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1.
AIDS ; 35(5): 727-736, 2021 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-33587445

RESUMEN

OBJECTIVE: Nearly half of individuals living with HIV in the USA are now 50 or older. This rapidly ageing populace may be at an increasingly greater risk of Alzheimer's disease. However, the potential interaction between HIV-disease and Alzheimer's disease pathogenesis (i.e. Alzheimer's disease genetic risk factors) on brain function remains an open question. The present study aimed to investigate the impact of APOE ε4 on brain function in middle-aged to older people with HIV (PWH), as well as the putative interaction between ε4 and HIV disease severity. METHODS: Ninety-nine PWH participated in a cross-sectional study (56.3 ±â€Š6.5 years, range 41-70 years, 27 women, 26 ε4 carriers and 73 noncarriers). Structural MRI and resting-state functional MRI were collected to assess alterations in brain structure and functional connectivity, respectively. RESULTS: APOE ε4 was associated with worse memory performance and reduced functional connectivity in the memory network. The functional connectivity reduction was centred at the caudate nucleus rather than hippocampus and correlated with worse memory performance. In ε4 carriers, low CD4+ cell count nadir was associated with reduced functional connectivity in the memory network, but this association was absent in noncarriers. Furthermore, there was an indirect detrimental impact of ε4 on memory performance through memory network functional connectivity. However, this indirect effect was contingent on CD4+ cell count nadir, that is the indirect effect of ε4 on memory was only significant when CD4+ cell count nadir was low. INTERPRETATION: APOE ε4 is associated with reduced memory and reduced functional connectivity within the memory network, and low CD4+ cell count nadir -- indicating a history of severe immunosuppression -- may exacerbate the effects of ε4.


Asunto(s)
Enfermedad de Alzheimer , Infecciones por VIH , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteína E4/genética , Encéfalo , Recuento de Linfocito CD4 , Estudios Transversales , Femenino , Infecciones por VIH/complicaciones , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Pruebas Neuropsicológicas
3.
Neurology ; 96(6): e916-e925, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33441454

RESUMEN

OBJECTIVE: To determine whether memory is preserved longitudinally in primary progressive aphasia (PPA) associated with Alzheimer disease (AD) and to identify potential factors that maintain memory despite underlying neurofibrillary degeneration of mediotemporal memory areas. METHODS: Longitudinal memory assessment was done in 17 patients with PPA with autopsy or biomarker evidence of AD (PPA-AD) and 14 patients with amnestic dementia of the Alzheimer type with AD at autopsy (DAT-AD). RESULTS: In PPA-AD, episodic memory, tested with nonverbal items, was preserved at the initial testing and showed no decline at retesting 2.35 ± 0.78 years later, at which time symptoms had been present for 6.26 ± 2.21 years. In contrast, language functions declined significantly during the same period. In DAT-AD, both verbal memory and language declined with equal severity. Although imaging showed asymmetric left-sided mediotemporal atrophy in PPA-AD, autopsy revealed bilateral hippocampo-entorhinal neurofibrillary degeneration at Braak stages V and VI. Compared to DAT-AD, however, the PPA-AD group had lower incidence of APOE ε4 and of mediotemporal TAR DNA-binding protein 43 (TDP-43) pathology. CONCLUSIONS: Memory preservation in PPA is not just an incidental finding at onset but a core feature that persists for years despite the hippocampo-entorhinal AD neuropathology that is as severe as that of DAT-AD. Asymmetry of mediotemporal atrophy and a lesser impact of APOE ε4 and of TDP-43 on the integrity of memory circuitry may constitute some of the factors underlying this resilience. Our results also suggest that current controversies on memory in PPA-AD reflect inconsistencies in the diagnosis of logopenic PPA, the clinical variant most frequently associated with AD. CLINICALTRIALSGOV IDENTIFIER: NCT00537004 and NCT03371706.


