deposition in the entorhinal cortex, inferior temporal cortex and a composite meta-region of interest of temporal lobe areas. We found a significant three-way interaction among sex, APOE ɛ4 status and cardiovascular disease risk on tau deposition in the entorhinal cortex (β = 0.04; 95% CI, 0.01-0.07; P = 0.008), inferior temporal cortex (β = 0.02; 95% CI, 0.0-0.05; P = 0.029) and meta-region (β = 0.02; 95% CI, 0.0-0.04; P = 0.042). After stratifying by APOE ɛ4 status to examine interactions between sex and cardiovascular disease risk on tau in APOE ɛ4 carriers and non-carriers, we found a significant two-way interaction between sex and cardiovascular disease risk on tau in the entorhinal cortex (β = 0.05; 95% CI, 0.02-0.08; P = 0.001), inferior temporal cortex (β = 0.03; 95% CI, 0.01-0.05; P =0.009) and meta-region (β = 0.02; 95% CI, 0.01-0.04; P = 0.008) only among APOE ɛ4 carriers. In analyses stratified by sex, higher cardiovascular risk scores were associated with higher levels of tau in the entorhinal cortex (β = 0.05; 95% CI, 0.02-0.08; P = 0.002), inferior temporal cortex (β = 0.02; 95% CI, 0.0-0.05; P = 0.023) and meta-region (β = 0.02; 95% CI, 0.01-0.04; P = 0.013) in female APOE ɛ4 carriers but not in male carriers. Our findings suggest that cognitively normal older women carrying at least one APOE ɛ4 allele, may be particularly vulnerable to the effects of cardiovascular disease risk on early tau deposition.

BackgroundStudies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored.MethodsOur sample included 238 amyloid-β (Aβ)-positive participants with MCI or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aβ42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data.ResultsTotal and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (β = 0.06 [-0.11 to -0.01], p = 0.031). Sex modified the association of CSF t-tau with total (β = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (β = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (β = -14.98 [-27.37 to -2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aβ42 among men (β = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (β = -2.10 [-3.97 to -0.27], p = 0.027 and β = -2.24 [-4.32 to -0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (β = 12.34 [3.02 to 21.65], p = 0.011) in women (β = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (β = 8.98 [0.27 to 17.68], p = 0.042).ConclusionsMMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women's elevated susceptibility to AD.

BackgroundConsensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials.MethodsAn ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations.ResultsConsensus 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.ConclusionsThis 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.

ObjectiveTo characterize age-related clinical heterogeneity in Alzheimer disease (AD) and determine whether it is modified by APOE genotype or concomitant non-AD pathology, we analyzed data from 1,750 patients with sporadic, pathologically confirmed severe AD.MethodsIn this retrospective cohort study, regression and mixed effects models assessed effects of estimated age at onset, APOE genotype, and their interaction on standardized clinical, cognitive, and pathologic outcome measures from the National Alzheimer's Coordinating Center database.ResultsA bimodal distribution of age at onset frequency in APOE ε4- cases showed best separation at age 63. Using this age cutoff, cases were grouped as ε4- early-onset AD (EOAD) (n = 169), ε4+ EOAD (n = 273), ε4- late-onset AD (LOAD) (n = 511), and ε4+ LOAD (n = 797). Patients with EOAD were more likely than patients with LOAD to present with noncognitive behavioral or motor symptoms or nonmemory cognitive complaints, and had more executive dysfunction, but less language impairment on objective cognitive testing. Age at onset and ε4- genotype were independently associated with lower baseline Mini-Mental State Examination scores and greater functional impairment and patients with EOAD had faster cognitive and functional decline than patients with LOAD regardless of APOE genotype. Patients with EOAD were more likely than patients with LOAD to receive a non-AD clinical diagnosis even though they were more likely to have pure AD without concomitant vascular or other non-AD neurodegenerative pathology.ConclusionsEarly-onset sporadic AD is associated with a greater likelihood of an atypical, non-memory-dominant clinical presentation, especially in the absence of the APOE ε4 allele, which may lead to misattribution to non-AD underlying pathology.

IntroductionDementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by cognitive alterations, visual hallucinations, and motor impairment. Diagnosis is based on type and timing of clinical manifestations; however, determination of clinical subtypes is challenging. The utility of blood DNA methylation as a biomarker for Lewy body disorders (LBD) is mostly unexplored.MethodsWe performed a cross-sectional analysis of blood methylation in 42 DLB and 50 PDD cases applying linear models to compare groups and logistic least absolute shrinkage and selection operator regression to explore the discriminant power of methylation signals.ResultsDLB blood shows differential methylation compared to PDD. Some methylation changes associate with core features of LBD. Sets of probes show high predictive value to discriminate between variants.DiscussionOur study is the first to explore LBD blood methylation. Despite overlapping clinical presentation, we detected differential epigenetic signatures that, if confirmed in independent cohorts, could be developed into useful biomarkers.

BackgroundGrowing awareness of Alzheimer's disease (AD) has prompted a demand for quick and effective ways to screen for memory loss and cognitive decline in large numbers of individuals in the community. Periodic Memory Screening Day events provide free, brief cognitive screening aimed at those 65 years and older, and can serve as an opportunity to gauge participants' attitudes towards AD research and recruit them into ongoing research projects.MethodsOver 6 single-day events in 2 years, more than 574 individuals were individually screened using the MoCA and a story recall task (immediate and delayed), given feedback about their performance, and introduced to AD research and opportunities to participate.ResultsScreening classified 297 individuals (52.0%) as having "No Decline," 192 (33.6%) as "Possible decline," and 82 (14.4%) as "Likely decline." Those with "Likely decline" were older and less educated, had more memory concerns, were more likely to be men, and were less likely to have a positive family history of dementia than those with "No Decline." Subsequent validation of screening procedures against a full clinical evaluation showed 72% classification accuracy with a skew towards over-calling Possible and Likely decline and thereby guiding questionable individuals to a more thorough evaluation. Of those screened, 378 (66%) agreed to additional research and consented to being listed in a research registry, and a majority (70-85%) of those consenting reported they were amenable to various AD research procedures including lumbar puncture, MRI, and autopsy. Overall, 19.1% of those screened met inclusion criteria for ongoing studies and were successfully recruited into AD research.ConclusionsConducting a few concentrated community memory screening events each year may help meet the public's demand for brief assessment of memory concerns and can be a relatively effective and efficient recruitment strategy for AD research.

ObjectiveTo examine whether domain-specific patterns of cognitive impairment and trajectories of decline differed in patients with clinically diagnosed Parkinson disease dementia (PDD) (N = 29) and autopsy-confirmed dementia with Lewy bodies (DLB) (N = 58) or Alzheimer disease (AD) (N = 174) and to determine the impact of pooling patients with PDD and DLB in clinical trials targeting cognition.MethodsPatients were matched on demographics and level of global cognitive impairment. Patterns of cross-sectional performance and longitudinal decline were examined in 4 cognitive domains: Visuospatial, Memory, Executive, and Language. Power analyses were performed to determine the numbers of participants needed to adequately power a hypothetical clinical trial to slow cognitive decline in pure PDD, pure DLB, or a mixed PDD/DLB group.ResultsBoth DLB and PDD were more impaired and declined more rapidly than AD in the Visuospatial domain. Patients with PDD exhibited the most impairment and fastest decline in Executive, although patients with DLB also declined faster than AD. Memory was more impaired in AD than DLB and in both compared with PDD; however, all 3 groups declined at comparable rates. In contrast, PDD declined at a slower rate on Language measures than DLB or AD. Power analyses suggest that Visuospatial and Executive outcome measures would be most sensitive in PDD, but Memory and Language in DLB.ConclusionDLB and PDD differ from each other, and from AD, in a cognitive domain-specific manner. As such, different outcome measures may be most sensitive to detecting changes in DLB vs PDD, suggesting that the 2 should be analyzed separately in clinical trials.

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.

