Joseph Winer

All Publications

• Impaired 24-h activity patterns are associated with an increased risk of Alzheimer's disease, Parkinson's disease, and cognitive decline. Alzheimer's research & therapy Winer, J. R., Lok, R., Weed, L., He, Z., Poston, K. L., Mormino, E. C., Zeitzer, J. M. 2024; 16 (1): 35

  Abstract

  Sleep-wake regulating circuits are affected during prodromal stages in the pathological progression of both Alzheimer's disease (AD) and Parkinson's disease (PD), and this disturbance can be measured passively using wearable devices. Our objective was to determine whether accelerometer-based measures of 24-h activity are associated with subsequent development of AD, PD, and cognitive decline.This study obtained UK Biobank data from 82,829 individuals with wrist-worn accelerometer data aged 40 to 79 years with a mean (± SD) follow-up of 6.8 (± 0.9) years. Outcomes were accelerometer-derived measures of 24-h activity (derived by cosinor, nonparametric, and functional principal component methods), incident AD and PD diagnosis (obtained through hospitalization or primary care records), and prospective longitudinal cognitive testing.One hundred eighty-seven individuals progressed to AD and 265 to PD. Interdaily stability (a measure of regularity, hazard ratio [HR] per SD increase 1.25, 95% confidence interval [CI] 1.05-1.48), diurnal amplitude (HR 0.79, CI 0.65-0.96), mesor (mean activity; HR 0.77, CI 0.59-0.998), and activity during most active 10 h (HR 0.75, CI 0.61-0.94), were associated with risk of AD. Diurnal amplitude (HR 0.28, CI 0.23-0.34), mesor (HR 0.13, CI 0.10-0.16), activity during least active 5 h (HR 0.24, CI 0.08-0.69), and activity during most active 10 h (HR 0.20, CI 0.16-0.25) were associated with risk of PD. Several measures were additionally predictive of longitudinal cognitive test performance.In this community-based longitudinal study, accelerometer-derived metrics were associated with elevated risk of AD, PD, and accelerated cognitive decline. These findings suggest 24-h rhythm integrity, as measured by affordable, non-invasive wearable devices, may serve as a scalable early marker of neurodegenerative disease.

  View details for DOI 10.1186/s13195-024-01411-0

  View details for PubMedID 38355598

  View details for PubMedCentralID 4163039

• Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease. JAMA neurology Young, C. B., Winer, J. R., Younes, K., Cody, K. A., Betthauser, T. J., Johnson, S. C., Schultz, A., Sperling, R. A., Greicius, M. D., Cobos, I., Poston, K. L., Mormino, E. C., Alzheimers Disease Neuroimaging Initiative and the Harvard Aging Brain Study, Weiner, M. W., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., Saykin, A. J., Morris, J. C., Perrin, R. J., Shaw, L. M., Khachaturian, Z., Carrillo, M., Potter, W., Barnes, L., Bernard, M., Gonzalez, H., Ho, C., Hsiao, J. K., Jackson, J., Masliah, E., Masterman, D., Okonkwo, O., Ryan, L., Silverberg, N., Fleisher, A., Sacrey, D. T., Fockler, J., Conti, C., Veitch, D., Neuhaus, J., Jin, C., Nosheny, R., Ashford, M., Flenniken, D., Kormos, A., Montine, T., Rafii, M., Raman, R., Jimenez, G., Donohue, M., Gessert, D., Salazar, J., Zimmerman, C., Cabrera, Y., Walter, S., Miller, G., Coker, G., Clanton, T., Hergesheimer, L., Smith, S., Adegoke, O., Mahboubi, P., Moore, S., Pizzola, J., Shaffer, E., Harvey, D., Forghanian-Arani, A., Borowski, B., Ward, C., Schwarz, C., Jones, D., Gunter, J., Kantarci, K., Senjem, M., Vemuri, P., Reid, R., Fox, N. C., Malone, I., Thompson, P., Thomopoulos, S. I., Nir, T. M., Jahanshad, N., DeCarli, C., Knaack, A., Fletcher, E., Tosun-Turgut, D., Chen, S. R., Choe, M., Crawford, K., Yuschkevich, P. A., Das, S., Koeppe, R. A., Reiman, E. M., Chen, K., Mathis, C., Landau, S., Cairns, N. J., Householder, E., Franklin, E., Bernhardt, H., Taylor-Reinwald, L., Korecka, M., Figurski, M., Neu, S., Nho, K., Risacher, S. L., Apostolova, L. G., Shen, L., Foroud, T. M., Nudelman, K., Faber, K., Wilmes, K., Thal, L., Johnson, K. A., Sperling, R. A. 2022

