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The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral Aß amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis-Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10-3), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10-5) and plasma tau concentration (0.06 log2(ng l-1) 95%CI 0.03; 0.08, p = 4.55 × 10-6). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.
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Estudio de Asociación del Genoma Completo , Enfermedades Neurodegenerativas , Componente Amiloide P Sérico , Humanos , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Componente Amiloide P Sérico/metabolismo , Componente Amiloide P Sérico/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/etiología , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Análisis de la Aleatorización Mendeliana , Biomarcadores , Proteínas tau/metabolismo , Proteínas tau/genética , Enfermedad por Cuerpos de Lewy/genética , Enfermedad por Cuerpos de Lewy/metabolismo , Masculino , FemeninoRESUMEN
BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.
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BACKGROUND: Binary reversals (exemplified by 'yes'/'no' confusions) have been described in patients with primary progressive aphasia (PPA) but their diagnostic value and phenotypic correlates have not been defined. METHODS: We conducted a retrospective cohort study analysing demographic, clinical, neuropsychological, linguistic and behavioural data from patients representing all major PPA syndromes (non-fluent/agrammatic variant, nfvPPA; logopenic variant, lvPPA; semantic variant, svPPA) and behavioural variant frontotemporal dementia (bvFTD). The prevalence of binary reversals and behavioural abnormalities, illness duration, parkinsonian features and neuropsychological test scores were compared between neurodegenerative syndromes, and the diagnostic predictive value of binary reversals was assessed using logistic regression. RESULTS: Data were obtained for 83 patients (21 nfvPPA, 13 lvPPA, 22 svPPA, 27 bvFTD). Binary reversals occurred in all patients with nfvPPA, but significantly less frequently and later in lvPPA (54%), svPPA (9%) and bvFTD (44%). Patients with bvFTD with binary reversals had significantly more severe language (but not general executive or behavioural) deficits than those without reversals. Controlling for potentially confounding variables, binary reversals strongly predicted a diagnosis of nfvPPA over other syndromes. CONCLUSIONS: Binary reversals are a sensitive (though not specific) neurolinguistic feature of nfvPPA, and should suggest this diagnosis if present as a prominent early symptom.
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Afasia Progresiva Primaria , Afasia , Demencia Frontotemporal , Humanos , Estudios Retrospectivos , Demencia Frontotemporal/psicología , Lenguaje , Afasia Progresiva Primaria/diagnósticoRESUMEN
BACKGROUND: Growing evidence indicates associations between neighbourhood-related factors such as pollution, social isolation and physical inactivity, and cognition, that is, our ability to think clearly, learn and remember. The evidence raises the possibility of neighbourhood intervention playing a role in protecting population cognitive health. However, there is little understanding of these associations among the public and policy-makers, what they mean and how they might be acted on. In this study we explored perceptions of the public and policy-makers about influences of neighbourhood factors on brain functioning, and how they should inform policy. METHODS: Qualitative methods were used in three phases; the study ran in parallel with a quantitative study looking at neighbourhood influences on cognition. In phase one, focus groups were conducted with middle-aged (40-69) members of the public to inform statistical modelling. In phase two, similar focus groups were held in four case study areas chosen based on the modelling results. In phase three, interviews with people in public health and policy roles were conducted, including people in the case study sites. RESULTS: Participants described effects on their cognition from community, culture and social interactions, access to green spaces and nature, upkeep and safety of the area, and pollution, traffic and noise. Solutions included better local consultation and involvement in policy and planning, support for community interactions and active and public transport, and education on cognition. There was little awareness, but much interest, from local policy-makers and implementers, about links between cognition and place. Barriers to implementation included lack of: effective engagement with local communities, local funding and joined-up health and neighbourhood policy. CONCLUSIONS: People can perceive impacts of neighbourhoods on brain functioning and suggest ways local areas can be improved to support cognitive health. There is support for the idea of population-level interventions to support cognitive health.
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Terapia de Aceptación y Compromiso , Cognición , Persona de Mediana Edad , Humanos , Personal Administrativo , Escolaridad , PolíticasRESUMEN
The direct causes of neurodegeneration underlying Alzheimer's disease (AD) and many other dementias, are not known. Here we identify serum amyloid P component (SAP), a constitutive plasma protein normally excluded from the brain, as a potential drug target. After meta-analysis of three genome-wide association studies, comprising 44,288 participants, cis-Mendelian randomization showed that genes responsible for higher plasma SAP values are significantly associated with AD, Lewy body dementia and plasma tau concentration. These genetic findings are consistent with experimental evidence of SAP neurotoxicity and the strong, independent association of neocortex SAP content with dementia at death. Depletion of SAP from the blood and from the brain, as is provided by the safe, well tolerated, experimental drug, miridesap, may therefore contribute to treatment of neurodegeneration.
