<i>APOE</i>
            ε4 associates with microglial activation independently of Aβ plaques and tau tangles

Ferrari‐Souza, João Pedro; Lussier, Firoza Z; Leffa, Douglas Teixeira; Therriault, Joseph; Tissot, Cécile; Bellaver, Bruna; Ferreira, Pamela C.L.; Malpetti, Maura; Wang, Yiting; Povala, Guilherme; Benedet, Andréa Lessa; Ashton, Nicholas J.; Chamoun, Mira; Servaes, Stijn; Bezgin, Gleb; Kang, Min Su; Stevenson, Jenna; Rahmouni, Nesrine; Pallen, Vanessa; Poltronetti, Nina Margherita; O’Brien, John T.; Rowe, James B.; Cohen, Ann D.; López, Oscar L.; Tudorascu, Dana L.; Karikari, Thomas K.; Klunk, William E.; Villemagne, Victor L.; Soucy, Jean‐Paul; Gauthier, Serge; Souza, Diogo Onofre Gomes de; Zetterberg, Henrik; Blennow, Kaj; Zimmer, Eduardo R.; Rosa‐Neto, Pedro; Pascoal, Tharick A.

doi:10.1126/sciadv.ade1474

Cited by 37 publications

(11 citation statements)

References 81 publications

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“…Alternatively, there may be a specific microglial response to tau that differs from that to amyloid, 60 and the pathway from amyloid to tau may depend on other aspects of neuroinflammation, including astrocyte reactivity, in cognitively normal, amyloid‐positive individuals. 61 APOE ε4 plays a modulatory role in neuroinflammation, such that APOE ε4 attenuates 62 or exaggerates 63 microglial activation, but the missingness pattern of APOE information precludes its inclusion in models. Simple main effects demonstrated higher PBR28 SUVR in APOE ε4 carriers, in addition to its known effects on amyloid, tau, neurodegeneration, and cognition.…”

Section: Discussionmentioning

confidence: 99%

Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model

Rossano,

Johnson,

Smith

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONEvidence suggests microglial activation precedes regional tau and neurodegeneration in Alzheimer's disease (AD). We characterized microglia with translocator protein (TSPO) positron emission tomography (PET) within an AD progression model where global amyloid beta (Aβ) precedes local tau and neurodegeneration, resulting in cognitive impairment.METHODSFlorbetaben, PBR28, and MK‐6240 PET, T1 magnetic resonance imaging, and cognitive measures were performed in 19 cognitively unimpaired older adults and 22 patients with mild cognitive impairment or mild AD to examine associations among microglia activation, Aβ, tau, and cognition, adjusting for neurodegeneration. Mediation analyses evaluated the possible role of microglial activation along the AD progression model.RESULTSHigher PBR28 uptake was associated with higher Aβ, higher tau, and lower MMSE score, independent of neurodegeneration. PBR28 mediated associations between tau in early and middle Braak stages, between tau and neurodegeneration, and between neurodegeneration and cognition.DISCUSSIONMicroglia are associated with AD pathology and cognition and may mediate relationships between subsequent steps in AD progression.

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Section: Discussionmentioning

confidence: 99%

Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model

Rossano,

Johnson,

Smith

et al. 2024

Alzheimer's & Dementia

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“…Across the aging and AD spectrum, APOE4 carriers present with increased microglial activation relative to noncarriers in early Braak stage regions within the MTL. This microglial activation mediates Aβ-independent effects of APOE4 on tau accumulation that are further associated with neurodegeneration and clinical impairment [ 87 ].…”

Section: Discussionmentioning

confidence: 99%

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

Lane,

Darreh-Shori,

Junge

et al. 2024

BMC Neurol

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Background The authors sought to examine the impact of the K-variant of butyrylcholinesterase (BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) in APOE4 carriers. Methods Patients aged 50–74 years with cerebrospinal fluid (CSF) biomarker-confirmed AD, were recruited to clinical trial (NCT03186989 since June 14, 2017). Baseline demographics, disease characteristics, and biomarkers were evaluated in 45 patients according to BCHE-K and APOE4 allelic status in this post-hoc study. Results In APOE4 carriers (N = 33), the mean age-at-diagnosis of AD in BCHE-K carriers (n = 11) was 6.4 years earlier than in BCHE-K noncarriers (n = 22, P < .001, ANOVA). In APOE4 noncarriers (N = 12) there was no observed influence of BCHE-K. APOE4 carriers with BCHE-K also exhibited slightly higher amyloid and tau accumulations compared to BCHE-K noncarriers. A predominantly amyloid, limited tau, and limbic-amnestic phenotype was exemplified by APOE4 homozygotes with BCHE-K. In the overall population, multiple regression analyses demonstrated an association of amyloid accumulation with APOE4 carrier status (P < .029), larger total brain ventricle volume (P < .021), less synaptic injury (Ng, P < .001), and less tau pathophysiology (p-tau181, P < .005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL, P = .002), more synaptic injury (Ng, P < .001), and higher levels of glial activation (YKL-40, P = .01). Conclusion These findings have implications for the genetic architecture of prognosis in early AD, not the genetics of susceptibility to AD. In patients with early AD aged less than 75 years, the mean age-at-diagnosis of AD in APOE4 carriers was reduced by over 6 years in BCHE-K carriers versus noncarriers. The functional status of glia may explain many of the effects of APOE4 and BCHE-K on the early AD phenotype. Trial registration NCT03186989 since June 14, 2017

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“…The cerebellar cortex was validated as a (pseudo)reference region using full quantification and another second-generation TSPO tracer ([ 11 C]-PBR-28) ( 15 ). The cerebellar cortex was also widely used as a (pseudo)reference region in early AD ( 2 , 4 , 5 , 18 , 20–23 ). However, a significant uptake was already observed in the cerebellum ( 3 ) and there is now evidence in neuropathology, structural and functional imaging, that this region is involved in AD pathophysiology ( 24–26 ).…”

Section: Methodsmentioning

confidence: 99%

Clinical heterogeneity of neuro-inflammatory PET profiles in early Alzheimer’s disease

Gouilly,

Salabert,

Bertrand

et al. 2023

Front. Neurol.

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The relationship between neuroinflammation and cognition remains uncertain in early Alzheimer’s disease (AD). We performed a cross-sectional study to assess how neuroinflammation is related to cognition using TSPO PET imaging and a multi-domain neuropsychological assessment. A standard uptake value ratio (SUVR) analysis was performed to measure [18F]-DPA-714 binding using the cerebellar cortex or the whole brain as a (pseudo)reference region. Among 29 patients with early AD, the pattern of neuroinflammation was heterogeneous and exhibited no correlation with cognition at voxel-wise, regional or whole-brain level. The distribution of the SUVR values was independent of sex, APOE phenotype, early and late onset of symptoms and the presence of cerebral amyloid angiopathy. However, we were able to demonstrate a complex dissociation as some patients with similar PET pattern had opposed neuropsychological profiles while other patients with opposite PET profiles had similar neuropsychological presentation. Further studies are needed to explore how this heterogeneity impacts disease progression.

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APOE ε4 associates with microglial activation independently of Aβ plaques and tau tangles

Cited by 37 publications

References 81 publications

Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model

Microglia measured by TSPO PET are associated with Alzheimer's disease pathology and mediate key steps in a disease progression model

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

Clinical heterogeneity of neuro-inflammatory PET profiles in early Alzheimer’s disease

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