Showing papers in "Alzheimers & Dementia in 2022"
TL;DR: 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 family caregivers, the dementia workforce and society are described are described.
Abstract: 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 family caregivers, the dementia workforce and society. The Special Report discusses consumers' and primary care physicians' perspectives on awareness, diagnosis and treatment of mild cognitive impairment (MCI), including MCI due to Alzheimer's disease. An estimated 6.5 million Americans age 65 and older are living with Alzheimer's dementia today. This number could grow to 13.8 million by 2060 barring the development of medical breakthroughs to prevent, slow or cure AD. Official death certificates recorded 121,499 deaths from AD in 2019, the latest year for which data are available. Alzheimer's disease was officially listed as the sixth‐leading cause of death in the United States in 2019 and the seventh‐leading cause of death in 2020 and 2021, when COVID‐19 entered the ranks of the top ten causes of death. Alzheimer's remains the fifth‐leading cause of death among Americans age 65 and older. Between 2000 and 2019, deaths from stroke, heart disease and HIV decreased, whereas reported deaths from AD increased more than 145%. More than 11 million family members and other unpaid caregivers provided an estimated 16 billion hours of care to people with Alzheimer's or other dementias in 2021. These figures reflect a decline in the number of caregivers compared with a decade earlier, as well as an increase in the amount of care provided by each remaining caregiver. Unpaid dementia caregiving was valued at $271.6 billion in 2021. Its costs, however, extend to family caregivers’ increased risk for emotional distress and negative mental and physical health outcomes — costs that have been aggravated by COVID‐19. Members of the dementia care workforce have also been affected by COVID‐19. As essential care workers, some have opted to change jobs to protect their own health and the health of their families. However, this occurs at a time when more members of the dementia care workforce are needed. Average per‐person Medicare payments for services to beneficiaries age 65 and older with AD or other dementias are almost three times as great as payments for beneficiaries without these conditions, and Medicaid payments are more than 22 times as great. Total payments in 2022 for health care, long‐term care and hospice services for people age 65 and older with dementia are estimated to be $321 billion. A recent survey commissioned by the Alzheimer's Association revealed several barriers to consumers’ understanding of MCI. The survey showed low awareness of MCI among Americans, a reluctance among Americans to see their doctor after noticing MCI symptoms, and persistent challenges for primary care physicians in diagnosing MCI. Survey results indicate the need to improve MCI awareness and diagnosis, especially in underserved communities, and to encourage greater participation in MCI‐related clinical trials.
765 citations
TL;DR: The AD drug development pipeline has agents representing a substantial array of treatment mechanisms and targets, and advances in drug design, outcome measures, use of biomarkers, and trial conduct promise to accelerate the delivery of new and better treatments for patients with AD.
Abstract: Alzheimer's disease (AD) represents a global health crisis. Treatments are needed to prevent, delay the onset, slow the progression, improve cognition, and reduce behavioral disturbances of AD. We review the current clinical trials and drugs in development for the treatment of AD.
146 citations
TL;DR: Additional data are needed before use of BBMs as stand-alone diagnostic AD markers, or before considering use in primary care, and it is recommended to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work-up of patients with cognitive symptoms.
Abstract: Blood‐based markers (BBMs) have recently showed promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer's disease (AD), as well as to improve the design of interventional trials.
93 citations
TL;DR: The mechanisms that lead to cognitive impairment associated with COVID‐19 are not well understood and further research is needed to better understand these mechanisms and their role in clinical practice.
Abstract: The mechanisms that lead to cognitive impairment associated with COVID‐19 are not well understood.
69 citations
TL;DR: In this paper, the authors discuss further research needed to be performed before widespread use of blood-based markers (BBMs) for diagnostic and prognostic work-up of Alzheimer's disease.
Abstract: Blood‐based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer's disease (AD), as well as to improve the design of interventional trials. Here we discuss in detail further research needed to be performed before widespread use of BBMs. We already now recommend use of BBMs as (pre‐)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease‐modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work‐up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand‐alone diagnostic AD markers, or before considering use in primary care.
69 citations
TL;DR: The number of persons with AD dementia, prodromal AD, and preclinical AD were estimated at 32, 69, and 315 million, respectively, which is much larger than conveyed in available literature.
Abstract: Global estimates on numbers of persons in early stages of Alzheimer's disease (AD), including prodromal and preclinical, are lacking, yet are needed to inform policy decisions on preventive measures and planning for future therapies targeting AD pathology.
64 citations
TL;DR: In this paper , a systematic review and meta-analysis of the cognitive effects of coronavirus disease 2019 (COVID-19) in adults with no prior history of cognitive impairment was conducted.