A primary goal of research in cognitive impairment and dementia is to understand how some individuals retain sufficient cognitive function for a fulfilling life while many others are robbed of their independence, sometimes their essence, in the last years and decades of life. In this commentary, we propose operational definitions of the types of factors that may help individuals retain cognitive function with aging. We propose operational definitions of resistance, resilience, reserve, with an eye toward how these may be measured and interpreted, and how they may enable research aimed at prevention. With operational definitions and quantification of resistance, resilience, and reserve, a focused analytic search for their determinants and correlates can be undertaken. This approach, essentially a search to identify protective risk factors and their mechanisms, represents a relatively unexplored pathway toward the identification of candidate preventive interventions.

IntroductionThe 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.MethodsParticipants 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.ResultsNP 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.DiscussionNP 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.

IntroductionWe examined reasons for low mild cognitive impairment (MCI)-to-cognitively normal (CN) reversion rates in the Alzheimer's Disease Neuroimaging Initiative (ADNI).MethodsCN 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.ResultsThe 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.DiscussionResults 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%.

Hippocampal sclerosis (HS) is a prevalent cause of dementia in the oldest old but is generally misdiagnosed as Alzheimer's disease (AD) due to similarities in clinical presentation. To determine if clinical and cognitive features diverge over time, we compared results from longitudinal evaluations of participants in the University of California, San Diego, Alzheimer's Disease Research Center with autopsy-confirmed AD (n = 195), HS (n = 21), or both HS + AD (n = 18). Each group exhibited decline in all cognitive measures, with HS declining at a slower rate than AD on the Mini-Mental State Examination, immediate recall condition of a word-list learning test, and Dementia Rating Scale total and subtest scores (except memory). Five years before the final evaluation, more prominent semantic and visuospatial deficits were apparent in AD participants than in HS participants despite comparable global cognitive impairment. Groups did not differ on any measure of executive function. HS + AD differed from AD only on the Boston Naming Test. Overall, results suggest that HS dementia is associated with cognitive deficits that progress more slowly than, but generally mimic, those observed in AD.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common prion disease in humans and has been iatrogenically transmitted through corneal graft transplantation. Approximately 40% of sCJD patients develop visual or oculomotor symptoms and may seek ophthalmological consultation. Here we used the highly sensitive real-time quaking-induced conversion (RT-QuIC) assay to measure postmortem prion seeding activities in cornea, lens, ocular fluid, retina, choroid, sclera, optic nerve, and extraocular muscle in the largest series of sCJD patient eyes studied by any assay to date. We detected prion seeding activity in 100% of sCJD eyes, representing three common sCJD subtypes, with levels varying by up to 4 log-fold among individuals. The retina consistently showed the highest seed levels, which in some cases were only slightly lower than brain. Within the retina, prion deposits were detected by immunohistochemistry (IHC) in the retinal outer plexiform layer in most sCJD cases, and in some eyes the inner plexiform layer, consistent with synaptic prion deposition. Prions were not detected by IHC in any other eye region. With RT-QuIC, prion seed levels generally declined in eye tissues with increased distance from the brain, and yet all corneas had prion seeds detectable. Prion seeds were also present in the optic nerve, extraocular muscle, choroid, lens, vitreous, and sclera. Collectively, these results reveal that sCJD patients accumulate prion seeds throughout the eye, indicating the potential diagnostic utility as well as a possible biohazard.IMPORTANCE Cases of iatrogenic prion disease have been reported from corneal transplants, yet the distribution and levels of prions throughout the eye remain unknown. This study probes the occurrence, level, and distribution of prions in the eyes of patients with sporadic Creutzfeldt-Jakob disease (sCJD). We tested the largest series of prion-infected eyes reported to date using an ultrasensitive technique to establish the prion seed levels in eight regions of the eye. All 11 cases had detectable prion seeds in the eye, and in some cases, the seed levels in the retina approached those in brain. In most cases, prion deposits could also be seen by immunohistochemical staining of retinal tissue; other ocular tissues were negative. Our results have implications for estimating the risk for iatrogenic transmission of sCJD as well as for the development of antemortem diagnostic tests for prion diseases.

Background/aimsMild 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.MethodsA 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.ResultsMCI 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.ConclusionsOur 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.

