Combined neuropathological pathways account for age‐related risk of dementia

Power, Melinda C.; Mormino, Elizabeth C.; Soldan, Anja; James, Bryan D.; Yu, Lei; Armstrong, Nicole; Bangen, Katherine J.; Delano‐Wood, Lisa; Lamar, Melissa; Lim, Yen Ying; Nudelman, Kelly; Zahodne, Laura B.; Gross, Alden L.; Mungas, Dan M; Widaman, Keith F.; Schneider, Julie A.

doi:10.1002/ana.25246

Cited by 153 publications

(104 citation statements)

References 54 publications

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“…While the results of our study implicate APOEε4 in the pathogenesis of both pathological hallmarks of Alzheimer disease, 55 APOEε4 is not sufficient for a diagnosis of Alzheimer disease nor to cause dementia. Instead, our study supports a framework in which isocortical/medial temporal (Braak stage 1-2) tau pathology may be a consequence of specific vulnerability factors (such as aging 51,56 or genotype 9 ), while amy-loid-β facilitates the spread of tau pathology from the medial temporal lobe to neocortical regions, 57,58 associated with greater cognitive decline. In fact, significant tau pathology in neocortical regions is seldom observed independently of amyloid-β pathology, 59 although exceptions do exist.…”

Section: Discussionsupporting

confidence: 63%

Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β

et al. 2020

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IMPORTANCE Apolipoprotein E ε4 (APOEε4) is the single most important genetic risk factor for Alzheimer disease. While APOEε4 is associated with increased amyloid-β burden, its association with cerebral tau pathology has been controversial. OBJECTIVE To determine whether APOEε4 is associated with medial temporal tau pathology independently of amyloid-β, sex, clinical status, and age. DESIGN, SETTING, AND PARTICIPANTS This is a study of 2 cross-sectional cohorts of volunteers who were cognitively normal, had mild cognitive impairment (MCI), or had Alzheimer disease dementia: the Translational Biomarkers in Aging and Dementia (TRIAD) study (data collected between October 2017 and July 2019) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (collected between November 2015 and June 2019). The first cohort (TRIAD) comprised cognitively normal elderly participants (n = 124), participants with MCI (n = 50), and participants with Alzheimer disease (n = 50) who underwent tau positron emission tomography (PET) with fluorine 18-labeled MK6240 and amyloid-β PET with [ 18 F]AZD4694. The second sample (ADNI) was composed of cognitively normal elderly participants (n = 157), participants with MCI (n = 83), and participants with Alzheimer disease (n = 25) who underwent tau PET with [ 18 F]flortaucipir and amyloid-β PET with [ 18 F]florbetapir. Exclusion criteria were a history of other neurological disorders, stroke, or head trauma. There were 489 eligible participants, selected based on availability of amyloid-PET, tau-PET, magnetic resonance imaging, and genotyping for APOEε4. Forty-five young adults (<30 years) from the TRIAD cohort were not selected for this study. MAIN OUTCOMES AND MEASURES A main association between APOEε4 and tau-PET standardized uptake value ratio, correcting for age, sex, clinical status, and neocortical amyloid-PET standardized uptake value ratio. RESULTS The mean (SD) age of the 489 participants was 70.5 (7.1) years; 171 were APOEε4 carriers (34.9%), and 230 of 489 were men. In both cohorts, APOEε4 was associated in increased tau-PET uptake in the entorhinal cortex and hippocampus independently of amyloid-β, sex, age, and clinical status after multiple comparisons correction (TRIAD: β = 0.33; 95% CI, 0.19-0.49; ADNI: β = 0.13; 95% CI, 0.08-0.19; P < .001). CONCLUSIONS AND RELEVANCE Our results indicate that the elevated risk of developing dementia conferred by APOEε4 genotype involves mechanisms associated with both amyloid-β and tau aggregation. These results contribute to an evolving framework in which APOEε4 has deleterious consequences in Alzheimer disease beyond its link with amyloid-β and suggest APOEε4 as a potential target for future disease-modifying therapeutic trials targeting tau pathology.

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Section: Discussionsupporting

confidence: 63%

Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β

et al. 2020

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“…1,23,24 Cognitive decline in Alzheimer disease may be driven by pathologic tau, 25 not amyloidosis (whose hypothesized pathogenic role is to facilitate the spread of pathological tau). 26 If so, it is not clear why the memory decline rate in A+T−(N)+ would be greater (eTable 5 in the Supplement) than that of A−T−(N)+. One possible explanation is an effect of subthreshold tau in A+T−(N)+ individuals, but this is speculative.…”

Section: Discussionmentioning

confidence: 99%

Associations of Amyloid, Tau, and Neurodegeneration Biomarker Profiles With Rates of Memory Decline Among Individuals Without Dementia

