Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease

Hanseeuw, Bernard; Betensky, Rebecca A.; Jacobs, Heidi I.L.; Schultz, Aaron P.; Sepulcre, Jorge; Becker, J. Alex; Cosio, Danielle M.; Farrell, Michelle E.; Quiroz, Yakeel T.; Mormino, Elizabeth C.; Buckley, Rachel F.; Papp, Kathryn V.; Amariglio, Rebecca; Dewachter, Ilse; Ivanoiu, Adrian; Huijbers, Willem; Hedden, Trey; Marshall, Gad A.; Chhatwal, Jasmeer P.; Rentz, Dorene M.; Sperling, Reisa A.; Johnson, Keith A.

doi:10.1001/jamaneurol.2019.1424

Cited by 590 publications

(586 citation statements)

References 41 publications

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“…Tau tangles block the transport of nutrients and other essential molecules inside neurons. Although the complete sequence of events is unclear, beta‐amyloid may begin accumulating before abnormal tau, and increasing beta‐amyloid accumulation is associated with subsequent increases in tau 7,8 …”

Section: Overview Of Alzheimer's Diseasementioning

confidence: 99%

“…Although the complete sequence of events is unclear, beta-amyloid may begin accumulating before abnormal tau, and increasing beta-amyloid accumulation is associated with subsequent increases in tau. 7,8 Other brain changes include inflammation and atrophy. The presence of toxic beta-amyloid and tau proteins are believed to activate immune system cells in the brain called microglia.…”

Section: Brain Changes Associated With Alzheimer's Diseasementioning

confidence: 99%

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2020 Alzheimer's disease facts and figures

2020

Alzheimer's & Dementia

1,966

653

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This article describes the public health impact of Alzheimer's disease (AD), including incidence and prevalence, mortality and morbidity, use and costs of care, and the overall impact on caregivers and society. The Special Report discusses the future challenges of meeting care demands for the growing number of people living with Alzheimer's dementia in the United States with a particular emphasis on primary care. By mid‐century, the number of Americans age 65 and older with Alzheimer's dementia may grow to 13.8 million. This represents a steep increase from the estimated 5.8 million Americans age 65 and older who have Alzheimer's dementia today. Official death certificates recorded 122,019 deaths from AD in 2018, the latest year for which data are available, making Alzheimer's the sixth leading cause of death in the United States and the fifth leading cause of death among Americans age 65 and older. Between 2000 and 2018, deaths resulting from stroke, HIV and heart disease decreased, whereas reported deaths from Alzheimer's increased 146.2%. In 2019, more than 16 million family members and other unpaid caregivers provided an estimated 18.6 billion hours of care to people with Alzheimer's or other dementias. This care is valued at nearly $244 billion, but its costs extend to family caregivers’ increased risk for emotional distress and negative mental and physical health outcomes. Average per‐person Medicare payments for services to beneficiaries age 65 and older with AD or other dementias are more than three times as great as payments for beneficiaries without these conditions, and Medicaid payments are more than 23 times as great. Total payments in 2020 for health care, long‐term care and hospice services for people age 65 and older with dementia are estimated to be $305 billion. As the population of Americans living with Alzheimer's dementia increases, the burden of caring for that population also increases. These challenges are exacerbated by a shortage of dementia care specialists, which places an increasing burden on primary care physicians (PCPs) to provide care for people living with dementia. Many PCPs feel underprepared and inadequately trained to handle dementia care responsibilities effectively. This report includes recommendations for maximizing quality care in the face of the shortage of specialists and training challenges in primary care.

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Section: Overview Of Alzheimer's Diseasementioning

confidence: 99%

Section: Brain Changes Associated With Alzheimer's Diseasementioning

confidence: 99%

2020 Alzheimer's disease facts and figures

2020

Alzheimer's & Dementia

1,966

653

View full text Add to dashboard Cite

show abstract

“…For example, early loss of spatial navigation parallels (and is assumed to be the functional result of) the early loss of entorhinal cortex, Most models, conceptually reliant on downstream biomarker events such as histologic evidence of amyloid microaggregate formation or tau tangles, have various degrees of difficulty in tying their specific downstream biomarkers to what are frequently more complex clinical presentations. Specific histological findings, as evidenced by imaging studies of amyloid or tau formation (and their temporal order of events), may not correlate precisely with such presentations, although the overall correlation with disease progress is usually adequate and although some markers show a better correlation than do others …”