  Abstract

  Importance: Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease.Objective: To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated beta-amyloid (A+).Design, Setting, and Participants: This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n=447; ADNI, n=433; HABS, n=190; and Wisconsin, n=328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022.Main Outcomes and Measures: Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined.Results: The 447 A4 participants (A+ group, 392; and normal beta-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867=-2.597; P=.03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin.Conclusions and Relevance: This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.

  View details for DOI 10.1001/jamaneurol.2022.0676

  View details for PubMedID 35435938

• Association of Short and Long Sleep Duration With Amyloid-beta Burden and Cognition in Aging. JAMA neurology Winer, J. R., Deters, K. D., Kennedy, G., Jin, M., Goldstein-Piekarski, A., Poston, K. L., Mormino, E. C. 2021

  Abstract

  Importance: Disrupted sleep is common in aging and is associated with cognition. Age-related changes to sleep are associated with multiple causes, including early Alzheimer disease pathology (amyloid beta [Abeta]), depression, and cardiovascular disease.Objective: To investigate the associations between self-reported sleep duration and brain Abeta burden as well as the demographic, cognitive, and lifestyle variables in adults with normal cognition.Design, Setting, and Participants: This cross-sectional study obtained data from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, which is being conducted in 67 sites in the United States, Canada, Australia, and Japan. The sample for this analysis consisted of individuals aged 65 to 85 years who underwent an Abeta positron emission tomography (PET) scan, had complete apolipoprotein E (APOE) genotype data, and were identified as clinically normal (per a Clinical Dementia Rating score of 0) and cognitively unimpaired (per a Mini-Mental State Examination score of 25 to 30 and Logical Memory Delayed Recall test score of 6 to 18). Data were analyzed from April 3, 2020, to June 20, 2021.Main Outcomes and Measures: The outcome was self-reported nightly sleep duration (grouped by short sleep duration: ≤6 hours, normal sleep duration: 7-8 hours, and long sleep duration: ≥9 hours) compared with demographic characteristics, Abeta burden (as measured with a fluorine 18-labeled-florbetapir PET scan), objective and subjective cognitive function measures, and lifestyle variables.Results: The 4417 participants in the study included 2618 women (59%) and had a mean (SD) age of 71.3 (4.7) years. Self-reported shorter sleep duration was linearly associated with higher Abeta burden (beta [SE]=-0.01 [0.00]; P=.005), and short sleep duration was associated with reduced cognition that was mostly in memory domains. No difference in Abeta was found between long and normal sleep duration groups (beta [SE]=0.00[0.01]; P=.99). However, compared with normal sleep duration, both short and long sleep durations were associated with higher body mass index (short vs normal sleep duration: beta [SE]=0.48 [0.17], P=.01; long vs normal sleep duration: beta [SE]=0.97 [0.31], P=.002), depressive symptoms (short vs normal sleep duration: beta [SE]=0.31 [0.05], P<.001; long vs normal sleep duration: beta [SE]=0.39 [0.09], P<.001), and daytime napping (short vs normal sleep duration: beta [SE]=2.66 [0.77], P=.001; long vs normal sleep duration: beta [SE]=3.62 [1.38], P=.01). Long sleep duration was associated with worse performance across multiple cognitive domains.Conclusions and Relevance: In this cross-sectional study, both short and long sleep durations were associated with worse outcomes for older adults, such as greater Abeta burden, greater depressive symptoms, higher body mass index, and cognitive decline, emphasizing the importance of maintaining adequate sleep.

