Colin Groot1, Carole H Sudre2, Frederik Barkhof2, Charlotte E Teunissen2, Bart N M van Berckel2, Sang Won Seo2, Sébastien Ourselin2, Philip Scheltens2, M Jorge Cardoso2, Wiesje M van der Flier2, Rik Ossenkoppele2. 1. From the Departments of Neurology and Alzheimer Center (C.G., P.S., W.M.v.d.F., R.O.), Radiology and Nuclear Medicine (C.G., F.B., B.N.M.v.B., R.O.), Neurochemistry Lab and Biobank (C.E.T.), and Clinical Chemistry, Epidemiology and Biostatistics (W.M.v.d.F.), VU University Medical Center, Neuroscience Campus Amsterdam, the Netherlands; Dementia Research Centre (C.H.S., S.O., M.J.C.), Department of Neurodegenerative Disease, UCL Institute of Neurology, Centre for Medical Image Computing (C.H.S., S.O., M.J.C.), and Institutes of Neurology & Healthcare Engineering (F.B.), University College London, UK; Department of Neurology (S.W.S.), Sungkyunkwan University School of Medicine, and Neuroscience Center (S.W.S.), Samsung Medical Center; Department of Clinical Research Design & Evaluation (S.W.S.), SAIHST, Sungkyunkwan University, Seoul, Korea; and Clinical Memory Research Unit (R.O.), Lund University, Sweden. c.groot3@vumc.nl. 2. From the Departments of Neurology and Alzheimer Center (C.G., P.S., W.M.v.d.F., R.O.), Radiology and Nuclear Medicine (C.G., F.B., B.N.M.v.B., R.O.), Neurochemistry Lab and Biobank (C.E.T.), and Clinical Chemistry, Epidemiology and Biostatistics (W.M.v.d.F.), VU University Medical Center, Neuroscience Campus Amsterdam, the Netherlands; Dementia Research Centre (C.H.S., S.O., M.J.C.), Department of Neurodegenerative Disease, UCL Institute of Neurology, Centre for Medical Image Computing (C.H.S., S.O., M.J.C.), and Institutes of Neurology & Healthcare Engineering (F.B.), University College London, UK; Department of Neurology (S.W.S.), Sungkyunkwan University School of Medicine, and Neuroscience Center (S.W.S.), Samsung Medical Center; Department of Clinical Research Design & Evaluation (S.W.S.), SAIHST, Sungkyunkwan University, Seoul, Korea; and Clinical Memory Research Unit (R.O.), Lund University, Sweden.
Abstract
OBJECTIVE: To examine the clinical phenotype, gray matter atrophy patterns, and small vessel disease in patients who developed prodromal or probable Alzheimer disease dementia, despite carrying the protective APOEε2 allele. METHODS: We included 36 β-amyloid-positive (by CSF or PET) APOEε2 carriers (all ε2/ε3) with mild cognitive impairment or dementia due to Alzheimer disease who were matched for age and diagnosis (ratio 1:2) to APOEε3 homozygotes and APOEε4 carriers (70% ε3/ε4 and 30% ε4/ε4). We assessed neuropsychological performance across 4 cognitive domains (memory, attention, executive, and language functions), performed voxelwise and region of interest analyses of gray matter atrophy on T1-weighted MRI, used fluid-attenuated inversion recovery images to automatically quantify white matter hyperintensity volumes, and assessed T2*-weighted images to identify microbleeds. Differences in cognitive domain scores, atrophy, and white matter hyperintensities between ε2 carriers, ε3 homozygotes, and ε4 carriers were assessed using analysis of variance analyses, and Pearson χ2 tests were used to examine differences in prevalence of microbleeds. RESULTS: We found that ε2 carriers performed worse on nonmemory domains compared to both ε3 homozygotes and ε4 carriers but better on memory compared to ε4 carriers. Voxelwise T1-weighted MRI analyses showed asymmetric (left > right) temporoparietal-predominant atrophy with subtly less involvement of medial-temporal structures in ε2 carriers compared to ε4 carriers. Finally, ε2 carriers had larger total white matter hyperintensity volumes compared to ε4 carriers (mean 10.4 vs 7.3 mL) and a higher prevalence of microbleeds compared to ε3 homozygotes (37.5% vs 18.3%). CONCLUSION: APOEε2 carriers who develop Alzheimer disease despite carrying the protective allele display a nonamnestic clinical phenotype with more severe small vessel disease.