Asunto(s)
Enfermedad de Alzheimer , Amnesia , Afasia Progresiva Primaria , Corteza Entorrinal/patología , Hipocampo/patología , Anciano , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Amnesia/patología , Amnesia/fisiopatología , Afasia Progresiva Primaria/patología , Afasia Progresiva Primaria/fisiopatología , Apolipoproteína E4/genética , Atrofia , Autopsia , Proteínas de Unión al ADN/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Memoria Episódica , Persona de Mediana Edad , Ovillos Neurofibrilares/patología , Índice de Severidad de la Enfermedad
4.
Neurology ; 96(9): e1347-e1357, 2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33408147

RESUMEN

OBJECTIVE: To understand the time course of ß-amyloid (Aß) deposition in the brain, which is crucial for planning therapeutic trials of Aß-lowering therapies in Alzheimer disease (AD). METHODS: Two samples of participants from the Alzheimer's Disease Neuroimaging Initiative were studied with [18F]Florbetapir (FBP) Aß PET and followed for up to 9 years. Sample A included 475 cognitively normal (CN) older people and those with mild cognitive impairment (MCI) and AD and sample B included 220 CN Aß- individuals. We examined the trajectory of FBP over time in sample A and the incidence rate of conversion from negative to positive Aß PET scans in sample B. RESULTS: The relationship between time and brain Aß was sigmoidal, taking 6.4 years to transition from amyloid negative to positive and another 13.9 years to the onset of MCI. Aß deposition rates began to slow only 3.8 years after reaching the positivity threshold. The incidence rate for scan positivity was 38/1,000 person-years, and factors associated with conversion were age, baseline FBP, and being a female APOE ε4 carrier. Among CN Aß- individuals, FBP slopes were associated with rates of memory decline and brain tau measured with [18F]Flortaucipir PET 5 years after baseline. CONCLUSIONS: Lowering brain Aß must be accomplished early in the evolution of AD. Transitions of PET scans from Aß- to Aß+ should be predictable, and it is reasonable to expect that lowering rates of Aß even in early stages could produce clinically significant benefits.


Asunto(s)
Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/psicología , Compuestos de Anilina , Apolipoproteína E4/genética , Carbolinas , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/psicología , Glicoles de Etileno , Femenino , Estudios de Seguimiento , Heterocigoto , Humanos , Estudios Longitudinales , Masculino , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Caracteres Sexuales , Proteínas tau/genética
5.
Neurology ; 96(7): e975-e985, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33443136

RESUMEN

OBJECTIVE: To assess the frequency of biologically defined Alzheimer disease (AD) in relation to age, sex, APOE ε4, and clinical diagnosis in a prospective cohort study evaluated with amyloid-PET and tau-PET. METHODS: We assessed cognitively unimpaired (CU) elderly (n = 166), patients with amnestic mild cognitive impairment (n = 77), and patients with probable AD dementia (n = 62) who underwent evaluation by dementia specialists and neuropsychologists in addition to amyloid-PET with [18F]AZD4694 and tau-PET with [18F]MK6240. Individuals were grouped according to their AD biomarker profile. Positive predictive value for biologically defined AD was assessed in relation to clinical diagnosis. Frequency of AD biomarker profiles was assessed using logistic regressions with odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The clinical diagnosis of probable AD dementia demonstrated good agreement with biologically defined AD (positive predictive value 85.2%). A total of 7.88% of CU were positive for both amyloid-PET and tau-PET. Frequency of biologically defined AD increased with age (OR 1.14; p < 0.0001) and frequency of APOE ε4 allele carriers (single ε4: OR 3.82; p < 0.0001; double ε4: OR 17.55, p < 0.0001). CONCLUSION: Whereas we observed strong, but not complete, agreement between clinically defined probable AD dementia and biomarker positivity for both ß-amyloid and tau, we also observed that biologically defined AD was not rare in CU elderly. Abnormal tau-PET was almost exclusively observed in individuals with abnormal amyloid-PET. Our results highlight that even in tertiary care memory clinics, detailed evaluation by dementia specialists systematically underestimates the frequency of biologically defined AD and related entities. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that biologically defined AD (abnormal amyloid PET and tau PET) was observed in 85.2% of people with clinically defined AD and 7.88% of CU elderly.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Apolipoproteína E4/genética , Encéfalo/diagnóstico por imagen , Cognición/fisiología , Disfunción Cognitiva/diagnóstico , Factores de Edad , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Factores Sexuales , Proteínas tau/metabolismo
6.
J Alzheimers Dis ; 79(3): 1015-1021, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33386809

