Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and <i>APOE</i> genotype

Vermunt, Lisa; Sikkes, Sietske A.M.; Hout, Ardo van den; Handels, Ron; Bos, Isabelle; Flier, Wiesje M. van der; Kern, Silke; Ousset, Pierre‐Jean; Maruff, Paul; Skoog, Ingmar; Verhey, Frans R.J.; Freund‐Levi, Yvonne; Tsolaki, Magda; Wallin, Åsa; Rikkert, Marcel G M Olde; Soininen, Hilkka; Spiru, L.; Zetterberg, Henrik; Blennow, Kaj; Scheltens, Philip; Muñiz‐Terrera, Graciela; Visser, Pieter Jelle

doi:10.1016/j.jalz.2019.04.001

Cited by 371 publications

(308 citation statements)

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“…Consequently, only age had both positive results and was considered more of an effect modifier than a confounder, which might explain 92.41% of the variance seen in this type of meta-analysis. Age imposes the greatest risk for dementia and mortality (Vermunt et al, 2019), and inhibition interventions of aging are possibly linked to LDL-c. Mice treated with metformin, for example, enjoyed an extended span of health and longevity as well as reduction in LDL-c (Martin-Montalvo et al, 2013). In current meta-analysis, subgroup analysis on age showed LDL-c levels higher in AD patients aged 60-70 than that of non-dementia, but no association of AD with LDL-c in patients over the age of 70, indicating that the neurotoxic role of LDL-c in AD may only apply to individuals aged 60-70 and gradually subsides with advancing age.…”

Section: Discussionmentioning

confidence: 99%

Low-Density Lipoprotein Cholesterol and Alzheimer's Disease: A Systematic Review and Meta-Analysis

Zhou

Liang

Zhang

et al. 2020

Front. Aging Neurosci.

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Objective: To assess the association between low-density lipoprotein cholesterol (LDL-c) and risk of Alzheimer's disease (AD).Methods: Embase, Pubmed, and Web of Science were searched until June 2019. Standard mean difference (SMD) with 95% confidence intervals (CI) was estimated using random-effects models.Results: Our meta-analysis of 26 studies revealed higher levels of LDL-c in AD than that of non-dementia controls (SMD = 0.35, 95% CI 0.12-0.58, p < 0.01). The meta-regression analysis on confounders showed that age (p < 0.01, Adj R-squared = 92.41%) and cardiovascular disease (p = 0.01, Adj R-squared = 85.21%), but not the body mass index, education, smoking, hypertension and diabetes mellitus, exerted an impact on the relationship between LDL-c and risk of ICH. Further subgroup analysis of age showed LDL-c levels in AD patients aged 60-70 were higher than that of non-dementia (60 ≤ age < 70: SMD = 0.80, 95% CI 0.23-1.37, p < 0.01); but no association between the SMD of AD in LDL-c and age over 70 was noted across the studies (70 ≤ age < 77: SMD = −0.02, 95% CI −0.39∼0.34, p = 9.0; 77 ≤ age < 80: SMD = 0.15, 95% CI −0.17∼0.47, p = 0.35; ≥80: SMD = 0.53, 95% CI −0.04∼1.11, p = 0.07). The concentrations of LDL-c during the quintile interval of 3∼4 were positively associated with AD (121 ≤ concentration < 137: SMD = 0.98, 95% CI 0.13∼1.82, p = 0.02; ≥137: SMD = 0.62, 95% CI 0.18∼1.06, p < 0.01); whereas there was no correlation between AD and LDL-c within the quintile interval of 1∼2 (103.9 ≤ concentration < 112: SMD = 0.08, 95% CI −0.20∼0.35, p = 0.59; 112 ≤ concentration < 121: SMD = −0.26, 95% CI −0.58∼0.06, p = 0.11). Conclusions: Elevated concentration of LDL-c (>121 mg/dl) may be a potential risk factor for AD. This association is strong in patients aged 60-70 years, but vanishes with advancing age.

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Section: Discussionmentioning

confidence: 99%

Low-Density Lipoprotein Cholesterol and Alzheimer's Disease: A Systematic Review and Meta-Analysis

Zhou

Liang

Zhang

et al. 2020

Front. Aging Neurosci.

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“…While we know the continuum starts with preclinical Alzheimer's and ends with severe Alzheimer's dementia, how long individuals spend in each part of the continuum varies. The length of each phase of the continuum is influenced by age, genetics, gender and other factors 24 …”

Section: Overview Of Alzheimer's Diseasementioning

confidence: 99%

“…The length of each phase of the continuum is influenced by age, genetics, gender and other factors. 24 While research settings have the tools and expertise to identify some of the early brain changes of Alzheimer's, additional research is needed to fine-tune the tools' accuracy before they become available for widespread use in hospitals, doctors' offices and other clinical settings. It is important to note that not all individuals with evidence of Alzheimer's-related brain changes go on to develop symptoms of MCI or dementia due to Alzheimer's.…”

Section: Alzheimer's Disease Continuummentioning

confidence: 99%

2020 Alzheimer's disease facts and figures

2020

Alzheimer's & Dementia

2,033

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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“…Alzheimer's disease is thought to develop over decades [39][40][41]. However, detailed molecular studies of AD brains can only be based on post-mortem tissues.…”

Section: Age-dependent Disruption Of Ire-driven Iron Homeostasis In Tmentioning

confidence: 99%

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

Hin

Newman

Pederson

et al. 2020

Preprint

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Background: Iron trafficking and accumulation has been associated with Alzheimer's disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterised, making it difficult to explore these in existing datasets. Results: We identified sets of genes predicted to contain Iron Responsive Elements (IREs), and used these to explore iron dyshomeostasis responses in transcript datasets involving (1) cultured cells under iron overload and deficiency treatments, (2) post-mortem brain tissues from AD and other neuropathologies, (3) 5XFAD transgenic mice modelling AD pathologies, and (4) a zebrafish knock-in model of early-onset, familial AD (fAD). IRE gene sets were sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, we see changes in 3' IRE transcript abundance as amongst the earliest observable in zebrafish fAD-like brains and preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some 3' IRE transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead show decreased stability, indicating that this is not a generalizable paradigm. Conclusions: Our results reveal iron dyshomeostasis as a likely early driver of fAD and as able to distinguish AD from other brain pathologies. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis responses in different species, tissues, and conditions.

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Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype

Abstract: research-team *** see acknowledgements.

Cited by 371 publications

References 45 publications

Low-Density Lipoprotein Cholesterol and Alzheimer's Disease: A Systematic Review and Meta-Analysis

Low-Density Lipoprotein Cholesterol and Alzheimer's Disease: A Systematic Review and Meta-Analysis

2020 Alzheimer's disease facts and figures

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

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