IntroductionCriteria for mild cognitive impairment (MCI) used in many clinical trials are susceptible to "false-positive (FP)" errors that can be avoided by an actuarial psychometric approach.MethodsCluster analysis was applied to baseline neuropsychological test data from 756 MCI participants in the Alzheimer's Disease Cooperative Study donepezil trial. Treatment groups were compared after FP MCI cases were removed.ResultsCluster analyses revealed three groups: "single-domain amnestic MCI" (31%), "multi-domain amnestic MCI" (39%), and "FP MCI" (30%). After removing FP MCI cases, the donepezil treatment group had a lower rate of progression to Alzheimer's disease and better performance on cognitive tests than the placebo/vitamin E group.DiscussionRemoval of FP MCI diagnoses unmasked beneficial effects of donepezil, despite a 30% reduction in sample size. MCI subject selection based on actuarial methods with comprehensive neuropsychological test data can result in more efficient clinical trials and improved ability to detect treatment effects.

IntroductionPractice effects (PEs) present a potential confound in clinical trials with cognitive outcomes. A single-blind placebo run-in design, with repeated cognitive outcome assessments before randomization to treatment, can minimize effects of practice on trial outcome.MethodsWe investigated the potential implications of PEs in Alzheimer's disease prevention trials using placebo arm data from the Alzheimer's Disease Cooperative Study donepezil/vitamin E trial in mild cognitive impairment. Frequent ADAS-Cog measurements early in the trial allowed us to compare two competing trial designs: a 19-month trial with randomization after initial assessment, versus a 15-month trial with a 4-month single-blind placebo run-in and randomization after the second administration of the ADAS-Cog. Standard power calculations assuming a mixed-model repeated-measure analysis plan were used to calculate sample size requirements for a hypothetical future trial designed to detect a 50% slowing of cognitive decline.ResultsOn average, ADAS-Cog 13 scores improved at first follow-up, consistent with a PE and progressively worsened thereafter. The observed change for a 19-month trial (1.18 points) was substantively smaller than that for a 15-month trial with 4-month run-in (1.79 points). To detect a 50% slowing in progression under the standard design (i.e., a 0.59 point slowing), a future trial would require 3.4 times more subjects than would be required to detect the comparable percent slowing (i.e., 0.90 points) with the run-in design.DiscussionAssuming the improvement at first follow-up observed in this trial represents PEs, the rate of change from the second assessment forward is a more accurate representation of symptom progression in this population and is the appropriate reference point for describing treatment effects characterized as percent slowing of symptom progression; failure to accommodate this leads to an oversized clinical trial. We conclude that PEs are an important potential consideration when planning future trials.

BackgroundComposite scales have recently been proposed as outcome measures for clinical trials. For example, the Prodromal Alzheimer's Cognitive Composite (PACC) is the sum of z-score normed component measures assessing episodic memory, timed executive function, and global cognition. Alternative methods of calculating composite total scores using the weighted sum of the component measures that maximize signal-to-noise of the resulting composite score have been proposed. Optimal weights can be estimated from pilot data, but it is an open question how large a pilot trial is required to calculate reliably optimal weights.MethodsIn this manuscript, we describe the calculation of optimal weights, and use large-scale computer simulations to investigate the question of how large a pilot study sample is required to inform the calculation of optimal weights. The simulations are informed by the pattern of decline observed in cognitively normal subjects enrolled in the Alzheimer's Disease Cooperative Study (ADCS) Prevention Instrument cohort study, restricting to n=75 subjects age 75 and over with an ApoE E4 risk allele and therefore likely to have an underlying Alzheimer neurodegenerative process.ResultsIn the context of secondary prevention trials in Alzheimer's disease, and using the components of the PACC, we found that pilot studies as small as 100 are sufficient to meaningfully inform weighting parameters. Regardless of the pilot study sample size used to inform weights, the optimally weighted PACC consistently outperformed the standard PACC in terms of statistical power to detect treatment effects in a clinical trial. Pilot studies of size 300 produced weights that achieved near-optimal statistical power, and reduced required sample size relative to the standard PACC by more than half.ConclusionsThese simulations suggest that modestly sized pilot studies, comparable to that of a phase 2 clinical trial, are sufficient to inform the construction of composite outcome measures. Although these findings apply only to the PACC in the context of prodromal AD, the observation that weights only have to approximate the optimal weights to achieve near-optimal performance should generalize. Performing a pilot study or phase 2 trial to inform the weighting of proposed composite outcome measures is highly cost-effective. The net effect of more efficient outcome measures is that smaller trials will be required to test novel treatments. Alternatively, second generation trials can use prior clinical trial data to inform weighting, so that greater efficiency can be achieved as we move forward.