Abstract: Introduction We conducted a systematic review and meta-analysis of the cognitive effects of coronavirus disease 2019 (COVID-19) in adults with no prior history of cognitive impairment. Methods Searches in Medline/Web of Science/Embase from January 1, 2020, to December 13, 2021, were performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A meta-analysis of the Montreal Cognitive Assessment (MoCA) total score comparing recovered COVID-19 and healthy controls was performed. Results Oof 6202 articles, 27 studies with 2049 individuals were included (mean age = 56.05 years, evaluation time ranged from the acute phase to 7 months post-infection). Impairment in executive functions, attention, and memory were found in post-COVID-19 patients. The meta-analysis was performed with a subgroup of 290 individuals and showed a difference in MoCA score between post-COVID-19 patients versus controls (mean difference = −0.94, 95% confidence interval [CI] −1.59, −0.29; P = .0049). Discussion Patients recovered from COVID-19 have lower general cognition compared to healthy controls up to 7 months post-infection.
61 citations
TL;DR: In this article , neurological complications among hospitalized COVID19 patients may be associated with elevated neurodegenerative biomarkers, which may indicate increased risk of brain tumor development.
Abstract: Neurological complications among hospitalized COVID‐19 patients may be associated with elevated neurodegenerative biomarkers.
56 citations
TL;DR: The Amyloid Cascade Model does not readily account for various parameters associated with Alzheimer's disease (AD), and a unified model correctly identifying the pathogenesis of AD is greatly needed to inform the development of successful therapeutics.
Abstract: To promote new thinking of the pathogenesis of Alzheimer's disease (AD), we examine the central role of mitochondrial dysfunction in AD. Pathologically, AD is characterized by progressive neuronal loss and biochemical abnormalities including mitochondrial dysfunction. Conventional thinking has dictated that AD is driven by amyloid beta pathology, per the Amyloid Cascade Hypothesis. However, the underlying mechanism of how amyloid beta leads to cognitive decline remains unclear. A model correctly identifying the pathogenesis of AD is critical and needed for the development of effective therapeutics. Mitochondrial dysfunction is closely linked to the core pathological feature of AD: neuronal dysfunction. Targeting mitochondria and associated proteins may hold promise for new strategies for the development of disease‐modifying therapies. According to the Mitochondrial Cascade Hypothesis, mitochondrial dysfunction drives the pathogenesis of AD, as baseline mitochondrial function and mitochondrial change rates influence the progression of cognitive decline.
38 citations
TL;DR: These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.
Abstract: For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo.
34 citations
TL;DR: The high accuracies for Aβ pathology and future AD dementia using fully automated instruments are promising for implementing plasma biomarkers in clinical trials and clinical routine.
Abstract: There is a great need for fully automated plasma assays that can measure amyloid beta (Aβ) pathology and predict future Alzheimer's disease (AD) dementia.
TL;DR: In this article , the authors provide definitions of gender, biologic sex, and sexual orientation and provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD.
Abstract: Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk.
TL;DR: Evaluating the efficacy of 3,6'-dithioPomalidomide in 5xFAD Alzheimer's disease mice to test the hypothesis that neuroinflammation is directly involved in the development of synaptic/neuronal loss and cognitive decline is tested.
Abstract: Evaluating the efficacy of 3,6’‐dithioPomalidomide in 5xFAD Alzheimer's disease (AD) mice to test the hypothesis that neuroinflammation is directly involved in the development of synaptic/neuronal loss and cognitive decline.
TL;DR: The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage, and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.
Abstract: The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3‐45 Study (BAN2401‐G000‐303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3‐45 Study is conducted as a Public‐Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc.
TL;DR: In this article , the longitudinal relationship between daytime napping and cognitive aging is unknown, however, it is shown that day-time napping is frequently seen in older adults and is associated with cognitive aging.
Abstract: Daytime napping is frequently seen in older adults. The longitudinal relationship between daytime napping and cognitive aging is unknown.
TL;DR: Findings are important for those using these biomarkers in clinical practice and clinical trials as plasma AD biomarkers vary significantly in association with common medical comorbidities as well as ethnicity.
Abstract: Despite the clinical implementation, there remain significant gaps in our knowledge regarding the impact of race/ethnicity or common medical comorbidity on plasma Alzheimer's disease (AD) biomarkers.
TL;DR: Low plasma levels of CRP at baseline were associated with high risk of AD in individuals from the general population and these observational findings were supported by genetic studies.
Abstract: Increased plasma levels of C‐reactive protein (CRP) in midlife are associated with increased risk of Alzheimer's disease (AD), whereas in older age the opposite association is observed. Whether genetically determined CRP is associated with AD remains unclear.
TL;DR: Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug‐like analogues of these endogenous regulators represents a novel therapeutic approach for AD.
Abstract: Alzheimer's disease (AD) is characterized by neurotoxic immuno‐inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aβ) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses.
TL;DR: Clinical trials testing tau-targeting therapies may benefit from using fluid biomarker associations with tau accumulation and estimated trial sample sizes and screening failure reductions by implementing these markers into participant selection for trials.
Abstract: Clinical trials targeting tau in Alzheimer's disease (AD) need to recruit individuals at risk of tau accumulation. Here, we studied cerebrospinal fluid (CSF) biomarkers and plasma phosphorylated tau (p‐tau)181 as predictors of tau accumulation on positron emission tomography (PET) to evaluate implications for trial designs.
TL;DR: In this article , it is uncertain whether subjective cognitive decline in individuals who seek medical help serves the identification of the initial symptomatic stage 2 of the Alzheimer's disease (AD) continuum.
