Alzheimer Disease Signature Neurodegeneration and APOE Genotype in Mild Cognitive Impairment With Suspected Non-Alzheimer Disease Pathophysiology.
There are conflicting results claiming that Alzheimer disease signature neurodegeneration may be more, less, or similarly advanced in individuals with β-amyloid peptide (Aβ)-negative (Aβ-) suspected non-Alzheimer disease pathophysiology (SNAP) than in Aβ-positive (Aβ+) counterparts.



To examine patterns of neurodegeneration in individuals with SNAP compared with their Aβ+ counterparts.



A longitudinal cohort study was conducted among individuals with mild cognitive impairment (MCI) and cognitively normal individuals receiving care at Alzheimer's Disease Neuroimaging Initiative sites in the United States and Canada for a mean follow-up period of 30.5 months from August 1, 2005, to June 30, 2015. Several neurodegeneration biomarkers and longitudinal cognitive function were compared between patients with distinct SNAP (Aβ- and neurodegeneration-positive [Aβ-N+]) subtypes and their Aβ+N+ counterparts.



Participants were classified according to the results of their florbetapir F-18 (Aβ) positron emission tomography and their Alzheimer disease-associated neurodegeneration status (temporoparietal glucose metabolism determined by fluorodeoxyglucose F 18 [FDG]-labeled positron emission tomography and/or hippocampal volume [HV] determined by magnetic resonance imaging: participants with subthreshold HV values were regarded as exhibiting hippocampal volume atrophy [HV+], while subthreshold mean FDG values were considered as FDG hypometabolism [FDG+]).



The study comprised 265 cognitively normal individuals (135 women and 130 men; mean [SD] age, 75.5 [6.7] years) and 522 patients with MCI (225 women and 297 men; mean [SD] age, 72.6 [7.8] years). A total of 469 individuals with MCI had data on neurodegeneration biomarkers; of these patients, 107 were Aβ-N+ (22.8%; 63 FDG+, 82 HV+, and 38 FDG+HV+) and 187 were Aβ+N+ (39.9%; 135 FDG+, 147 HV+, and 95 FDG+HV+ cases). A total of 209 cognitively normal participants had data on neurodegeneration biomarkers; of these, 52 were Aβ-N+ (24.9%; 30 FDG+, 33 HV+, and 11 FDG+HV+) and 37 were Aβ+N+ (17.7%; 22 FDG+, 26 HV+, and 11 FDG+HV+). Compared with their Aβ+ counterparts, all patients with MCI SNAP subtypes displayed better preservation of temporoparietal FDG metabolism (mean [SD] FDG: Aβ-N+, 1.25 [0.11] vs Aβ+N+, 1.19 [0.11]), less severe atrophy of the lateral temporal lobe, and lower mean (SD) cerebrospinal fluid levels of tau (59.2 [32.8] vs 111.3 [56.4]). In MCI with SNAP, sustained glucose metabolism and gray matter volume were associated with disproportionately low APOE ε4 (Aβ-N+, 18.7% vs Aβ+N+, 70.6%) and disproportionately high APOE ε2 (18.7% vs 4.8%) carrier prevalence. Slower cognitive decline and lower rates of progression to Alzheimer disease (Aβ-N+, 6.5% vs Aβ+N+, 32.6%) were also seen in patients with MCI with SNAP subtypes compared with their Aβ+ counterparts. In cognitively normal individuals, neurodegeneration biomarkers did not differ between Aβ-N+ and Aβ+N+ cases.



In MCI with SNAP, low APOE ε4 and high APOE ε2 carrier prevalence may account for differences in neurodegeneration patterns between Aβ-N+ and Aβ+N+ cases independent from the neuroimaging biomarker modality used to define neurodegeneration associated with Alzheimer disease.
Helen Wills Neuroscience Institute, University of California, Berkeley2Department of Neurology, Otto-Von-Guericke University, Magdeburg, Germany3German Center for Neurodegenerative Diseases, Magdeburg, Germany.
Stefanie
S
Schreiber
Department of Neurology, Otto-Von-Guericke University, Magdeburg, Germany3German Center for Neurodegenerative Diseases, Magdeburg, Germany4Institute of Control Engineering, Technische Universität Braunschweig, Braunschweig, Germany.
Frank
F
Schreiber
Helen Wills Neuroscience Institute, University of California, Berkeley.
Samuel N
SN
Lockhart
Helen Wills Neuroscience Institute, University of California, Berkeley.
Andy
A
Horng
Memory and Aging Center, Department of Neurology, University of California, San Francisco.
Alexandre
A
Bejanin
Helen Wills Neuroscience Institute, University of California, Berkeley6Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, California.
Susan M
SM
Landau
Helen Wills Neuroscience Institute, University of California, Berkeley6Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, California.
William J
WJ
Jagust
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds; D001057:Apolipoproteins E / Q000235:genetics*; D015415:Biomarkers; D002540:Cerebral Cortex / Q000000981:diagnostic imaging* / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005026:Ethylene Glycols; D005260:Female; D019788:Fluorodeoxyglucose F18; D005500:Follow-Up Studies; D006624:Hippocampus / Q000000981:diagnostic imaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D010296:Parietal Lobe / Q000000981:diagnostic imaging / Q000378:metabolism; D049268:Positron-Emission Tomography; D013702:Temporal Lobe / Q000000981:diagnostic imaging / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; C000612345:ApoE protein, human; D001057:Apolipoproteins E; D015415:Biomarkers; D005026:Ethylene Glycols; D019788:Fluorodeoxyglucose F18; C545186:florbetapir