Section: Part 3: Addressing Key Questionsmentioning

confidence: 99%

A unified model of dementias and age‐related neurodegeneration

Fossel

2020

Alzheimer's & Dementia

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Those working with Alzheimer's and other dementias have been frustrated by the implacability of these diseases. Regardless of limited symptomatic treatment, 1 there are no proven disease-modifying interventions. Despite huge and growing costs of care, 2 a pipeline of candidate drugs, 3 >400 registered trials, 4 tens of thousands of patients, 5 billions of dollars in both US federal 6 and pharmaceutical company investment, 7,8 more than a century of clinical expertise, and thousands of professional careers, dozens of pharmaceutical and biotechnology firms have foundered and failed 9 in attempts to prevent, slow, or alter the course of the dementias.This article presents a novel model to explain the relationships between age-related neurodegenerative disorders (eg, dementias) and the underlying molecular mechanisms of the aging process. The hypothesis is prompted by the fact that accepted conceptual models have failed to yield effective interventions for Alzheimer's or other dementias. 10 This article is a specific response to the Alzheimer's & Dementia editorial of November 2015, 11 which called for a systemic re-evaluation of our current models and their ability to answer fundamental questions regarding complex brain disorders and their relationship to clinical dementia, as well as the failure to yield effective clinical interventions.The article is divided into three parts. The first part explores current models of age-related neurogenerative diseases. The second part proposes a specific model and details both its working and its implications.The third part applies the model to answering the 10 key questions proposed by the Alzheimer's & Dementia editorial. The intent is to provide a conceptual model that accords with known data and proposes a novel point of clinical intervention. The model is intended to provoke discussion and provide a point of departure, rather than to offer a complete and final model for age-related neurodegenerative disease. The value of any such model rests on the outcome of clinical trials, but the model offers potentially innovative pathways to such trials. Current dementia modelsAlthough there is no general explanation for the failure to identify an effective intervention, there is growing consensus that a major factor is the lack of a comprehensive model for the dementias. 12 Over the past century, 13 several models have attained varying degrees of acceptance.Such models generally assume (or imply) a predominant single cause of Alzheimer's disease (AD; Figure 1).Such models suggest that, although several factors may contribute to the pathology, most Alzheimer's pathology results from a single predominant cause, such as amyloid plaque. In Figure 1, A (the predominant cause) is the leading causal factor, whereas B, C, D, and E represent contributing (but less significant or even incidental) factors.Until recently, the foremost among such explanations has been amyloid (A ) theory, [14][15][16][17] in various iterations. Other candidates have been tau tangles, 18-20 mitochondrial dysfun...

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“…Microtubule associated protein Tau locates intracellularly and is composed of six isoforms classified into 4-repeat (4R) and 3-repeat (3R) species, and the composition of tau isoforms differ among diverse tauopathies [2]. Tau abnormal accumulation in patients with Alzheimer's disease was found to be closely related to axonal damage, neurodegeneration and cognitive impairment [3][4][5]. This designates tauopathy an important target for early diagnostic and therapeutic intervention for Alzheimer's disease, FTLD, and other tauopathy disorders [6].…”

Section: Introductionmentioning

confidence: 99%

“…At macroscopic level, in vivo imaging of tauopathy was enabled by PET in P301L mouse line using 11 C-PBB3 [20][21][22] or 18 F-PI-2620 [10] tau probes. However, the limited resolution of microPET (1 mm) relative to the mouse brain (~10 mm 3 ) and the need for dedicated and expensive infrastructure for radiolabeling limit usability in preclinical setting. Near-infrared fluorescence imaging using PBB5, PBB3 [20], fluorescently labelled antibodies, and antibody fragments [23] have also been applied for tauopathy detection in animal models.…”

Section: Introductionmentioning

confidence: 99%

Detection of cerebral tauopathy in P301L mice using high-resolution large-field multifocal illumination fluorescence microscopy

Chen

Gerez

et al. 2020

Preprint

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Current intravital microscopy techniques visualize tauopathy with high-resolution, but have a small field-of-view and depth-of-focus. Herein, we report a transcranial detection of tauopathy over the entire cortex of P301L tauopathy mice using large-field multifocal illumination (LMI) fluorescence microscopy technique and luminescent conjugated oligothiophenes. In vitro assays revealed that fluorescent ligand h-FTAA is optimal for in vivo tau imaging, which was confirmed by observing elevated probe retention in the cortex of P301L mice compared to non-transgenic littermates. Immunohistochemical staining further verified the specificity of h-FTAA to detect tauopathy in P301L mice. The new imaging platform can be leveraged in pre-clinical mechanistic studies of tau spreading and clearance as well as longitudinal monitoring of tau targeting therapeutics.

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Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease

Cited by 590 publications

References 41 publications

2020 Alzheimer's disease facts and figures

2020 Alzheimer's disease facts and figures

A unified model of dementias and age‐related neurodegeneration

Detection of cerebral tauopathy in P301L mice using high-resolution large-field multifocal illumination fluorescence microscopy

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