Alzheimer's & Dementia
1552-5260
Cơ quản chủ quản: John Wiley & Sons Inc. , WILEY
Lĩnh vực:
Psychiatry and Mental HealthDevelopmental NeuroscienceEpidemiologyHealth PolicyNeurology (clinical)Cellular and Molecular NeuroscienceGeriatrics and Gerontology
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Prevalence and incidence of clinically diagnosed Alzheimer's disease dementia from 1994 to 2012 in a population study Abstract Introduction The trends in prevalence and incidence of Alzheimer's disease (AD) dementia remain uncertain. Methods A sample of 2794 participants with a clinical diagnosis for AD dementia were included. Results The 2010 census standardized prevalence of AD dementia was 14.5% (95% CI = 13.7–15.3), and annual incidence was 2.3% (1.7–2.9). Both prevalence and incidence showed substantial variation over time, but no secular trends. The prevalence of AD dementia did not change significantly from 14.6% (95% CI = 13.0, 16.2) in 1994–1997 to 14.7% (95% CI = 13.2, 16.2) in 2010–2012 (P = .84). The annual incidence of AD dementia was 2.8% (95% CI = 2.2, 3.2) in 1998–2000 and 2.2% (95% CI = 1.6, 2.8) in 2004–2006 (P = .20) and remained steady in 2010–2012. The prevalence and incidence among African Americans were approximately twice than those among European Americans. Conclusions The prevalence and incidence of AD dementia showed substantial variation between 1994 and 2012, but no secular trend.
Tập 15 - Trang 1-7 - 2019
Florbetapir (F18‐AV‐45) PET to assess amyloid burden in Alzheimer's disease dementia, mild cognitive impairment, and normal aging Objective To evaluate the performance characteristics of florbetapir F18 positron emission tomography (PET) in patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy control subjects (HCs). Methods Florbetapir PET was acquired in 184 subjects (45 AD patients, 60 MCI patients, and 79 HCs) within a multicenter phase 2 study. Amyloid burden was assessed visually and quantitatively, and was classified as positive or negative. Results Florbetapir PET was rated visually amyloid positive in 76% of AD patients, 38% of MCI patients, and 14% of HCs. Eighty‐four percent of AD patients, 45% of MCI patients, and 23% of HCs were classified as amyloid positive using a quantitative threshold. Amyloid positivity and mean cortical amyloid burden were associated with age and apolipoprotein E ε4 carrier status. Conclusions The data are consistent with expected rates of amyloid positivity among individuals with clinical diagnoses of AD and MCI, and indicate the potential value of florbetapir F18 PET as an adjunct to clinical diagnosis.
Tập 9 - Trang S72-S83 - 2013
Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs Abstract Introduction Alzheimer apolipoprotein E (APOE ) ɛ4/ɛ4 carriers have earlier disease onset and more protein aggregates than patients with other APOE genotypes. Autophagy opposes aggregation, and important autophagy genes are coordinately regulated by transcription factor EB (TFEB) binding to “coordinated lysosomal expression and regulation” (CLEAR) DNA motifs. Methods Autophagic gene expression was assessed in brains of controls and Alzheimer's disease (AD) patients parsed by APOE genotype and in a glioblastoma cell line expressing either apoE3 or apoE4. Computational modeling assessed interactions between apoE and mutated apoE with CLEAR or modified DNA. Results Three TFEB‐regulated mRNA transcripts—SQSTM, MAP1LC3B , and LAMP2 —were lower in AD ɛ4/ɛ4 than in AD ɛ3/ɛ3 brains. Computational modeling predicted avid specific binding of apoE4 to CLEAR motifs. ApoE was found in cellular nuclei, and in vitro binding assays suggest competition between apoE4 and TFEB at CLEAR sites. Conclusion ApoE4‐CLEAR interactions may account for suppressed autophagy in APOE ɛ4/ɛ4 carriers and, in this way, contribute to earlier AD onset.
Tập 14 Số 2 - Trang 230-242 - 2018
Intracerebral propagation of Alzheimer's disease: Strengthening evidence of a herpes simplex virus etiology Background A faulty human protein, abnormally phosphorylated tau, was recently publicized to spread “like a virus” from neuron to neuron in Alzheimer's patients’ brains. For several decades, we have been amassing arguments showing that herpes simplex virus type 1 (HSV‐1), not p‐tau, propagates this interneuronal, transsynaptic pathologic cascade. Methods We reiterate convincing data from our own (and other) laboratories, reviewing the first anatomic foothold neurofibrillary tangles gain in brainstem and/or entorhinal cortex; the chronic immunosurveillance cellularity of the trigeminal ganglia wherein HSV‐1 awakens from latency to reactivate; the inabilities of p‐tau protein's physical properties to promote it to jump synapses; the amino acid homology between human p‐tau and VP22, a key target for phosphorylation by HSV serine/threonine–protein kinase UL13; and the exosomic secretion of HSV‐1–infected cells’ L‐particles, attesting to the cell‐to‐cell passage of microRNAs of herpesviruses. Results The now‐maturing construct that reactivated HSV‐1 best accounts for the intracerebral propagation of AD changes in the human brain should at last seem highly attractive. This hypothesis might even explain statins' apparent mechanism in some studies for lowering AD incidence. Conclusion Provided that funding agencies will quickly ignite a new realm of investigation, the rejuvenated enthusiasm for testing this optimistic construct holds incalculable potential for rapid, efficacious clinical application, through already available and relatively safe antiviral therapeutics.