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INTRODUCTION: We report dementia incidence, comorbidities, reasons for health-care visits, mortality, causes of death, and examined dementia patterns by relative deprivation in the UK. METHOD: A longitudinal cohort analysis of linked electronic health records from 4.3 million people in the UK was conducted to investigate dementia incidence and mortality. Reasons for hospitalization and causes of death were compared in individuals with and without dementia. RESULTS: From 1998 to 2016 we observed 145,319 (3.1%) individuals with incident dementia. Repeated hospitalizations among senior adults for infection, unknown morbidity, and multiple primary care visits for chronic pain were observed prior to dementia diagnosis. Multiple long-term conditions are present in half of the individuals at the time of diagnosis. Individuals living in high deprivation areas had higher dementia incidence and high fatality. DISCUSSION: There is a considerable disparity of dementia that informs priorities of prevention and provision of patient care.
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Demencia , Registros Electrónicos de Salud , Adulto , Humanos , Incidencia , Morbilidad , Estudios de Cohortes , Demencia/epidemiologíaRESUMEN
The characteristics and determinants of health and disease are often organized in space, reflecting our spatially extended nature. Understanding the influence of such factors requires models capable of capturing spatial relations. Drawing on statistical parametric mapping, a framework for topological inference well established in the realm of neuroimaging, we propose and validate an approach to the spatial analysis of diverse clinical data-GeoSPM-based on differential geometry and random field theory. We evaluate GeoSPM across an extensive array of synthetic simulations encompassing diverse spatial relationships, sampling, and corruption by noise, and demonstrate its application on large-scale data from UK Biobank. GeoSPM is readily interpretable, can be implemented with ease by non-specialists, enables flexible modeling of complex spatial relations, exhibits robustness to noise and under-sampling, offers principled criteria of statistical significance, and is through computational efficiency readily scalable to large datasets. We provide a complete, open-source software implementation.
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Introduction: Multidomain interventions to address modifiable risk factors for dementia are promising, but require more cost-effective, scalable delivery. This study investigated the feasibility of the "Active Brains" digital behavior change intervention and its trial procedures. Materials and methods: Active Brains aims to reduce cognitive decline by promoting physical activity, healthy eating, and online cognitive training. We conducted 12-month parallel-design randomized controlled feasibility trials of "Active Brains" amongst "lower cognitive scoring" (n = 180) and "higher cognitive scoring" (n = 180) adults aged 60-85. Results: We collected 67.2 and 76.1% of our 12-month primary outcome (Baddeley verbal reasoning task) data for the "lower cognitive score" and "higher cognitive score" groups, respectively. Usage of "Active Brains" indicated overall feasibility and satisfactory engagement with the physical activity intervention content (which did not require sustained online engagement), but engagement with online cognitive training was limited. Uptake of the additional brief telephone support appeared to be higher in the "lower cognitive score" trial. Preliminary descriptive trends in the primary outcome data might indicate a protective effect of Active Brains against cognitive decline, but further investigation in fully-powered trials is required to answer this definitively. Discussion: Whilst initial uptake and engagement with the online intervention was modest, it was in line with typical usage of other digital behavior change interventions, and early indications from the descriptive analysis of the primary outcome and behavioral data suggest that further exploration of the potential protective benefits of Active Brains are warranted. The study also identified minor modifications to procedures, particularly to improve online primary-outcome completion. Further investigation of Active Brains will now seek to determine its efficacy in protecting cognitive performance amongst adults aged 60-85 with varied levels of existing cognitive performance.
