Alzheimer Disease Signature Neurodegeneration and APOE Genotype in Mild Cognitive Impairment With Suspected Non–Alzheimer Disease Pathophysiology

Abstract

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. OBJECTIVE To examine patterns of neurodegeneration in individuals with SNAP compared with their Aβ+ counterparts. DESIGN, SETTING, AND PARTICIPANTS 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. MAIN OUTCOMES AND MEASURES 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+]). RESULTS 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. CONCLUSIONS AND RELEVANCE In...

Defining SNAP by cross-sectional and longitudinal definitions of neurodegeneration

“…( Mormino et al, 2016 )). This heterogeneity is reflected in the wide range of reported outcomes in those with SNAP-MCI ( Caroli et al, 2015 ; Prestia et al, 2013 ; Wisse et al, 2015 ; Schreiber et al, 2017 ). We hypothesized that utilizing a longitudinal definition of neurodegeneration in addition to a cross-sectional one might partly explain this observed heterogeneity.…”

“…However, the clinical implication of SNAP-MCI status remains unclear, as previous reports have shown widely varying results with regard to progression to dementia and cognitive decline. The reported progression vary from 0% to 56% in 2–3 years of follow-up ( Caroli et al, 2015 ; Prestia et al, 2013 ; Wisse et al, 2015 ; Schreiber et al, 2017 ) and one study even reported a higher dementia progression rate in SNAP than in an amyloid and neurodegeneration positive, or prodromal AD (pAD), group ( Petersen et al, 2013 ). Similar inconsistent findings are present for cognitive decline in these groups, with some studies showing almost similar cognitive decline in SNAP and pAD ( Caroli et al, 2015 ), whereas others showed significantly less cognitive decline in SNAP as compared to pAD ( Schreiber et al, 2017 ; Knopman et al, 2015 ; Chung et al, 2017 ).…”

Cardiovascular Risk Factor Burden in Veterans and Non-Veterans with Parkinson Disease

“…APO E genotype), there is no existing literature to support this idea. Veterans and non-Veterans in our cohort showed near identical findings in terms of total cortical gray and supratentorial white matter volumes, suggesting that the two study arms do not manifest the typical brain volumetric patterns that would be associated with genetic differences in APOE genotype status [16]. …”

The personalized Alzheimer's disease cortical thickness index predicts likely pathology and clinical progression in mild cognitive impairment

“…To compare the pADi to a commonly used MRI biomarker in the field, we analyzed hippocampal volume using the measures provided by the automated segmentation procedure from FreeSurfer (summed across hemispheres) divided by total intracranial volume (ICV). We dichotomized ICV-corrected hippocampal volume for analysis based on a previously published threshold of 4.65 [32] .…”