High-density lipoprotein (HDL) is protective against cardiovascular disease. Exercise can increase HDL concentration, and some evidence suggests that this effect occurs more strongly in women than in men. Both HDL and exercise are associated with inflammation. We hypothesized a sex-by-exercise interaction on HDL level, whereby women would benefit from exercise more strongly than men, and tumor necrosis factor alpha and serum soluble tumor necrosis factor receptor-2 would mediate this relationship. This study included 2,957 older adult participants (1,520 women; 41% Black, 59% White; 73.6-years-old) from the Health, Aging, and Body Composition study. Regression models revealed a positive exercise-HDL relationship in women only (sex-by-exercise interaction: β = 0.09, p =.013; exercise on HDL in women: β = 0.07, p =.015), mediated by TNFα (axb = 0.15; CI: 0.01, 0.30), suggesting that exercise may increase HDL levels in women through reduced inflammation. Given that vascular risk contributes to Alzheimer's disease risk, findings have implications for sex differences in AD risk factors. [ABSTRACT FROM AUTHOR]

IntroductionThe goal was to compare subgroups of dementia with Lewy Bodies (DLB) using neuropathological measures to differentiate 'pure' Lewy body (LB) dementia from 'mixed' DLB [co-occurring LB and Alzheimer's disease (AD) pathology] to facilitate diagnostic decision-making and future development of interventions based on predicted type(s) of neuropathology. Studies comparing these groups are rare relative to those differentiating 'pure' AD and all-cause DLB, and are limited by insufficient sample size, brief cognitive batteries, and/or absence of autopsy confirmation. To address these limitations, we assessed cognition and other features in a large, autopsy-confirmed DLB sample using an extensive neuropsychological battery.MethodsSubjects from an AD research center autopsy series satisfying DLB pathology criteria were divided by an AD neuropathology index into DLB-LB (Braak stage 0-3) (n = 38) and DLB-AD (Braak stage 4-6) (n = 41) and compared on baseline variables from chart reviews and standardized measures.ResultsDLB-LB subjects were more impaired on visuospatial constructions, visual conceptual reasoning, and speed of processing, but less impaired on verbal memory and confrontation naming. All-type hallucinations occurred more frequently in DLB-LB, while delusions were common in both groups. Groups were similar in education and age at onset, and in baseline age, dementia severity, and functional capacity.ConclusionSalient findings included greater impairment on visual tasks and speed of processing and more frequent reports of all-type hallucinations in DLB-LB compared to DLB-AD. Relatively intact confrontation naming in DLB-LB and no differences in reported delusions were of note. Identifying differences in phenotypic features can improve prediction of underlying neuropathology.

IntroductionLittle is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD).MethodsWe 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).ResultsBaseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 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 Aβ compared with placebo. We found significant storage time effects and considerable plate-to-plate variation.DiscussionWe found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic studies of antiamyloid drugs.