RESUMEN

We explored the impact of the Spanish COVID-19 strict home confinement on mental health and cognition in non-infected subjects (N = 16, 60-80 years) diagnosed with subjective cognitive decline and APOEɛ3/ɛ4 carriers. Mental health was monitored for 2 months on a daily, weekly, or monthly basis, and compared to pre-confinement values. Emotional distress, anxiety, and depression scores increased to pathological threshold values during and after confinement. Those with lower mood during confinement experienced a decline in their mood after confinement. Cognition did not change. These preliminary results suggest that mental health consequences of corona measures in preclinical stages of Alzheimer's disease should be further evaluated.


Asunto(s)
Enfermedad de Alzheimer/psicología , Trastornos del Conocimiento/psicología , Salud Mental , Cuarentena/psicología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/genética , Trastornos de Ansiedad/psicología , Apolipoproteína E3/genética , Apolipoproteína E4/genética , /terapia , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/genética , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/genética , Trastorno Depresivo/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Distrés Psicológico , Riesgo , España
7.
Med Hypotheses ; 147: 110479, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33422806

RESUMEN

The association of the coronavirus disease 2019 (COVID-19) with significant neurological and neuropsychiatric complications has been increasingly reported, both during the acute illness and in its aftermath. However, due to the short duration of patient follow up until now, it is not clear whether this infection will be associated with longer-term neurological and/or neuropsychiatric sequelae. In particular, the question of whether COVID-19 will be associated with an increased risk and rate of future dementia remains open and subject to speculation. During the course of the COVID-19 pandemic, an increasing number of patients have reported sudden anosmia or other olfactory dysfunction as concurrent symptoms. The possibility that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may reach the brain via the olfactory nerve or an upper nasal trancribrial route is an interesting working hypothesis. Among the identified genetic risk factors for Late-onset Alzheimer's disease (LOAD), Apo E4 is one of the strongest and most frequent. People carrying one or two copies of the e4 allele of Apo E4 have significant odor recognition deficits in comparison to those not carrying this haplotype. The hypothesis invoked in this paper is that anosmia/olfactory dysfunctions induced by SARS-CoV-2 may cause an increased a risk of future neurodegenerative dementia in ApoE4 carriers, and that this risk would be higher than in Apo E4 carriers affected by anosmia not induced by SARS-CoV-2. This would be associated with virus-induced chronic modifications in the central nervous system. It is proposed that COVID-19 patients with anosmia and no other serious symptoms should be followed up as part of specifically designed and approved studies in order to identify the early stages of dementia (especially LOAD and Dementia with Lewy Bodies), thereby improving our knowledge of the mechanisms involved in pre-cognitive stages of neurodegenerative dementia and making best use of any available therapies. This latter opportunity is unique and should not be lost.


Asunto(s)
Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Demencia/genética , Trastornos del Olfato/complicaciones , Enfermedad de Alzheimer/complicaciones , Demencia/complicaciones , Humanos , Inflamación , Modelos Teóricos , Prevalencia , Riesgo , Olfato
8.
Otol Neurotol ; 42(1): e15-e21, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33301284

