Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome

Bejanin, Alexandre; Iulita, M. Florencia; Vilaplana, Eduard; Carmona-Iragui, María; Benejam, Bessy; Videla, Laura; Barroeta, Isabel; Fernández, Susana; Altuna, Miren; Pegueroles, Jordi Malé i; Montal, Víctor; Valldeneu, Sílvia; Giménez, Sandra; González‐Ortiz, Sofía; Muñoz, Laia; Padilla, Concepción; Aranha, Mateus Rozalem; Estellés, Teresa; Illán-Gala, Ignacio; Camacho, Valle; Wilson, Liam R.; Annus, Tiina; Osorio, Ricardo S.; Videla, Sebastián; Lehmann, Sylvain; Holland, Anthony; Zetterberg, Henrik; Blennow, Kaj; Alcolea, Daniel; Clarimón, Jordi; Zaman, Shahid; Blesa, Rafael; Lleó, Alberto; Fortea, Juan

doi:10.1001/jamaneurol.2021.1893

Cited by 36 publications

(55 citation statements)

References 53 publications

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“…In a longitudinal study on DS, CSF Aβ42/40 was found to change between 28 and 30 years of age, which is more than 20 years earlier than in sporadic AD and 10 years before Aβ PET changes [13]. DS individuals carrying the AD-associated apolipoprotein E (APOE) ε4 allele exhibited these changes earlier than non-carriers [45]. Other Aβ species (Aβx-38, Aβx-40, and Aβx-42) and soluble APP fragments (sAPPα and sAPPβ) showed higher concentrations in CSF from DS individuals than in CSF from healthy age-and sex-matched controls [46].…”

Section: Csf Biomarkersmentioning

confidence: 98%

“…This study concluded that plasma p-tau181 correlates with core fluid biomarkers of AD (CSF Aβ42/40, CSF t-tau, CSF NfL, and plasma NfL), as well as with atrophy in AD-related brain regions, including the temporal regions, angular and supramarginal gyri, and precuneus of both hemispheres (measured by MRI), and lower brain metabolism in temporoparietal regions (measured by FDG-PET) [90]. The latest research analyzing the association of the APOE genotype with AD biomarkers in patients with DS showed that APOE ε4 allele carriers showed earlier increases in plasma p-tau181, starting from the mid-40s and with confidence intervals not overlapping by age 50 years [45].…”

Section: Tau: Plasma Total and Phosphorylated Taumentioning

confidence: 99%

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Blood Biomarkers for Alzheimer’s Disease in Down Syndrome

Montoliu‐Gaya

Strydom

Blennow

et al. 2021

JCM

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Epidemiological evidence suggests that by the age of 40 years, all individuals with Down syndrome (DS) have Alzheimer’s disease (AD) neuropathology. Clinical diagnosis of dementia by cognitive assessment is complex in these patients due to the pre-existing and varying intellectual disability, which may mask subtle declines in cognitive functioning. Cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, although accurate, are expensive, invasive, and particularly challenging in such a vulnerable population. The advances in ultra-sensitive detection methods have highlighted blood biomarkers as a valuable and realistic tool for AD diagnosis. Studies with DS patients have proven the potential blood-based biomarkers for sporadic AD (amyloid-β, tau, phosphorylated tau, and neurofilament light chain) to be useful in this population. In addition, biomarkers related to other pathologies that could aggravate dementia progression—such as inflammatory dysregulation, energetic imbalance, or oxidative stress—have been explored. This review serves to provide a brief overview of the main findings from the limited neuroimaging and CSF studies, outline the current state of blood biomarkers to diagnose AD in patients with DS, discuss possible past limitations of the research, and suggest considerations for developing and validating blood-based biomarkers in the future.