ImportanceIncreased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear.ObjectivesTo determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia.Design, setting, and participantsIn this retrospective cohort study, 877 participants without dementia (55-91 years of age) from the Alzheimer's Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and β-amyloid 1-42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months tracked progression to dementia.Main outcomes and measuresRegression and analysis of covariance analyses investigated relationships between pulse pressure and distinct cerebral spinal fluid biomarker profiles. Very old participants (80 years or older) were compared with younger participants (55-79 years of age) on clinical measures and pulse pressure × age group interactions were investigated. Survival analysis examined the effect of baseline pulse pressure on progression to dementia. Covariates were age, sex, apolipoprotein E genotype, body mass index, vascular risk factors, and antihypertensive medication use.ResultsIndividuals with a P-tau-positive biomarker profile exhibited mean (SD) elevated pulse pressure regardless of age (62.0 [15.6] mm Hg for a P-tau-positive biomarker vs 57.4 [14.0] mm Hg for P-tau-negative biomarker; P = .04). In very old participants, a further increase in pulse pressure was observed in those exhibiting both P-tau elevation and β-amyloid 1-42 reduction vs either biomarkers alone (69.7 [16.0] mm Hg for both positive biomarkers vs 63.18 [13.0] mm Hg for P-tau alone vs 60.1 [16.4] mm Hg for β-amyloid 1-42 alone vs 56.6 [14.5] mm Hg for negative biomarkers; P = .003). Those with higher baseline pulse pressure progressed to dementia more rapidly (95% CI, 1.000-1.048; P = .05; hazard ratio = 1.024). Systolic pressure exhibited similar relationships with Alzheimer disease biomarkers and progression to dementia in the very old subgroup (P < .05) but showed no associations in the young old subgroup (P > .10). Diastolic pressure was reduced in young old participants with isolated phosphorylated tau elevation (P = .04).Conclusions and relevancePulse pressure, an index of vascular aging, was associated with neurodegenerative change prior to the onset of dementia across a broad age range. Among those with more advanced age, higher pulse pressure was also associated with cerebral amyloidosis in the presence of neurodegeneration and more rapid progression to dementia. Diastolic contributions to these biomarker associations were limited to young old participants whereas systolic contributions were found only in very old participants.

Background: Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. Objective: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. Methods: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. Conclusion: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. Trial registration: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360. [ABSTRACT FROM AUTHOR]

ObjectiveThe current study examined the association between pulse pressure (PP) and CSF-based biomarkers for Alzheimer disease, including β-amyloid 1-42 (Aβ1-42) and phosphorylated tau (P-tau) protein, in cognitively normal older adults.MethodsOne hundred seventy-seven cognitively normal, stroke-free older adult participants (aged 55-100 years) underwent blood pressure assessment for determination of PP (systolic - diastolic blood pressure) and lumbar puncture for measurement of CSF Aβ1-42 and P-tau. Pearson correlations and multiple linear regression, controlling for age, sex, APOE genotype, and body mass index, evaluated the relationship between PP and Alzheimer disease biomarkers.ResultsPP elevation was associated with increased P-tau (r = 0.23, p = 0.002), reduced Aβ1-42 (r = -0.19, p = 0.01), and increased P-tau to Aβ1-42 ratio (r = 0.27, p < 0.001). After controlling for covariates, PP remained associated with P-tau (β = 0.18, p = 0.0196) and P-tau to Aβ1-42 ratio (β = 0.0016, p < 0.001) but was no longer associated with Aβ1-42 (β = -0.1, p = 0.35). Post hoc multivariate analyses indicated that increased PP was associated with all biomarkers in younger participants (aged 55-70 years) (Aβ1-42: p = 0.050; P-tau: p = 0.003; P-tau to Aβ ratio: p = 0.0007) but not older participants (aged 70-100 years).ConclusionsPP elevation is associated with increased CSF P-tau and decreased Aβ1-42 in cognitively normal older adults, suggesting that pulsatile hemodynamics may be related to amyloidosis and tau-related neurodegeneration. The relationship between PP and CSF biomarkers is age-dependent and observed only in participants in the fifth and sixth decades of life.