RESUMEN

OBJECTIVE: Hearing loss (HL) and apolipoprotein E ε4 (ApoE4) allele are both dementia risk factors. No research has investigated the association of these variables regarding dementia, specifically Alzheimer's disease. Our goal was to evaluate HL and ApoE4 allele positivity toward degree of Alzheimer's neurodegeneration. STUDY DESIGN: Retrospective. SETTING: Academic. PATIENTS: Alzheimer's neuropathology obtained from brain tissue databank. Documented demographics, subjective hearing status, cognition, and ApoE4. Subjects divided into four groups based on hearing status and ApoE4 positivity. MAIN OUTCOME MEASURES: Differences in cognition (clinical dementia rating, mini mental state examination (MMSE), geriatric depression score) and Alzheimer's neuropathology staging (Braak, CERAD) between groups. RESULTS: Two-hundred and fifty-nine subjects. No significant difference between groups, with regard to hearing status or ApoE4 positivity, in premorbid cognition, including scores for clinical dementia rating and MMSE (p = 0.2332). HL subjects had less severe neuropathology, as compared with normal hearing subjects. For example, high grade Braak stage was present in 27.1 and 51.0% of HL and normal hearing subjects, respectively (p = 0.0263). This finding was in context of equivocal clinical cognition between groups. ApoE4+ individuals had more severe neurodegeneration; for example, 65.7 and 33.5% with high grade Braak stage for ApoE4+ and ApoE4- subjects, respectively (p < 0.0001). CONCLUSION: Subjective HL subjects had less severe neuropathology with no difference in cognition, suggesting an additive effect of HL to cognitive burden of Alzheimer's neuropathology. HL appeared to increase cognitive burden, but wasn't manifested by greater neurodegeneration. This is clinically relevant in that treating HL could slow Alzheimer's disease progression.


Asunto(s)
Enfermedad de Alzheimer , Pérdida Auditiva , Anciano , Alelos , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Pérdida Auditiva/epidemiología , Pérdida Auditiva/genética , Humanos , Estudios Retrospectivos
9.
Int J Geriatr Psychiatry ; 36(1): 152-162, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32819031

RESUMEN

OBJECTIVES: Previous studies have observed protective effects of high mental demands at work on cognitive functioning and dementia risk. However, it is unclear what types of demands drive this effect and whether this effect is subject to a person's genetic risk. We investigated to what extent eight different types of mental demands at work together with the APOE e4 allele, a major risk gene for late-onset Alzheimer's disease, affect cognitive functioning in late life. METHODS/DESIGN: The population-based German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe, n = 2 154) followed cognitively healthy individuals aged 75 years and older in seven assessment waves. Cognitive functioning was assessed via the mini-mental status examination. RESULTS: Mixed-effects modeling (adjusted for education, gender, marital status, stroke, depression, and diabetes) indicated that participants who had an occupational history of working in jobs with high compared to low demands in "Language & Knowledge", "Pattern detection", "Information processing", and "Service" had a slower cognitive decline. APOE e4-allele carriers had an accelerated cognitive decline, but this decline was significantly smaller if they had a medium compared to a low level of demands in contrast to non-carriers. CONCLUSIONS: Our longitudinal observations suggest that cognitive decline could be slowed by an intellectually enriched lifestyle even in risk gene carriers. Fostering intellectual engagement throughout the life-course could be a key prevention initiative to promote better cognitive health in old age.


Asunto(s)
Disfunción Cognitiva , Demencia , Anciano , Envejecimiento , Alelos , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Cognición , Disfunción Cognitiva/genética , Demencia/genética , Humanos , Lenguaje , Atención Primaria de Salud
10.
Neuron ; 109(3): 438-447.e6, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33321072

RESUMEN

The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer's disease (AD) and multiple vascular conditions. ApoE is abundantly expressed in multiple brain cell types, including astrocytes, microglia, and vascular mural cells (VMCs). Here, we show that VMC-specific expression of apoE4 in mice impairs behavior and cerebrovascular function. Expression of either apoE3 or apoE4 in VMCs was sufficient to rescue the hypercholesterolemia and atherosclerosis phenotypes seen in Apoe knockout mice. Intriguingly, vascular expression of apoE4, but not apoE3, reduced arteriole blood flow, impaired spatial learning, and increased anxiety-like phenotypes. Single-cell RNA sequencing of vascular and glial cells revealed that apoE4 in VMCs was associated with astrocyte activation, while apoE3 was linked to angiogenic signature in pericytes. Together, our data support cell-autonomous effects of vascular apoE on brain homeostasis in an isoform-dependent manner, suggesting a critical contribution of vascular apoE to AD pathogenesis.