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Section: Csf Biomarkersmentioning

confidence: 98%

Section: Tau: Plasma Total and Phosphorylated Taumentioning

confidence: 99%

Blood Biomarkers for Alzheimer’s Disease in Down Syndrome

Montoliu‐Gaya

Strydom

Blennow

et al. 2021

JCM

Self Cite

View full text Add to dashboard Cite

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“…The increased Aβ is associated with the allele ε4 is seen in the general population [ 177 ], but its role in ADAD [ 142 ] and DS was controversial when comparing the results obtained by the previously cited studies [ 178 , 179 , 180 ]. However, Bejanin et al [ 36 ] demonstrated in a DS cohort of 464 that the ε4 allele does indeed influence the earlier onset of the presence of amyloid biomarkers.…”

Section: Neuroimaging and Neuropathologymentioning

confidence: 99%

“…The evidence for APOE’s effect on the clinical presentation of ADAD [ 22 , 32 ] and DSAD [ 33 , 34 , 35 ] is becoming clearer despite genetic mutations that cause AD masking the effect of APOE. For instance, it has been found that the APOE ε4 allele correlated with earlier clinical and biomarker changes of AD in DS [ 36 ]. It is also noted that the Christchurch mutation, R136S in APOE3 (homozygous) in a PSEN1-E280A mutation carrier, reported relatively little decline in cognition despite ageing and little evidence of tau-deposition despite relatively greater amounts of amyloid being detected using PET imaging [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

The Clinical and Neuropathological Features of Sporadic (Late-Onset) and Genetic Forms of Alzheimer’s Disease

Rujeedawa

Félez

Clare

et al. 2021

JCM

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The purpose of this review is to compare and highlight the clinical and pathological aspects of genetic versus acquired Alzheimer’s disease: Down syndrome-associated Alzheimer’s disease in (DSAD) and Autosomal Dominant Alzheimer’s disease (ADAD) are compared with the late-onset form of the disease (LOAD). DSAD and ADAD present in a younger population and are more likely to manifest with non-amnestic (such as dysexecutive function features) in the prodromal phase or neurological features (such as seizures and paralysis) especially in ADAD. The very large variety of mutations associated with ADAD explains the wider range of phenotypes. In the LOAD, age-associated comorbidities explain many of the phenotypic differences.

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“…Similarly, in people with DS the presence of the APOEε4 allele increases the risk of dementia, although to a lesser extent than in the general population ( Prasher et al, 2008 ; Rohn et al, 2014 ). It also lowers the age of disease onset ( Schupf et al, 1996 ; Deb et al, 2000 ; Coppus et al, 2008 ; Bejanin et al, 2021 ), aggravates Aβ deposition ( Hyman et al, 1995 ; Bejanin et al, 2021 ), and accelerates neurodegeneration ( Bejanin et al, 2021 ). Additionally, DS individuals harboring the APOEε4 allele are at additional increased risk for early mortality ( Prasher et al, 2008 ; Hithersay et al, 2019 ).…”

Section: Alzheimer Pathology In Dsmentioning

confidence: 99%

Nerve Growth Factor Compromise in Down Syndrome

Carmo

Kannel

Cuello

2021

Front. Aging Neurosci.

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The basal forebrain cholinergic system relies on trophic support by nerve growth factor (NGF) to maintain its phenotype and function. In Alzheimer’s disease (AD), basal forebrain cholinergic neurons (BFCNs) undergo progressive atrophy, suggesting a deficit in NGF trophic support. Within the central nervous system, NGF maturation and degradation are tightly regulated by an activity-dependent metabolic cascade. Here, we present a brief overview of the characteristics of Alzheimer’s pathology in Down syndrome (DS) with an emphasis on this NGF metabolic pathway’s disruption during the evolving Alzheimer’s pathology. Such NGF dysmetabolism is well-established in Alzheimer’s brains with advanced pathology and has been observed in mild cognitive impairment (MCI) and non-demented individuals with elevated brain amyloid levels. As individuals with DS inexorably develop AD, we then review findings that support the existence of a similar NGF dysmetabolism in DS coinciding with atrophy of the basal forebrain cholinergic system. Lastly, we discuss the potential of NGF-related biomarkers as indicators of an evolving Alzheimer’s pathology in DS.

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Association of Apolipoprotein E ɛ4 Allele With Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults With Down Syndrome

Cited by 36 publications

References 53 publications

Blood Biomarkers for Alzheimer’s Disease in Down Syndrome

Blood Biomarkers for Alzheimer’s Disease in Down Syndrome

The Clinical and Neuropathological Features of Sporadic (Late-Onset) and Genetic Forms of Alzheimer’s Disease

Nerve Growth Factor Compromise in Down Syndrome

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