  View details for DOI 10.1001/jamaneurol.2021.2876

  View details for PubMedID 34459862

• Tau and beta-amyloid burden predict actigraphy-measured and self-reported impairment and misperception of human sleep. The Journal of neuroscience : the official journal of the Society for Neuroscience Winer, J. R., Morehouse, A., Fenton, L., Harrison, T. M., Ayangma, L., Reed, M., Kumar, S., Baker, S. L., Jagust, W. J., Walker, M. P. 2021

  Abstract

  Alzheimer's disease (AD) is associated with poor sleep, but the impact of tau and beta-amyloid (Abeta) pathology on sleep remains largely unknown. Here, we test the hypothesis that tau and Abeta predict unique impairments in objective and self-perceived human sleep under real-life, free-living conditions. Eighty-nine male and female cognitively healthy older adults received 18F-FTP-tau and 11C-PIB-Abeta PET imaging, 7 nights of sleep actigraphy and questionnaire measures, and neurocognitive assessment. Tau burden, but not Abeta, was associated with markedly worse objective sleep. In contrast, Abeta and tau were associated with worse self-reported sleep quality. Of clinical relevance, Abeta burden predicted a unique perceptual mismatch between objective and subject sleep evaluation, with individuals under-estimating their sleep. The magnitude of this mismatch was further predicted by worse executive function. Thus, early-stage tau and Abeta deposition are linked with distinct phenotypes of real-world sleep impairment, one that includes a cognitive misperception of their own sleep health.Significance StatementAlzheimer's disease is associated with sleep disruption, often before significant memory decline. Thus real-life patterns of sleep behavior have the potential to serve as a window into early disease progression. In 89 cognitive healthy older adults, we found that tau burden was associated with worse wristwatch actigraphy-measured sleep quality, and that both tau and beta-amyloid were independently predictive of self-reported sleep quality. Furthermore, individuals with greater beta-amyloid deposition were more likely to underestimate their sleep quality, and sleep quality underestimation was associated with worse executive function. These data support the role of sleep impairment as a key marker of early Alzheimer's disease, and offer the possibility that actigraphy may be an affordable and scalable tool in quantifying Alzheimer's-related behavioral changes.

  View details for DOI 10.1523/JNEUROSCI.0353-21.2021

  View details for PubMedID 34290080

• Sleep Disturbance Forecasts β-Amyloid Accumulation across Subsequent Years. Current biology : CB Winer, J. R., Mander, B. A., Kumar, S., Reed, M., Baker, S. L., Jagust, W. J., Walker, M. P. 2020; 30 (21): 4291-4298.e3

  Abstract

  Experimental sleep-wake disruption in rodents and humans causally modulates β-amyloid (Aβ) dynamics (e.g., [1-3]). This leads to the hypothesis that, beyond cross-sectional associations, impaired sleep structure and physiology could represent prospective biomarkers of the speed with which Aβ accumulates over time. Here, we test the hypothesis that initial baseline measures of non-rapid eye movement (NREM) sleep slow-wave activity (SWA) and sleep quality (efficiency) provide future forecasting sensitivity to the rate of Aβ accumulation over subsequent years. A cohort of clinically normal older adults was assessed using objective sleep polysomnography in combination with longitudinal tracking of Aβ accumulation with [11C]PiB positron emission tomography (PET) imaging. Both the proportion of NREM SWA below 1 Hz and the measure of sleep efficiency predicted the speed (slope) of subsequent Aβ deposition over time, and these associations remained robust when taking into account additional cofactors of interest (e.g., age, sex, sleep apnea). Moreover, these measures were specific, such that no other macro- and microphysiological architecture metrics of sleep demonstrated such sensitivity. Our data support the proposal that objective sleep markers could be part of a set of biomarkers that statistically forecast the longitudinal trajectory of cortical Aβ deposition in the human brain. Sleep may therefore represent a potentially affordable, scalable, repeatable, and non-invasive tool for quantifying of Aβ pathological progression, prior to cognitive symptoms of Alzheimer's disease (AD).