Tập 9 - Trang 169-175 - 2013
Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome Abstract Introduction Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut‐brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). Methods Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD‐related genetic variants, adjusting for confounders and multiple testing. Results In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α‐dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response–related genes implicated in AD showed associations with BA profiles. Discussion We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut‐liver‐brain axis in the pathogenesis of AD.
Tập 15 Số 1 - Trang 76-92 - 2019
Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers Abstract Introduction Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co‐metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer's disease (AD) including neuroinflammation and amyloid‐β deposition. Method Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the “A/T/N” (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18 F]FDG PET). Results Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ1‐42 (“A”) and three with CSF p‐tau181 (“T”) (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t‐tau, glucose metabolism, and atrophy (“N”), respectively (corrected P < .05). Discussion This is the first study to show serum‐based BA metabolites are associated with “A/T/N” AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.
Tập 15 - Trang 232-244 - 2019
Cognitive resilience depends on white matter connectivity: The Maastricht Study Abstract Introduction Differences in brain network connectivity may reflect the capability of the neurological substrate to compensate for brain damage and preserve cognitive function (cognitive reserve). We examined the associations between white matter connectivity, brain damage markers, and cognition in a population sample of middle‐aged individuals. Methods A total of 4759 participants from The Maastricht Study (mean age = 59.2, SD = 8.7, 50.2% male) underwent cognitive testing and diffusion magnetic resonance imaging (dMRI), from which brain volume, structural connectivity, and vascular damage were quantified. Multivariable linear regression was used to investigate whether connectivity modified the association between brain damage and cognition, adjusted for demographic and cardiometabolic risk factors. Results More atrophic and vascular brain damage was associated with worse cognition scores. Increasing connectivity moderated the negative association between damage and cognition (χ2 = 8.64, df = 3, p ≤ 0.001); individuals with high damage but strong connectivity showed normal cognition. Discussion Findings support the reserve hypothesis by showing that brain connectivity is associated with cognitive resilience.
Tập 19 Số 4 - Trang 1164-1174 - 2023
2022 Alzheimer's disease facts and figures 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.
Tập 18 Số 4 - Trang 700-789 - 2022
Estimation of lifetime risks of Alzheimer's disease dementia using biomarkers for preclinical disease Abstract Introduction Lifetime risks are the probabilities of progressing to Alzheimer's disease (AD) dementia during one's lifespan. Here, we report the first estimates of the lifetime and ten‐year risks of AD dementia based on age, gender, and biomarker tests for preclinical disease. Methods We used a multistate model for the disease process together with US death rates. Results Lifetime risks of AD dementia vary considerably by age, gender, and the preclinical or clinical disease state of the individual. For example, the lifetime risks for a female with only amyloidosis are 8.4% for a 90‐year old and 29.3% for a 65‐year old. Persons younger than 85 years with mild cognitive impairment, amyloidosis, and neurodegeneration have lifetime risks of AD dementia greater than 50%. Discussion Most persons with preclinical AD will not develop AD dementia during their lifetimes. Lifetime risks help interpret the clinical significance of biomarker screening tests for AD.
Tập 14 - Trang 981-988 - 2018
Variants in <i>PPP3R1</i> and <i>MAPT</i> are associated with more rapid functional decline in Alzheimer's disease: The Cache County Dementia Progression Study Abstract Background Single‐nucleotide polymorphisms (SNPs) located in the gene encoding the regulatory subunit of the protein phosphatase 2B (PPP3R1 , rs1868402) and the microtubule‐associated protein tau (MAPT , rs3785883) gene were recently associated with higher cerebrospinal fluid (CSF) tau levels in samples from the Knight Alzheimer's Disease Research Center at Washington University (WU) and Alzheimer's Disease Neuroimaging Initiative (ADNI). In these same samples, these SNPs were also associated with faster functional decline, or progression of Alzheimer's disease (AD) as measured by the Clinical Dementia Rating sum of boxes scores (CDR‐sb). We attempted to validate the latter association in an independent, population‐based sample of incident AD cases from the Cache County Dementia Progression Study (DPS). Methods All 92 AD cases from the DPS with a global CDR‐sb ≤1 (mild) at initial clinical assessment who were later assessed on CDR‐sb data on at least two other time points were genotyped at the two SNPs of interest (rs1868402 and rs3785883). We used linear mixed models to estimate associations between these SNPs and CDR‐sb trajectory. All analyses were performed using Proc Mixed in SAS. Results Although we observed no association between rs3785883 or rs1868402 alone and change in CDR‐sb (P > .10), there was a significant association between a combined genotype model and change in CDR‐sb: carriers of the high‐risk genotypes at both loci progressed >2.9 times faster than noncarriers (P = .015). When data from DPS were combined with previously published data from WU and ADNI, change in CDR‐sb was 30% faster for each copy of the high‐risk allele at rs3785883 (P = .0082) and carriers of both high‐risk genotypes at both loci progressed 6 times faster (P < .0001) than all others combined. Conclusions We replicate a previous report by Cruchaga et al that specific variations in rs3785883 and rs1868402 are associated with accelerated progression of AD. Further characterization of this association will provide a better understanding of how genetic factors influence the rate of progression of AD and could provide novel insights into preventative and therapeutic strategies.
Tập 10 - Trang 366-371 - 2014