Asunto(s)
Apolipoproteína E4/genética , Arteriolas/metabolismo , Astrocitos/metabolismo , Encéfalo/metabolismo , Gliosis/genética , Animales , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/metabolismo , Arteriolas/patología , Astrocitos/patología , Encéfalo/patología , Gliosis/metabolismo , Gliosis/patología , Ratones , Ratones Transgénicos
12.
BMC Bioinformatics ; 21(Suppl 21): 535, 2020 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-33371873

RESUMEN

BACKGROUND: Although genetic risk factors and network-level neuroimaging abnormalities have shown effects on cognitive performance and brain atrophy in Alzheimer's disease (AD), little is understood about how apolipoprotein E (APOE) ε4 allele, the best-known genetic risk for AD, affect brain connectivity before the onset of symptomatic AD. This study aims to investigate APOE ε4 effects on brain connectivity from the perspective of multimodal connectome. RESULTS: Here, we propose a novel multimodal brain network modeling framework and a network quantification method based on persistent homology for identifying APOE ε4-related network differences. Specifically, we employ sparse representation to integrate multimodal brain network information derived from both the resting state functional magnetic resonance imaging (rs-fMRI) data and the diffusion-weighted magnetic resonance imaging (dw-MRI) data. Moreover, persistent homology is proposed to avoid the ad hoc selection of a specific regularization parameter and to capture valuable brain connectivity patterns from the topological perspective. The experimental results demonstrate that our method outperforms the competing methods, and reasonably yields connectomic patterns specific to APOE ε4 carriers and non-carriers. CONCLUSIONS: We have proposed a multimodal framework that integrates structural and functional connectivity information for constructing a fused brain network with greater discriminative power. Using persistent homology to extract topological features from the fused brain network, our method can effectively identify APOE ε4-related brain connectomic biomarkers.


Asunto(s)
Alelos , Apolipoproteína E4/genética , Encéfalo/diagnóstico por imagen , Conectoma , Adulto , Anciano , Encéfalo/fisiopatología , Imagen de Difusión por Resonancia Magnética , Femenino , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino
13.
JAMA Netw Open ; 3(12): e2028634, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33331917

RESUMEN

Importance: Plasma measurement of amyloid-ß (Aß) peptides has been associated with cognitive function, but evidence of its ability to identify cognitive decline is still scarce. Objective: To investigate the associations between plasma Aß42/40 and cognitive decline over time among community-dwelling older adults with subjective memory concerns. Design, Setting, and Participants: This multicenter cohort study used data from volunteers in the 5-year study Multidomain Alzheimer Preventive Trial (MAPT). Participants were aged 70 years or older and observed for a median (interquartile range) of 3.9 (2.0-4.0) years. Recruitment of participants started in May 2008 and ended in February 2011. Follow-up ended in April 2016. Data analysis was conducted from April to October 2020. Exposure: Plasma Aß42 and Aß40 were measured at 12 months for 448 participants (92.8%) and at 24 months for the rest. The moment of Aß assessment was defined as the baseline for this study. Main Outcomes and Measures: Cognitive function was assessed at 12, 24, 36, 48, and 60 months by a composite cognitive score based on 4 tests; Mini Mental State Examination (MMSE); Clinical Dementia Rating, sum of boxes; and Alzheimer Disease Cooperative Study-Activities of Daily Living. Mixed-effect linear regressions were performed. Results: A total of 483 participants (median [IQR] age, 76.0 [73.0-80.0]; 286 [59.2%] women) were analyzed. Of them, 161 (33.3%) were classified as low plasma Aß42/40 (≤0.107). After adjusting for age, sex, education, body mass index, Geriatric Depression Scale score, apolipoprotein E ε4 genotype, and MAPT intervention groups, low plasma Aß42/40 was associated with more pronounced decline in composite cognitive score (adjusted between-group mean difference: -0.20, 95% CI, -0.34 to -0.07; P = .004) and decline in MMSE score (adjusted between-group mean difference: -0.59; 95% CI, -1.07 to -0.11; P = .02) during the follow-up period compared with the group with an Aß42/40 ratio greater than 0.107. Conclusions and Relevance: In this study, low plasma Aß42/40 was associated with more pronounced decline in cognitive function (measured by multiple outcomes) over time. Findings suggest that plasma Aß42/40 may be used to identify people at risk of cognitive decline, being an alternative to more complex and expensive measures, such as positron emission tomography imaging or cerebrospinal fluid measurement.


