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APOE?2 is associated with milder clinical and pathological Alzheimer disease.

ABSTRACT: The Alzheimer disease (AD) APOE?4 risk allele associates with an earlier age at onset and increased amyloid-? deposition, whereas the protective APOE?2 allele delays the onset and appears to prevent amyloid-? deposition. Yet the clinical and pathological effects of APOE?2 remain uncertain because of its relative rarity. We investigated the effects of APOE?2 and ?4 alleles on AD pathology and cognition in a large US data set of well-characterized AD patients.We studied individuals from the National Alzheimer's Coordinating Center autopsy cohort across the entire clinicopathological continuum of AD. Multivariate models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOE?3/?3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination).Compared to APOE?3/?3, APOE?2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOE?4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance (?2?>??3?>??4). Mediation analysis suggests that this is largely explained through effects on pathology.Even when adjusted for age at onset, symptom duration, and other demographic variables, APOE?2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOE?3 and ?4 alleles, suggesting a relative neuroprotective effect of APOE?2 in AD.

SUBMITTER: Serrano-Pozo A

PROVIDER: S-EPMC4447539 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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APOEε2 is associated with milder clinical and pathological Alzheimer disease.

Serrano-Pozo Alberto A Qian Jing J Monsell Sarah E SE Betensky Rebecca A RA Hyman Bradley T BT

Annals of neurology 20150601 6

<h4>Objective</h4>The Alzheimer disease (AD) APOEε4 risk allele associates with an earlier age at onset and increased amyloid-β deposition, whereas the protective APOEε2 allele delays the onset and appears to prevent amyloid-β deposition. Yet the clinical and pathological effects of APOEε2 remain uncertain because of its relative rarity. We investigated the effects of APOEε2 and ε4 alleles on AD pathology and cognition in a large US data set of well-characterized AD patients.<h4>Methods</h4>We s ...[more]

PMID: 25623662

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Project description:Importance:There are conflicting results claiming that Alzheimer disease signature neurodegeneration may be more, less, or similarly advanced in individuals with ?-amyloid peptide (A?)-negative (A?-) suspected non-Alzheimer disease pathophysiology (SNAP) than in A?-positive (A?+) counterparts. Objective:To examine patterns of neurodegeneration in individuals with SNAP compared with their A?+ 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 (A?- and neurodegeneration-positive [A?-N+]) subtypes and their A?+N+ counterparts. Main Outcomes and Measures:Participants were classified according to the results of their florbetapir F-18 (A?) 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 A?-N+ (22.8%; 63 FDG+, 82 HV+, and 38 FDG+HV+) and 187 were A?+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 A?-N+ (24.9%; 30 FDG+, 33 HV+, and 11 FDG+HV+) and 37 were A?+N+ (17.7%; 22 FDG+, 26 HV+, and 11 FDG+HV+). Compared with their A?+ counterparts, all patients with MCI SNAP subtypes displayed better preservation of temporoparietal FDG metabolism (mean [SD] FDG: A?-N+, 1.25 [0.11] vs A?+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 ?4 (A?-N+, 18.7% vs A?+N+, 70.6%) and disproportionately high APOE ?2 (18.7% vs 4.8%) carrier prevalence. Slower cognitive decline and lower rates of progression to Alzheimer disease (A?-N+, 6.5% vs A?+N+, 32.6%) were also seen in patients with MCI with SNAP subtypes compared with their A?+ counterparts. In cognitively normal individuals, neurodegeneration biomarkers did not differ between A?-N+ and A?+N+ cases. Conclusions and Relevance:In MCI with SNAP, low APOE ?4 and high APOE ?2 carrier prevalence may account for differences in neurodegeneration patterns between A?-N+ and A?+N+ cases independent from the neuroimaging biomarker modality used to define neurodegeneration associated with Alzheimer disease.

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APOE?2 is associated with milder clinical and pathological Alzheimer disease.

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APOEε2 is associated with milder clinical and pathological Alzheimer disease.

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