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An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults.

ABSTRACT: BACKGROUND:The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele's effect on hippocampal neurodegeneration needs to be examined. OBJECTIVE:To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults. METHODS:We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n?=?174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-? (A?) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis. RESULTS:rs3846455G was associated with greater PACC decline (?=?-0.087/year, 95% CI -0.169 to -0.005, p?=?0.039) after controlling for baseline A?. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline A? (?=?-57.3 mm3/year, 95% CI -102.8 to -11.9, p?=?0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale)?=?-0.014, 95% CI -0.032 to -6.0×10-4, p?=?0.039). CONCLUSION:UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults.

SUBMITTER: Yang HS

PROVIDER: S-EPMC6571137 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults.

Yang Hyun-Sik HS Chhatwal Jasmeer P JP Xu Jishu J White Charles C CC Hanseeuw Bernard B Rabin Jennifer S JS Papp Kathryn V KV Buckley Rachel F RF Schultz Aaron P AP Properzi Michael J MJ Gatchel Jennifer R JR Amariglio Rebecca E RE Donovan Nancy J NJ Mormino Elizabeth C EC Hedden Trey T Marshall Gad A GA Rentz Dorene M DM Johnson Keith A KA De Jager Philip L PL Sperling Reisa A RA

Journal of Alzheimer's disease : JAD 20190101 3

<h4>Background</h4>The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele's effect on hippocampal neurodegeneration needs to be examined.<h4>Objective</h4>To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adult ...[more]

PMID: 30883345

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Project description:ImportanceAssessing the ability of Alzheimer disease neuroimaging markers to predict short-term cognitive decline among clinically normal (CN) individuals is critical for upcoming secondary prevention trials using cognitive outcomes.ObjectiveTo determine whether neuroimaging markers of β-amyloid (Aβ) and neurodegeneration (ND) are independently or synergistically associated with longitudinal cognitive decline in CN individuals.Design, setting, and participantsAcademic medical center longitudinal natural history study among 166 CN individuals (median age, 74 years; 92 women).Main outcomes and measuresThe Aβ status was determined with Pittsburgh Compound B-positron emission tomography, while ND was assessed using 2 a priori measures, hippocampus volume (magnetic resonance imaging) and glucose metabolism (positron emission tomography with fludeoxyglucose F 18), extracted from Alzheimer disease-vulnerable regions. Based on imaging markers, CN individuals were categorized into the following preclinical Alzheimer disease stages: stage 0 (Aβ-/ND-), stage 1 (Aβ(+)/ND-), stage 2 (Aβ(+)/ND(+)), and suspected non-Alzheimer disease pathology (Aβ-/ND(+)). Cognition was assessed with a composite of neuropsychological tests administered annually.ResultsThe Aβ(+) CN individuals were more likely to be classified as ND+: 59.6% of Aβ(+) CN individuals were ND(+), whereas 31.9% of Aβ- CN individuals were ND(+) (odds ratio, 3.14; 95% CI, 1.44-7.02; P = .004). In assessing longitudinal cognitive performance, practice effects were evident in CN individuals negative for both Aβ and ND, whereas diminished practice effects were observed in CN individuals positive for either Aβ or ND. Decline over time was observed only in CN individuals positive for both Aβ and ND, and decline in this group was significantly greater than that in all other groups (P < .001 for all). A significant interaction term between Aβ and ND confirmed that this decline was greater than the additive contributions of Aβ and ND (P = .04).Conclusions and relevanceThe co-occurrence of Aβ and ND accelerates cognitive decline in CN individuals. Therefore, both factors are important to consider in upcoming secondary prevention trials targeting CN individuals at high risk for progression to the symptomatic stages of Alzheimer disease.

Dataset Information

An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults.

Publications

An UNC5C Allele Predicts Cognitive Decline and Hippocampal Atrophy in Clinically Normal Older Adults.

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