Asunto(s)
Péptidos beta-Amiloides/sangre , Disfunción Cognitiva , Vida Independiente , Fragmentos de Péptidos/sangre , Anciano , Apolipoproteína E4/genética , Cognición/fisiología , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Correlación de Datos , Autoevaluación Diagnóstica , Femenino , Evaluación Geriátrica/métodos , Humanos , Masculino , Trastornos de la Memoria/sangre , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/psicología
14.
Nat Commun ; 11(1): 5540, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33139712

RESUMEN

APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer's disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aß and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Organoides/metabolismo , Sinapsis/metabolismo , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Regulación de la Expresión Génica , Genotipo , Humanos , Organoides/patología , ARN/metabolismo , Transcriptoma
15.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 5523-5526, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-33019230

RESUMEN

Early detection of Alzheimer's disease (AD) is of vital importance in the development of disease-modifying therapies. This necessitates the use of early pathological indicators of the disease such as amyloid abnormality to identify individuals at early disease stages where intervention is likely to be most effective. Recent evidence suggests that cerebrospinal fluid (CSF) amyloid ß1-42 (Aß42) level may indicate AD risk earlier compared to amyloid positron emission tomography (PET). However, the method of collecting CSF is invasive. Blood-based biomarkers indicative of CSF Aß42 status may remedy this limitation as blood collection is minimally invasive and inexpensive. In this study, we show that APOE4 genotype and blood markers comprising EOT3, APOC1, CGA, and Aß42 robustly predict CSF Aß42 with high classification performance (0.84 AUC, 0.82 sensitivity, 0.62 specificity, 0.81 PPV and 0.64 NPV) using machine learning approach. Due to the method employed in the biomarker search, the identified biomarker signature maintained high performance in more than a single machine learning algorithm, indicating potential to generalize well. A minimally invasive and cost-effective solution to detecting amyloid abnormality such as proposed in this study may be used as a first step in a multi-stage diagnostic workup to facilitate enrichment of clinical trials and population-based screening.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Enfermedad de Alzheimer/diagnóstico , Amiloide , Apolipoproteína E4 , Humanos , Tomografía Computarizada por Rayos X
16.
Nat Commun ; 11(1): 4727, 2020 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-32948752

RESUMEN

The apolipoprotein E (APOE) gene contains both the major common risk variant for late onset Alzheimer's disease (AD), e4, and the major neuroprotective variant, e2. Here we examine the association of APOE e2 with multiple neurodegenerative pathologies, leveraging the NACC v. 10 database of 1557 brains that included 130 e2 carriers and 679 e4 carriers in order to examine potential neuroprotective effects. For AD-related pathologies of amyloid plaques and Braak stage, e2 had large and highly significant protective effects contrasted with e3/e3 and e4 carriers with odds ratios of about 0.50 for e3 contrasts and 0.10 for e4 contrasts. When we separately examined e2/e4 carriers, risk for AD pathologies was similar to that of e4 carriers, not e2 carriers. For multiple fronto-temporal lobar pathologies and tauopathies, e2 was not significantly associated with pathology. In sum, we found that e2 was associated with large but circumscribed protective effects.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Apolipoproteína E2/genética , Apolipoproteína E2/metabolismo , Genotipo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Encéfalo/metabolismo , Femenino , Degeneración Lobar Frontotemporal/metabolismo , Humanos , Modelos Logísticos , Masculino , Placa Amiloide/patología , Tauopatías/metabolismo , alfa-Sinucleína/metabolismo
17.
PLoS Med ; 17(8): e1003289, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32817639