OBJECTIVE: To examine the clinical phenotype, gray matter atrophy patterns, and small vessel disease in patients who developed prodromal or probable Alzheimer disease dementia, despite carrying the protective APOEε2 allele. METHODS: We included 36 β-amyloid-positive (by CSF or PET) APOEε2 carriers (all ε2/ε3) with mild cognitive impairment or dementia due to Alzheimer disease who were matched for age and diagnosis (ratio 1:2) to APOEε3 homozygotes and APOEε4 carriers (70% ε3/ε4 and 30% ε4/ε4). We assessed neuropsychological performance across 4 cognitive domains (memory, attention, executive, and language functions), performed voxelwise and region of interest analyses of gray matter atrophy on T1-weighted MRI, used fluid-attenuated inversion recovery images to automatically quantify white matter hyperintensity volumes, and assessed T2*-weighted images to identify microbleeds. Differences in cognitive domain scores, atrophy, and white matter hyperintensities between ε2 carriers, ε3 homozygotes, and ε4 carriers were assessed using analysis of variance analyses, and Pearson χ2 tests were used to examine differences in prevalence of microbleeds. RESULTS: We found that ε2 carriers performed worse on nonmemory domains compared to both ε3 homozygotes and ε4 carriers but better on memory compared to ε4 carriers. Voxelwise T1-weighted MRI analyses showed asymmetric (left > right) temporoparietal-predominant atrophy with subtly less involvement of medial-temporal structures in ε2 carriers compared to ε4 carriers. Finally, ε2 carriers had larger total white matter hyperintensity volumes compared to ε4 carriers (mean 10.4 vs 7.3 mL) and a higher prevalence of microbleeds compared to ε3 homozygotes (37.5% vs 18.3%). CONCLUSION: APOEε2 carriers who develop Alzheimer disease despite carrying the protective allele display a nonamnestic clinical phenotype with more severe small vessel disease.
Authors: Emily J Hill; Laurie A Robak; Rami Al-Ouran; Jennifer Deger; Jamie C Fong; Paul Jerrod Vandeventer; Emily Schulman; Sindhu Rao; Hiba Saade; Joseph M Savitt; Rainer von Coelln; Neeja Desai; Harshavardhan Doddapaneni; Sejal Salvi; Shannon Dugan-Perez; Donna M Muzny; Amy L McGuire; Zhandong Liu; Richard A Gibbs; Chad Shaw; Joseph Jankovic; Lisa M Shulman; Joshua M Shulman Journal: Neurol Genet Date: 2022-06-09
Authors: Michelle R Caunca; Andres De Leon-Benedetti; Lawrence Latour; Richard Leigh; Clinton B Wright Journal: Front Aging Neurosci Date: 2019-06-27 Impact factor: 5.750
Authors: Jin San Lee; Hyejoo Lee; Seongbeom Park; Yeongsim Choe; Yu Hyun Park; Bo Kyoung Cheon; Alice Hahn; Rik Ossenkoppele; Hee Jin Kim; Seonwoo Kim; Heejin Yoo; Hyemin Jang; Soo Hyun Cho; Seung Joo Kim; Jun Pyo Kim; Young Hee Jung; Key-Chung Park; Charles DeCarli; Michael W Weiner; Duk L Na; Sang Won Seo Journal: Neurology Date: 2020-09-14 Impact factor: 9.910
Authors: Daniel Ferreira; Zuzana Nedelska; Jonathan Graff-Radford; Scott A Przybelski; Timothy G Lesnick; Christopher G Schwarz; Hugo Botha; Matthew L Senjem; Julie A Fields; David S Knopman; Rodolfo Savica; Tanis J Ferman; Neill R Graff-Radford; Val J Lowe; Clifford R Jack; Ronald C Petersen; Afina W Lemstra; Marleen van de Beek; Frederik Barkhof; Frederic Blanc; Paulo Loureiro de Sousa; Nathalie Philippi; Benjamin Cretin; Catherine Demuynck; Jakub Hort; Ketil Oppedal; Bradley F Boeve; Dag Aarsland; Eric Westman; Kejal Kantarci Journal: Neurobiol Aging Date: 2021-05-14 Impact factor: 5.133