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Association of Apolipoprotein E ?4 With Medial Temporal Tau Independent of Amyloid-?.

ABSTRACT: Importance:Apolipoprotein E ?4 (APOE?4) is the single most important genetic risk factor for Alzheimer disease. While APOE?4 is associated with increased amyloid-? burden, its association with cerebral tau pathology has been controversial. Objective:To determine whether APOE?4 is associated with medial temporal tau pathology independently of amyloid-?, sex, clinical status, and age. Design, Setting, and Participants:This is a study of 2 cross-sectional cohorts of volunteers who were cognitively normal, had mild cognitive impairment (MCI), or had Alzheimer disease dementia: the Translational Biomarkers in Aging and Dementia (TRIAD) study (data collected between October 2017 and July 2019) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (collected between November 2015 and June 2019). The first cohort (TRIAD) comprised cognitively normal elderly participants (n?=?124), participants with MCI (n?=?50), and participants with Alzheimer disease (n?=?50) who underwent tau positron emission tomography (PET) with fluorine 18-labeled MK6240 and amyloid-? PET with [18F]AZD4694. The second sample (ADNI) was composed of cognitively normal elderly participants (n?=?157), participants with MCI (n?=?83), and participants with Alzheimer disease (n?=?25) who underwent tau PET with [18F]flortaucipir and amyloid-? PET with [18F]florbetapir. Exclusion criteria were a history of other neurological disorders, stroke, or head trauma. There were 489 eligible participants, selected based on availability of amyloid-PET, tau-PET, magnetic resonance imaging, and genotyping for APOE?4. Forty-five young adults (<30 years) from the TRIAD cohort were not selected for this study. Main Outcomes and Measures:A main association between APOE?4 and tau-PET standardized uptake value ratio, correcting for age, sex, clinical status, and neocortical amyloid-PET standardized uptake value ratio. Results:The mean (SD) age of the 489 participants was 70.5 (7.1) years; 171 were APOE?4 carriers (34.9%), and 230 of 489 were men. In both cohorts, APOE?4 was associated in increased tau-PET uptake in the entorhinal cortex and hippocampus independently of amyloid-?, sex, age, and clinical status after multiple comparisons correction (TRIAD: ??=?0.33; 95% CI, 0.19-0.49; ADNI: ??=?0.13; 95% CI, 0.08-0.19; P?

SUBMITTER: Therriault J

PROVIDER: S-EPMC6990684 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β.

Therriault Joseph J Benedet Andrea L AL Pascoal Tharick A TA Mathotaarachchi Sulantha S Chamoun Mira M Savard Melissa M Thomas Emilie E Kang Min Su MS Lussier Firoza F Tissot Cecile C Parsons Marlee M Qureshi Muhammad Naveed Iqbal MNI Vitali Paolo P Massarweh Gassan G Soucy Jean-Paul JP Rej Soham S Saha-Chaudhuri Paramita P Gauthier Serge S Rosa-Neto Pedro P

JAMA neurology 20200401 4

<h4>Importance</h4>Apolipoprotein E ε4 (APOEε4) is the single most important genetic risk factor for Alzheimer disease. While APOEε4 is associated with increased amyloid-β burden, its association with cerebral tau pathology has been controversial.<h4>Objective</h4>To determine whether APOEε4 is associated with medial temporal tau pathology independently of amyloid-β, sex, clinical status, and age.<h4>Design, setting, and participants</h4>This is a study of 2 cross-sectional cohorts of volunteers ...[more]

PMID: 31860000

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Project description:ImportanceAn increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear.ObjectiveTo study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A-), and the association of this condition with the AD continuum.Design, setting, and participantsA multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL-).ExposuresTau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments.Main outcomes and measuresCross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset).ResultsAmong the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aβ accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+.Conclusions and relevanceIn this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD.

Project description:BackgroundThe translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with the apolipoprotein E (APOE) gene, has been implicated in Alzheimer's disease (AD). TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD-related morphology changes. While early reports indicated that the longer length poly-T allele of TOMM40 increases risk for AD, these findings have not been consistently replicated in further studies. We examined the effect of TOMM40 and APOE on regional brain positron emission tomography (PET) 2-(1-{6-[(2 [F18]fluoroethyl) (methyl) amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) binding values in MTL.MethodsA total of 73 non-demented older adults (42 females; mean age: 62.9(10.9) completed genotyping for both APOE and TOMM40 and received FDDNP-PET scans. For TOMM40, the lengths of the poly-T sequence were classified as short (14-20 repeats; S), long (21-29 repeats, L) or very long (>29 repeats, VL). Using general linear models, we examined medial temporal lobe FDDNP binding and cognitive functioning between TOMM40 and APOE-4 groups, with age, sex, and education as covariates.ResultsData from 30 individuals with APOE-4 and L TOMM40 poly-T length, 11 non E4 TOMM40 S/S, 14 non E4 TOMM40 S/VL and 13 non E4 TOMM40 VL/VL were analyzed. Medial temporal FDDNP binding differed significantly between TOMM40/APOE groups (F(3,62) = 3.3,p = .03). Participants with TOMM40 S/S exhibited significantly lower binding compared to TOMM40 S/VL and APOE-4 carriers. We did not find a significant relationship between TOMM40 poly-T lengths/APOE risk groups and cognitive functioning.ConclusionsThis is the first report to demonstrate a significant association between longer TOMM40 poly-T lengths and higher medial temporal plaque and tangle burden in non-demented older adults. Identifying biomarkers that are risk factors for AD will enhance our ability to identify subjects likely to benefit from novel AD treatments.

Project description:The elusive relationship between underlying pathology and clinical disease hampers diagnosis of Alzheimer's disease (AD) and preventative intervention development. We seek to understand the relationship between two classical AD biomarkers, amyloid-?1-42 (A?1-42) and total-tau (t-tau), and define their trajectories across disease development, as defined by disease onset at diagnosis of mild cognitive impairment (MCI). Using longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we performed a correlation analysis of biomarkers CSF A?1-42 and t-tau, and longitudinal quantile analysis. Using a mixed effects model, with MCI onset as an anchor, we develop linear trajectories to describe the rate of change across disease development. These trajectories were extended through the incorporation of data from cognitively normal, healthy adults (aged 20-62 years) from the literature, to fit sigmoid curves by means of non-linear least squares estimators, to create curves encompassing the 50 years prior to MCI onset. A strong right-angled relationship between the biomarkers A?1-42 and t-tau is detected, implying a highly non-linear relationship. The rate of change of A?1-42 is correlated with the baseline concentration per quantile, reflecting a reduction in the rate of loss across disease within subjects. Regression models reveal significant amyloid loss relative to MCI onset (- 2.35 pg/mL/year), compared to minimal loss relative to AD onset (- 0.97 pg/mL/year). Tau accumulates consistently relative to MCI and AD onset, (2.05 pg/mL/year) and (2.46 pg/mL/year), respectively. The fitted amyloid curve shows peak loss of amyloid 8.06 years prior to MCI diagnosis, while t-tau exhibits peak accumulation 14.17 years following MCI diagnosis, with the upper limit not yet reached 30 years post diagnosis. Biomarker trajectories aid unbiased, objective assessment of disease progression. Quantitative trajectories are likely to be of use in clinical trial design, as they allow for a more detailed insight into the effectiveness of treatments designed to delay development of biological disease.

Dataset Information

Association of Apolipoprotein E ?4 With Medial Temporal Tau Independent of Amyloid-?.

Publications

Association of Apolipoprotein E ε4 With Medial Temporal Tau Independent of Amyloid-β.

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