  View details for DOI 10.1016/j.cub.2020.08.017

  View details for PubMedID 32888482

  View details for PubMedCentralID PMC7642104

• Sleep as a Potential Biomarker of Tau and β-Amyloid Burden in the Human Brain. The Journal of neuroscience : the official journal of the Society for Neuroscience Winer, J. R., Mander, B. A., Helfrich, R. F., Maass, A., Harrison, T. M., Baker, S. L., Knight, R. T., Jagust, W. J., Walker, M. P. 2019; 39 (32): 6315-6324

  Abstract

  Recent proposals suggest that sleep may be a factor associated with accumulation of two core pathological features of Alzheimer's disease (AD): tau and β-amyloid (Aβ). Here we combined PET measures of Aβ and tau, electroencephalogram sleep recordings, and retrospective sleep evaluations to investigate the potential utility of sleep measures in predicting in vivo AD pathology in male and female older adults. Regression analyses revealed that the severity of impaired slow oscillation-sleep spindle coupling predicted greater medial temporal lobe tau burden. Aβ burden was not associated with coupling impairment but instead predicted the diminished amplitude of <1 Hz slow-wave-activity, results that were statistically dissociable from each other. Additionally, comparisons of AD pathology and retrospective, self-reported changes in sleep duration demonstrated that changes in sleep across the lifespan can predict late-life Aβ and tau burden. Thus, quantitative and qualitative features of human sleep represent potential noninvasive, cost-effective, and scalable biomarkers (current and future forecasting) of AD pathology, and carry both therapeutic and public health implications.SIGNIFICANCE STATEMENT Several studies have linked sleep disruption to the progression of Alzheimer's disease (AD). Tau and β-amyloid (Aβ), the primary pathological features of AD, are associated with both objective and subjective changes in sleep. However, it remains unknown whether late life tau and Aβ burden are associated with distinct impairments in sleep physiology or changes in sleep across the lifespan. Using polysomnography, retrospective questionnaires, and tau- and Aβ-specific PET, the present study reveals human sleep signatures that dissociably predict levels of brain tau and Aβ in older adults. These results suggest that a night of polysomnography may aid in evaluating tau and Aβ burden, and that treating sleep deficiencies within decade-specific time windows may serve in delaying AD progression.

  View details for DOI 10.1523/JNEUROSCI.0503-19.2019

  View details for PubMedID 31209175

  View details for PubMedCentralID PMC6687908

• Waking Up to the Importance of Sleep in the Pathogenesis of Alzheimer Disease. JAMA neurology Winer, J. R., Mander, B. A. 2018; 75 (6): 654-656

  View details for DOI 10.1001/jamaneurol.2018.0005

  View details for PubMedID 29532083

• Associations Between Tau, β-Amyloid, and Cognition in Parkinson Disease. JAMA neurology Winer, J. R., Maass, A., Pressman, P., Stiver, J., Schonhaut, D. R., Baker, S. L., Kramer, J., Rabinovici, G. D., Jagust, W. J. 2018; 75 (2): 227-235