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Disfunción Cognitiva , Encéfalo , Cognición , Disfunción Cognitiva/prevención & control , Disfunción Cognitiva/psicología , Ejercicio Físico , Estudios de Factibilidad , HumanosRESUMEN
OBJECTIVE: To investigate whether herpes simplex virus type 1 (HSV-1) infection was associated with rates of cognitive decline or whole brain atrophy among individuals from the Dominantly Inherited Alzheimer Network (DIAN). METHODS: Among two subsets of the DIAN cohort (age range 19.6-66.6 years; median follow-up 3.0 years) we examined (i) rate of cognitive decline (N = 164) using change in mini-mental state examination (MMSE) score, (ii) rate of whole brain atrophy (N = 149), derived from serial MR imaging, calculated using the boundary shift integral (BSI) method. HSV-1 antibodies were assayed in baseline sera collected from 2009-2015. Linear mixed-effects models were used to compare outcomes by HSV-1 seropositivity and high HSV-1 IgG titres/IgM status. RESULTS: There was no association between baseline HSV-1 seropositivity and rates of cognitive decline or whole brain atrophy. Having high HSV-1 IgG titres/IgM was associated with a slightly greater decline in MMSE points per year (difference in slope - 0.365, 95% CI: -0.958 to -0.072), but not with rate of whole brain atrophy. Symptomatic mutation carriers declined fastest on both MMSE and BSI measures, however, this was not influenced by HSV-1. Among asymptomatic mutation carriers, rates of decline on MMSE and BSI were slightly greater among those who were HSV-1 seronegative. Among mutation-negative individuals, no differences were seen by HSV-1. Stratifying by APOE4 status yielded inconsistent results. INTERPRETATION: We found no evidence for a major role of HSV-1, measured by serum antibodies, in cognitive decline or whole brain atrophy among individuals at high risk of early-onset AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Simplexvirus , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Atrofia/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Inmunoglobulina G , Inmunoglobulina MRESUMEN
INTRODUCTION/AIMS: Sporadic inclusion body myositis (IBM) is a degenerative and inflammatory acquired myopathy characterized by muscle deposition of various proteins typically associated with Alzheimer disease and other neurodegenerative diseases. Although cognitive impairment is not noted as a clinical feature of IBM, evidence is lacking. In this study we investigated whether cognitive performance of patients with IBM differs from population norms, focusing on cognitive domains affected in early Alzheimer disease (memory, executive function), and to test whether disease duration and the level of disability of IBM are associated with cognitive function. METHODS: Twenty-four patients with IBM (mean [standard deviation]: age, 62.0 [7.2] years; disease duration, 9.6 [4.8] years) were assessed cross-sectionally on neuropsychological tests covering multiple cognitive domains, including the Preclinical Alzheimer Cognitive Composite (PACC). Performance was compared with published normative data adjusted for age, sex, and education (National Alzheimer's Coordinating Center; N = 3268). Associations were examined between PACC score, disease duration, and level of disability (assessed using the IBM Functional Rating Scale [IBMFRS]). RESULTS: Across all cognitive tests, group performance was within ±1 standard deviation of the normative mean. There was no evidence of associations between PACC score and either disease duration (ρ = -0.04, P = .87) or IBMFRS total score (ρ = 0.14, P = .52). DISCUSSION: Memory and executive function in patients with IBM did not differ from normative data, and we observed no evidence of associations between the cognitive composite and disease duration or level of disability. This addresses a question frequently asked by patients and will be of value for clinicians and patients alike.
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Enfermedad de Alzheimer , Miositis por Cuerpos de Inclusión , Estudios Transversales , Función Ejecutiva/fisiología , Humanos , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
INTRODUCTION: Barriers to recruitment for dementia studies are well documented. As part of the UK government's Dementia 2020 strategy, a nationally consistent system to increase public engagement and participation in research was launched in February 2015. METHODS: We describe the development of the "Join Dementia Research" registry, including evolution of policy, involvement of people with dementia in co-production, data requirements, governance, technology, and the impact on study recruitment and what factors may have contributed to the services success. RESULTS: The UK-wide online, telephone, and postal service has registered 47,071 volunteers, with 33,139 people (67.9% of all volunteers) taking part in 378 studies, with 49,954 total study enrolments. This has taken place across 295 research sites, involved 1522 researchers, and resulted in 134 peer-reviewed publications. DISCUSSION: Public registries of individuals interested in research, with user-provided data enabling basic phenotyping, are effective at increasing public engagement with research and removing barriers to study recruitment. Deeper pheno/genotyping could be undertaken to improve matching, but how and when that information is collected will be a key factor.
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Recruiting participants for dementia research takes time. For those who are interested, opportunities to participate can be ad hoc. Delays in finding the right participants can result in studies taking longer to deliver, often requiring funding extensions, and ultimately increasing the cost and limiting the effectiveness of research and evaluation. To address these issues, a digital platform, StepUp for Dementia Research, was developed in 2019 and evaluated through ongoing data analytics, researcher feedback and annual volunteer surveys in 2019 and 2021. Using innovative matching technology, StepUp provides volunteers with an opt-in, secure way of registering interest in dementia studies and allows researchers to access matched volunteers in Australia. As of June 2021, 1070 volunteers registered (78% female), and 25 organizations became 'champions' for StepUp promotion. Of 122 registered researchers, 90 completed training. Forty studies from 17 research/health institutions recruited participants using StepUp. The evaluation demonstrated program feasibility and recruitment efficiency with a high level of satisfaction from users. Evaluation outcomes highlighted disparities in public participation in dementia research (e.g., gender, education and race/ethnicity) and provided valuable insights for further enhancements of StepUp. A concerted and strategic effort is needed by leading registries such as StepUp to ensure narrowing volunteer participation gaps in dementia research.