RESUMEN

BACKGROUND: The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of ß-amyloid peptide (A, ß-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. METHODS AND FINDINGS: This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. CONCLUSIONS: In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.


Asunto(s)
Envejecimiento/líquido cefalorraquídeo , Envejecimiento/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Apolipoproteína E4/líquido cefalorraquídeo , Apolipoproteína E4/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad
18.
Neurology ; 95(17): e2378-e2388, 2020 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-32788242

RESUMEN

OBJECTIVE: To evaluate sex differences in CSF biomarkers, taking the potential modifying role of clinical disease stage and APOE ε4 genotype into account. METHOD: We included participants (n = 1,801) with probable Alzheimer disease (AD) dementia (n = 937), mild cognitive impairment (MCI; n = 437), and subjective cognitive decline (SCD; n = 427). Main outcomes were CSF ß-amyloid1-42 (Aß42), total tau (t-Tau), and tau phosphorylated at threonine 181 (p-Tau) levels. Age-corrected 3-way interactions between sex, disease stage (i.e., syndrome diagnosis at baseline), and APOE ε4 were tested with linear regression analyses for each outcome measure. In case of significant interactions (p < 0.05), sex differences were further evaluated by stratifying analyses for clinical disease stage and APOE ε4 genotype, including age as a covariate. RESULTS: Three-way interactions were significant for t-Tau (p < 0.001) and p-Tau (p < 0.01) but not Aß42. In APOE ε4 carriers, women showed higher p-Tau concentrations than men in SCD (Cohen d [95% confidence interval]: t-Tau = 0.52 [0.19-0.84], p < 0.001; p-Tau = 0.44 [0.11-0.77] p = 0.004) and MCI (Cohen d [95% CI]: t-Tau = 0.54 [0.28-0.80], p < 0.001; p-Tau = 0.52 [0.26-0.77], p < 0.001) but not in AD dementia. In APOE ε4 noncarriers, women showed higher p-Tau concentrations in MCI (Cohen d [95% CI]: t-Tau = 0.49 [0.17-0.80], p = 0.002; p-Tau = 0.47 [0.16-0.78], p = 0.003) and AD dementia (Cohen d [95% CI]: t-Tau = 0.42 [0.19-0.65], p < 0.001; p-Tau = 0.38 [0.15-0.61] p = 0.002) but not in SCD. CONCLUSIONS: Within APOE ε4 carriers, sex differences in CSF p-Tau are more evident in early disease stages, whereas for APOE ε4 noncarriers, sex differences are more evident in advanced disease stages. These findings suggest that the effect of APOE ε4 on sex differences in CSF biomarkers depends on disease stage in AD.


Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Progresión de la Enfermedad , Femenino , Genotipo , Heterocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fosforilación , Caracteres Sexuales , Proteínas tau/líquido cefalorraquídeo
19.
Neurology ; 95(11): e1554-e1564, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32759192