  Abstract

  Multiple disease processes are associated with cognitive impairment in Parkinson disease (PD), including Lewy bodies, cerebrovascular disease, and Alzheimer disease. It remains unknown whether tau pathology relates to cognition in patients with PD without dementia.To compare tau aggregation in patients with PD who are cognitively normal (PD-CN), patients with PD with mild cognitive impairment (PD-MCI), and healthy control participants, and evaluate the relationships between β-amyloid (Aβ), tau, and cognition in patients with PD who did not have dementia.This cross-sectional study recruited 30 patients with Parkinson disease (15 with PD-CN and 15 with PD-MCI) from a tertiary care medical center and research institutions from July 2015 through October 2016. One patient with PD-MCI did not receive a magnetic resonance imaging scan and thus was excluded from all analyses; 29 patients with PD were included in the present study. Participants underwent tau positron emission tomographic (PET) scanning with fluorine 18-labeled AV-1451, Aβ PET scanning with carbon 11-labeled Pittsburgh compound B, magnetic resonance imaging, cognitive testing, and neurologic evaluation. Imaging measures were compared with 49 healthy control participants.Outcomes were tau PET measurements of groups of patients with PD-CN and PD-MCI. We hypothesized that tau aggregation across groups would be related to age and Aβ status.Of the 78 participants, 47 (60%) were female, and the mean (SD) age was 71.1 (6.6) years. Six patients with PD (21%) were Aβ-positive, of whom 1 was mildly cognitively impaired; 23 were Aβ-negative (79%). (Of the 49 healthy controls, 25 were Aβ-negative and 24 Aβ-positive.) Voxelwise contrasts of whole-brain tau PET uptake between patients with PD-CN and patients with PD-MCI, and additionally between all patients with PD and Aβ-negative controls, did not reveal significant differences. Tau PET binding did not differ between patients with PD-MCI and PD-CN in brain regions reflecting Alzheimer disease Braak stages 1/2, 3/4, or 5/6, and did not differ from Aβ-negative healthy older adults. Mean (SD) tau PET binding was significantly elevated in Aβ-positive patients with PD relative to Aβ-negative patients with PD within brain regions reflecting Alzheimer disease Braak stage 3/4 (1.22 [0.07] vs 1.14 [0.07]; P = .03) and Braak stage 5/6 (1.20 [0.07] vs 1.11 [0.08]; P = .02).These findings suggest that patterns of cortical Aβ and tau do not differ in people with PD-CN, people with PD-MCI, and healthy older adults. Age, Aβ, and tau do not differentiate patients with PD-CN and PD-MCI. Tau deposition is related to Aβ status and age in both people with PD and healthy older adults. Cognitive deficits in people with PD without dementia do not appear to reflect measureable Alzheimer disease.

  View details for DOI 10.1001/jamaneurol.2017.3713

  View details for PubMedID 29228071

  View details for PubMedCentralID PMC5838622

• Sleep and Human Aging. Neuron Mander, B. A., Winer, J. R., Walker, M. P. 2017; 94 (1): 19-36

  Abstract

  Older adults do not sleep as well as younger adults. Why? What alterations in sleep quantity and quality occur as we age, and are there functional consequences? What are the underlying neural mechanisms that explain age-related sleep disruption? This review tackles these questions. First, we describe canonical changes in human sleep quantity and quality in cognitively normal older adults. Second, we explore the underlying neurobiological mechanisms that may account for these human sleep alterations. Third, we consider the functional consequences of age-related sleep disruption, focusing on memory impairment as an exemplar. We conclude with a discussion of a still-debated question: do older adults simply need less sleep, or rather, are they unable to generate the sleep that they still need?

  View details for DOI 10.1016/j.neuron.2017.02.004

  View details for PubMedID 28384471

  View details for PubMedCentralID PMC5810920

• Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer's Disease? Trends in neurosciences Mander, B. A., Winer, J. R., Jagust, W. J., Walker, M. P. 2016; 39 (8): 552-566

  Abstract

  Sleep disruption appears to be a core component of Alzheimer's disease (AD) and its pathophysiology. Signature abnormalities of sleep emerge before clinical onset of AD. Moreover, insufficient sleep facilitates accumulation of amyloid-β (Aβ), potentially triggering earlier cognitive decline and conversion to AD. Building on such findings, this review has four goals: evaluating (i) associations and plausible mechanisms linking non-rapid-eye-movement (NREM) sleep disruption, Aβ, and AD; (ii) a role for NREM sleep disruption as a novel factor linking cortical Aβ to impaired hippocampus-dependent memory consolidation; (iii) the potential diagnostic utility of NREM sleep disruption as a new biomarker of AD; and (iv) the possibility of sleep as a new treatment target in aging, affording preventative and therapeutic benefits.

  View details for DOI 10.1016/j.tins.2016.05.002

  View details for PubMedID 27325209

  View details for PubMedCentralID PMC4967375