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Participación de la Comunidad , Demencia , Australia , Demencia/epidemiología , Femenino , Humanos , Masculino , Sistema de Registros , Encuestas y CuestionariosRESUMEN
The early and accurate diagnosis of dementia is more important than ever before but remains challenging. Dementia is increasingly the business of neurologists and, with ageing populations worldwide, will become even more so in future. Here we outline a practical, symptom-led, bedside approach to suspecting dementia and its likely diagnosis, inspired by clinical experience and based on recognition of characteristic syndromic patterns. We show how clinical intuition reflects underlying signature profiles of brain involvement by the diseases that cause dementia and suggest next steps that can be taken to define the diagnosis. We propose 'canaries' that provide an early warning signal of emerging dementia and highlight the 'chameleons' that disguise or mimic this, as well as the 'zebras' that herald a rare (and sometimes curable) diagnostic opportunity.
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OBJECTIVES: In response to a commissioned research update on dementia during the COVID-19 pandemic, a UK-based working group, comprising dementia researchers from a range of fields and disciplines, aimed to describe the impact of the pandemic on dementia wellbeing and identify priorities for future research. METHODS: We supplemented a rapid literature search (including unpublished, non-peer reviewed and ongoing studies/reports) on dementia wellbeing in the context of COVID-19 with expert group members' consensus about future research needs. From this we generated potential research questions the group judged to be relevant that were not covered by the existing literature. RESULTS: Themes emerged from 141 studies within the six domains of the NHS England COVID-19 Dementia Wellbeing Pathway: Preventing Well, Diagnosing Well, Treating Well, Supporting Well, Living Well and Dying Well. We describe current research findings and knowledge gaps relating to the impact on people affected by dementia (individuals with a diagnosis, their carers and social contacts, health and social care practitioners and volunteers), services, research activities and organisations. Broad themes included the potential benefits and risks of new models of working including remote healthcare, the need for population-representative longitudinal studies to monitor longer-term impacts, and the importance of reporting dementia-related findings within broader health and care studies. CONCLUSIONS: The COVID-19 pandemic has had a disproportionately negative impact on people affected by dementia. Researchers and funding organisations have responded rapidly to try to understand the impacts. Future research should highlight and resolve outstanding questions to develop evidence-based measures to improve the quality of life of people affected by dementia.
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COVID-19 , Demencia , Consenso , Demencia/epidemiología , Humanos , Pandemias , Calidad de Vida , SARS-CoV-2RESUMEN
Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal ageing, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state functional MRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: (i) 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls; and (ii) 156 amyloid-PET-positive subjects across the spectrum of sporadic Alzheimer's disease and 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal lobe tau-PET (i.e. composite across Braak stage I and III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher functional MRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (P = 0.007). Similarly, for patients with sporadic Alzheimer's disease, higher functional MRI-assessed system segregation was associated with less decrement in global cognition (P = 0.001) and episodic memory (P = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease.
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Enfermedad de Alzheimer/fisiopatología , Reserva Cognitiva/fisiología , Red Nerviosa/fisiopatología , Anciano , Enfermedad de Alzheimer/complicaciones , Encéfalo/fisiopatología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de PositronesRESUMEN
Mutations in the Presenilin 1 (PSEN1) gene are the most common cause of autosomal dominant familial Alzheimer's disease. We report the clinical, imaging and postmortem findings of kindred carrying a novel duplication mutation (Ile168dup) in the PSEN1 gene. We interpret the pathogenicity of this novel variant and discuss the additional neurological features (pyramidal dysfunction, myoclonus and seizures) that accompanied cognitive decline. This report broadens the clinical phenotype of PSEN1 insertion mutations while also highlighting the importance of considering duplication, insertion and deletion mutations in cases of young onset dementia.
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Enfermedad de Alzheimer/genética , Mutagénesis Insercional/genética , Mioclonía/genética , Presenilina-1/genética , Convulsiones/genética , Demencia/genética , Femenino , Humanos , Mutación INDEL/genética , MasculinoRESUMEN
In Alzheimer's disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aß) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aß, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aß-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.