RESUMEN

OBJECTIVE: To determine whether years of education and the ε4 risk allele at APOE influence ß-amyloid (Aß) pathology similarly in asymptomatic individuals with a family history of sporadic Alzheimer disease (AD) and presymptomatic autosomal dominant AD mutation carriers. METHODS: We analyzed cross-sectional data from 106 asymptomatic individuals with a parental history of sporadic AD (PREVENT-AD cohort; age 67.28 ± 4.72 years) and 117 presymptomatic autosomal dominant AD mutation carriers (DIAN cohort; age 35.04 ± 9.43 years). All participants underwent structural MRI and Aß-PET imaging. In each cohort we investigated the influence of years of education, APOE ε4 status, and their interaction on Aß-PET. RESULTS: Asymptomatic individuals with a parental history of sporadic AD showed increased Aß burden associated with APOE ε4 carriage and lower level of education, but no interaction between these. Presymptomatic mutation carriers of autosomal dominant AD showed no relation between APOE ε4 and Aß burden, but increasing level of education was associated with reduced Aß burden. The association between educational attainment and Aß burden was similar in the 2 cohorts. CONCLUSIONS: While the APOE ε4 allele confers increased tendency toward Aß accumulation in sporadic AD only, protective environmental factors, like increased education, may promote brain resistance against Aß pathology in both sporadic and autosomal dominant AD.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Apolipoproteína E4/genética , Escolaridad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Adulto Joven
20.
Nature ; 584(7820): 291-297, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32728216

RESUMEN

The majority of therapies that target individual proteins rely on specific activity-modulating interactions with the target protein-for example, enzyme inhibition or ligand blocking. However, several major classes of therapeutically relevant proteins have unknown or inaccessible activity profiles and so cannot be targeted by such strategies. Protein-degradation platforms such as proteolysis-targeting chimaeras (PROTACs)1,2 and others (for example, dTAGs3, Trim-Away4, chaperone-mediated autophagy targeting5 and SNIPERs6) have been developed for proteins that are typically difficult to target; however, these methods involve the manipulation of intracellular protein degradation machinery and are therefore fundamentally limited to proteins that contain cytosolic domains to which ligands can bind and recruit the requisite cellular components. Extracellular and membrane-associated proteins-the products of 40% of all protein-encoding genes7-are key agents in cancer, ageing-related diseases and autoimmune disorders8, and so a general strategy to selectively degrade these proteins has the potential to improve human health. Here we establish the targeted degradation of extracellular and membrane-associated proteins using conjugates that bind both a cell-surface lysosome-shuttling receptor and the extracellular domain of a target protein. These initial lysosome-targeting chimaeras, which we term LYTACs, consist of a small molecule or antibody fused to chemically synthesized glycopeptide ligands that are agonists of the cation-independent mannose-6-phosphate receptor (CI-M6PR). We use LYTACs to develop a CRISPR interference screen that reveals the biochemical pathway for CI-M6PR-mediated cargo internalization in cell lines, and uncover the exocyst complex as a previously unidentified-but essential-component of this pathway. We demonstrate the scope of this platform through the degradation of therapeutically relevant proteins, including apolipoprotein E4, epidermal growth factor receptor, CD71 and programmed death-ligand 1. Our results establish a modular strategy for directing secreted and membrane proteins for lysosomal degradation, with broad implications for biochemical research and for therapeutics.


Asunto(s)
Espacio Extracelular/metabolismo , Lisosomas/metabolismo , Proteínas de la Membrana/metabolismo , Proteolisis , Proteínas Recombinantes de Fusión/metabolismo , Animales , Anticuerpos/química , Anticuerpos/metabolismo , Antígenos CD/metabolismo , Apolipoproteína E4/metabolismo , Antígeno B7-H1/metabolismo , Sistemas CRISPR-Cas , Línea Celular , Receptores ErbB/metabolismo , Femenino , Glicopéptidos/síntesis química , Glicopéptidos/metabolismo , Humanos , Ligandos , Proteínas de la Membrana/química , Ratones , Dominios Proteicos , Transporte de Proteínas , Receptor IGF Tipo 2/metabolismo , Receptores de Transferrina/metabolismo , Proteínas Recombinantes de Fusión/síntesis química , Proteínas Recombinantes de Fusión/química , Solubilidad , Especificidad por Sustrato
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