Jack

Wiste

Therneau

et al. 2019

JAMA

228

218

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on Aging and Alzheimer's Association workgroup proposed a research framework for Alzheimer disease in which biomarker classification of research participants is labeled AT(N) for amyloid, tau, and neurodegeneration biomarkers. OBJECTIVE To determine the associations between AT(N) biomarker profiles and memory decline in a population-based cohort of individuals without dementia age 60 years or older, and to determine whether biomarkers provide incremental prognostic value beyond more readily available clinical and genetic information. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study of cognitive aging in Olmsted County, Minnesota, that included 480 nondemented Mayo Clinic Study of Aging participants who had a clinical evaluation and amyloid positron emission tomography (PET) (A), tau PET (T), and magnetic resonance imaging (MRI) cortical thickness (N) measures between April 16, 2015, and November 1, 2017, and at least 1 clinical evaluation follow-up by November 12, 2018. EXPOSURES Age, sex, education, cardiovascular and metabolic conditions score, APOE genotype, and AT(N) biomarker profiles. Each of A, T, or (N) can be abnormal (+) or normal (−), resulting in 8 AT(N) profiles. MAIN OUTCOMES AND MEASURES Primary outcome was a composite memory score measured longitudinally at 15-month intervals. Analyses measured the associations between predictor variables and the memory score, and whether AT(N) biomarker profiles significantly improved prediction of memory z score rates of change beyond a model with clinical and genetic variables only. RESULTS Participants were followed up for a median of 4.8 years (interquartile range [IQR], 3.8-5.1) and 44% were women (211/480). Median (IQR) ages ranged from 67 years (65-73) in the A−T−(N)− group to 83 years (76-87) in the A+T+(N)+ group. Of the participants, 92% (441/480) were cognitively unimpaired but the A+T+(N)+ group had the largest proportion of mild cognitive impairment (30%). AT(N) biomarkers improved the prediction of memory performance over a clinical model from an R 2 of 0.26 to 0.31 (P < .001). Memory declined fastest in the A+T+(N)+, A+T+(N)−, and A+T−(N)+ groups compared with the other 5 AT(N) groups (P = .002). Estimated rates of decline in the 3 fastest declining groups were −0.13 (95% CI, −0.17 to −0.09), −0.10 (95% CI, −0.16 to −0.05), and −0.10 (95% CI, −0.13 to −0.06) z score units per year, respectively, for an 85-year-old APOE ε4 noncarrier. CONCLUSIONS AND RELEVANCE Among older persons without baseline dementia followed for a median of 4.8 years, a prediction model that included amyloid PET, tau PET, and MRI cortical thickness resulted in a small but statistically significant improvement in predicting memory decline over a model with more readily available clinical and genetic variables. The clinical importance of this difference is uncertain.

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“…Please see Table 1 for a glossary of abbreviations used in this review. As many of the reports cited in this review did not explicitly separate individuals with AD from patients with other causes of CID (e.g., vascular cognitive impairment and dementia, dementia with Lewy bodies, frontotemporal dementias), and with the recognition that the sporadic AD phenotype in older individuals is often due to mixed pathologies that include AD (e.g., AD+vascular-ischemic brain injury pathologies; AD+Lewy body pathologies) [15][16][17][18] the term 'Alzheimer's and related dementias (ADRD)', as employed in other reviews, was used when presenting and discussing the costs of diseases [14]. The terms 'Alzheimer's' or 'AD' were used when the data or discussion is relevant only to AD; for example, when discussing diagnostic criteria and biomarkers [19].…”

Section: Definitionsmentioning

confidence: 99%

Tip of the Iceberg: Assessing the Global Socioeconomic Costs of Alzheimer’s Disease and Related Dementias and Strategic Implications for Stakeholders

El-Hayek¹,

Wiley

Khoury³

et al. 2019

JAD

159

135

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While it is generally understood that Alzheimer's disease (AD) and related dementias (ADRD) is one of the costliest diseases to society, there is widespread concern that researchers and policymakers are not comprehensively capturing and describing the full scope and magnitude of the socioeconomic burden of ADRD. This review aimed to 1) catalogue the different types of AD-related socioeconomic costs described in the literature; 2) assess the challenges and gaps of existing approaches to measuring these costs; and 3) analyze and discuss the implications for stakeholders including policymakers, healthcare systems, associations, advocacy groups, clinicians, and researchers looking to improve the ability to generate reliable data that can guide evidence-based decision making. A centrally emergent theme from this review is that it is challenging to gauge the true value of policies, programs, or interventions in the ADRD arena given the long-term, progressive nature of the disease, its insidious socioeconomic impact beyond the patient and the formal healthcare system, and the complexities and current deficiencies (in measures and real-world data) in accurately calculating the full costs to society. There is therefore an urgent need for all stakeholders to establish a common understanding of the challenges in evaluating the full cost of ADRD and define approaches that allow us to measure these costs more accurately, with a view to prioritizing evidence-based solutions to mitigate this looming public health crisis.

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Combined neuropathological pathways account for age‐related risk of dementia

Abstract: Age-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies. Ann Neurol 2018;84:10-22.

Cited by 153 publications

References 54 publications

Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β

Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β

Associations of Amyloid, Tau, and Neurodegeneration Biomarker Profiles With Rates of Memory Decline Among Individuals Without Dementia

Tip of the Iceberg: Assessing the Global Socioeconomic Costs of Alzheimer’s Disease and Related Dementias and Strategic Implications for Stakeholders

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