Abstract: It is uncertain whether subjective cognitive decline (SCD) in individuals who seek medical help serves the identification of the initial symptomatic stage 2 of the Alzheimer's disease (AD) continuum.
TL;DR: In this paper , the main blood phosphorylated tau immunoassays in memory clinic populations are compared in order to understand possible differences in possible differences between different groups of patients.
Abstract: Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences.
TL;DR: Overall MCI was associated with demographic factors, non-alcohol consumption, and stroke, but not with APOE genotype and cardiometabolic factors.
Abstract: Epidemiological studies of mild cognitive impairment (MCI) and subtypes of MCI have rarely focused on rural residents in China.
TL;DR: The incidence rate of breakthrough infections among fully vaccinated patients with dementia increased since December 2020 and accelerated after May 2021, highlighting the need to continuously monitor breakthrough severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infections and outcomes in vaccinated patientsWith dementia.
Abstract: There is lack of data on COVID‐19 breakthrough infections in vaccinated patients with dementia in the United States.
TL;DR: In this article , the authors tested whether daily administration of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin-mineral versus placebo improved cognition in older women and men.
Abstract: Dietary supplements are touted for cognitive protection, but supporting evidence is mixed. COSMOS‐Mind tested whether daily administration of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin‐mineral (MVM) versus placebo improved cognition in older women and men.
TL;DR: Findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women.
Abstract: Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimer's disease (AD) among persons lacking apolipoprotein E ε4 (ε4–).
TL;DR: Strong generalizable evidence is demonstrated for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.
Abstract: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total‐tau (t‐tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders.
TL;DR: It is hypotheses that CHI3L1 functions as a signaling molecule mediating distinct neuroinflammatory responses in brain cells and misfunctions to precipitate neurodegeneration and recommends future research directions to validate such assertions for better understanding of disease mechanisms.
Abstract: Chitinase‐3‐like protein 1 (CHI3L1/YKL‐40) has long been known as a biomarker for early detection of neuroinflammation and disease diagnosis of Alzheimer's disease (AD). In the brain, CHI3L1 is primarily provided by astrocytes and heralds the reactive, neurotoxic state triggered by inflammation and other stress signals. However, how CHI3L1 acts in neuroinflammation or how it contributes to AD and relevant neurodegenerative conditions remains unknown. In peripheral tissues, our group and others have uncovered that CHI3L1 is a master regulator for a wide range of injury and repair events, including the innate immunity pathway that resembles the neuroinflammation process governed by microglia and astrocytes. Based on assessment of current knowledge regarding CHI3L1 biology, we hypothesize that CHI3L1 functions as a signaling molecule mediating distinct neuroinflammatory responses in brain cells and misfunctions to precipitate neurodegeneration. We also recommend future research directions to validate such assertions for better understanding of disease mechanisms.
TL;DR: In this article , the clinical interpretation of white matter hyperintensities (WMHs) is discussed and a summary of methodological approaches is provided, allowing researchers to design future studies targeting current knowledge gaps.
Abstract: The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological approaches, allowing researchers to design future studies targeting current knowledge gaps.
TL;DR: Investigation of the distribution of APP in human AD brain samples and in mouse models of AD finds that alteration of APP distribution and its accumulation together with presynaptic proteins around dense-core amyloid plaques is a key histopathological feature in AD, lending support to the notion that Presynaptic failure is a strong physiopathological component of AD.
Abstract: In Alzheimer's disease (AD), the distribution of the amyloid precursor protein (APP) and its fragments other than amyloid beta, has not been fully characterized. Here, we investigate the distribution of APP and its fragments in human AD brain samples and in mouse models of AD in reference to its proteases, synaptic proteins, and histopathological features characteristic of the AD brain, by combining an extensive set of histological and analytical tools. We report that the prominent somatic distribution of APP observed in control patients remarkably vanishes in human AD patients to the benefit of dense accumulations of extra‐somatic APP, which surround dense‐core amyloid plaques enriched in APP‐Nter. These features are accentuated in patients with familial forms of the disease. Importantly, APP accumulations are enriched in phosphorylated tau and presynaptic proteins whereas they are depleted of post‐synaptic proteins suggesting that the extra‐somatic accumulations of APP are of presynaptic origin. Ultrastructural analyses unveil that APP concentrates in autophagosomes and in multivesicular bodies together with presynaptic vesicle proteins. Altogether, alteration of APP distribution and its accumulation together with presynaptic proteins around dense‐core amyloid plaques is a key histopathological feature in AD, lending support to the notion that presynaptic failure is a strong physiopathological component of AD.
TL;DR: In this article , the authors investigated the relationship between mild behavioral impairment (MBI) and progression to Alzheimer's disease (AD) and found that MBI is a predictor of AD. But, their study focused on early stages of MBI.
Abstract: Mild behavioral impairment (MBI) is characterized by later‐life emergence of neuropsychiatric symptoms. Investigating its relationship with progression to Alzheimer's disease (AD) would provide insight on its importance as a predictor of AD.