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Staging biomarkers in preclinical autosomal dominant Alzheimer's disease by estimated years to symptom onset.

ABSTRACT: INTRODUCTION:Staging preclinical Alzheimer disease (AD) by the expected years to symptom onset (EYO) in autosomal dominant AD (ADAD) through biomarker correlations is important. METHODS:We estimated the correlation matrix between EYO/cognition and imaging/CSF biomarkers, and searched for the EYO cutoff where a change in the correlations occurred before and after the cutoff among the asymptomatic mutation carriers of ADAD. We then estimated the longitudinal rate of change for biomarkers/cognition within each preclinical stage defined by the EYO. RESULTS:Based on the change in the correlations, the preclinical ADAD was divided by EYOs -7 and -13 years. Mutation carriers demonstrated a temporal ordering of biomarker/cognition changes across the three preclinical stages. DISCUSSION:Duration of each preclinical stage can be estimated in ADAD, facilitating better planning of prevention trials with the EYO cutoffs under the recently released FDA guidance. The generalization of these results to sporadic AD warrants further investigation.

SUBMITTER: Wang G

PROVIDER: S-EPMC6461496 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Staging biomarkers in preclinical autosomal dominant Alzheimer's disease by estimated years to symptom onset.

Wang Guoqiao G Coble Dean D McDade Eric M EM Hassenstab Jason J Fagan Anne M AM Benzinger Tammie L S TLS Bateman Randall J RJ Morris John C JC Xiong Chengjie C

Alzheimer's & dementia : the journal of the Alzheimer's Association 20190215 4

<h4>Introduction</h4>Staging preclinical Alzheimer disease (AD) by the expected years to symptom onset (EYO) in autosomal dominant AD (ADAD) through biomarker correlations is important.<h4>Methods</h4>We estimated the correlation matrix between EYO/cognition and imaging/CSF biomarkers, and searched for the EYO cutoff where a change in the correlations occurred before and after the cutoff among the asymptomatic mutation carriers of ADAD. We then estimated the longitudinal rate of change for bioma ...[more]

PMID: 30773445

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Project description:White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain.

Dataset Information

Staging biomarkers in preclinical autosomal dominant Alzheimer's disease by estimated years to symptom onset.

Publications

Staging biomarkers in preclinical autosomal dominant Alzheimer's disease by estimated years to symptom onset.

Similar Datasets

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