ObjectiveLittle is known about the relationship between cigarette smoking initiation and subsequent alcohol involvement. To address this question, the present study compared alcohol use between students who initiated smoking during college and a matched sample of never-smoking students. We hypothesized greater increases in alcohol involvement among smoking initiators, mediated by exposure to cigarette use situations.MethodIncluded in the present study were 104 Chinese American and Korean American undergraduates who at baseline (freshman year) reported never having smoked a cigarette. Subjects were drawn from 433 participants in a naturalistic longitudinal study of tobacco use who were assessed annually each year in college. Cigarette smoking status was assessed annually as part of a structured interview. Initiators and never-smokers were matched on gender, ethnicity, baseline alcohol use, parental smoking status, and behavioral undercontrol.ResultsAs predicted, participants who initiated smoking during college reported significantly greater increases in the number of past-30-day total drinks consumed (p < .001) and reported greater prevalence of heavy drinking episodes (p < .05). The effect of smoking initiation on the change in the number of past-30-day drinks at the final assessment was partially mediated by exposure to smoking (p < .05). Exploratory analyses indicated that greater recent smoking significantly predicted increased alcohol consumption over and above the effect of exposure.ConclusionsStudents who initiate smoking during college appear at risk for increased alcohol involvement. Part of this risk is explained by environmental contextual factors, specifically exposure to situations involving other smokers that also may result in greater exposure to alcohol use.

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. [ABSTRACT FROM AUTHOR]

Background: Patients with sporadic early‐onset AD (EOAD) show less pronounced memory impairment, faster cognitive decline, and greater likelihood of focal cortical syndromes than those with later onset (LOAD), while often lacking the APOE ε4 allele classically associated with younger onset. This heterogeneity could arise from differences in the distribution of AD pathology or presence of concomitant pathologies. Method: We examined clinical and cognitive heterogeneity in relation to age‐at‐onset, APOE genotype, and concomitant neuropathology (Lewy body, TDP‐43, and vascular) in patients with autopsy‐confirmed severe AD from the National Alzheimer's Coordinating Center database (N=1750). In patients from the UCSD Alzheimer's Disease Research Center (N=121) we examined how age‐related heterogeneity relates to differences in distribution of neurofibrillary tangle (NFT) pathology and plasma biomarkers of AD. Result: Age‐at‐onset distribution in APOE ε4‐ patients was bimodal with best separation at age 63. Patients with EOAD (age ≤63) had faster cognitive and functional decline than LOAD regardless of APOE genotype; and were more likely to present with nonmemory cognitive complaints (OR=5.56, 99%CI: 3.32‐9.39), show greater executive dysfunction (β=2.59 SD, 99%CI: 2.10‐3.09), and receive a non‐AD clinical diagnosis (OR=1.54, 99%CI: 1.19‐1.97), particularly for ε4‐ EOAD (p's<0.01, APOE × age‐at‐onset interactions). Despite this atypicality, groups did not differ in their high rates of AD biomarker positivity, and ε4‐ EOAD patients were most likely to have pure AD without concomitant pathology. TDP‐43 (OR=0.37; 99%CI: 0.18–0.72) and microvascular (OR=0.65; 99%CI: 0.47–0.88) pathology were less common in EOAD, while Lewy pathology was more common in ε4+ (OR=1.48; 99% CI, 1.02–2.17). Midfrontal NFT density was higher in EOAD than LOAD (β= 0.87 SD, 99%CI: 0.44‐1.29). Greater hippocampal NFT density was associated with APOE ε4+ (β=0.49 SD, 99%CI: 0.02‐0.96). Mediation analyses suggest that differences in midfrontal/hippocampal NFT ratio, rather than concomitant neuropathology, mediate the atypical cognitive profiles and decline of EOAD (p<0.01). Conclusion: A relatively more neocortical NFT distribution, rather than concomitant non‐AD pathology, accounts for the atypical, non‐memory dominant clinical presentation and rapid progression in EOAD. This suggests that selective cortical vulnerability may explain the earlier‐than‐expected onset and atypical profile in these individuals without the APOE ε4 risk allele. [ABSTRACT FROM AUTHOR]

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 (β = 1.9, 95% CI = 0.9-3.0), DRS (β = 7.8, 95% CI = 3.4-12.7), CDR-sob (β = 1.9, 95% CI = 0.4-3.7), language composite (β = 0.5 SD, 95% CI = 0.1-0.8), and vascular pathology with more rapid decline on the DRS (β = 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. [ABSTRACT FROM AUTHOR]

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-β42, 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-β42. 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. [ABSTRACT FROM AUTHOR]