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Heterogeneity in Suspected Non-Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals.

ABSTRACT: A substantial proportion of clinically normal (CN) older individuals are classified as having suspected non-Alzheimer disease pathophysiology (SNAP), defined as biomarker negative for ?-amyloid (A?-) but positive for neurodegeneration (ND+). The etiology of SNAP in this population remains unclear.To determine whether CN individuals with SNAP show evidence of early Alzheimer disease (AD) processes (ie, elevated tau levels and/or increased risk for cognitive decline).This longitudinal observational study performed in an academic medical center included 247 CN participants from the Harvard Aging Brain Study. Participants were classified into preclinical AD stages using measures of A? (Pittsburgh Compound B [PIB]-labeled positron emission tomography) and ND (hippocampal volume or cortical glucose metabolism from AD-vulnerable regions). Classifications included stages 0 (A?-/ND-), 1 (A?+/ND-), and 2 (A?+/ND+) and SNAP (A?-/ND+). Continuous levels of PiB and ND, tau levels in the medial and inferior temporal lobes, and longitudinal cognition were examined. Data collection began in 2010 and is ongoing. Data were analyzed from 2015 to 2016.Evidence of amyloid-independent tau deposition and/or cognitive decline.Of the 247 participants (142 women [57.5%]; 105 men [42.5%]; mean age, 74 [range, 63-90] years), 64 (25.9%) were classified as having SNAP. Compared with the stage 0 group, the SNAP group was not more likely to have subthreshold PiB values (higher values within the A?- range), suggesting that misclassification due to the PiB cutoff was not a prominent contributor to this group (mean [SD] distribution volume ratio, 1.08 [0.05] for the SNAP group; 1.09 [0.05] for the stage 1 group). Tau levels in the medial and inferior temporal lobes were indistinguishable between the SNAP and stage 0 groups (entorhinal cortex, ??=?-0.005 [SE, 0.036]; parahippocampal gyrus, ??=?-0.001 [SE, 0.027]; and inferior temporal lobe, ??=?-0.004 [SE, 0.027]; P???.88) and were lower in the SNAP group compared with the stage 2 group (entorhinal cortex, ??=?-0.125 [SE, 0.041]; parahippocampal gyrus, ??=?-0.074 [SE, 0.030]; and inferior temporal lobe, ??=?-0.083 [SE, 0.031]; P???.02). The stage 2 group demonstrated greater cognitive decline compared with all other groups (stage 0, ??=?-0.239 [SE, 0.042]; stage 1, ??=?-0.242 [SE, 0.051]; and SNAP, ??=?-0.157 [SE, 0.044]; P???.001), whereas the SNAP group showed a diminished practice effect over time compared with the stage 0 group (??=?-0.082 [SE, 0.037]; P?=?.03).In this study, clinically normal adults with SNAP did not exhibit evidence of elevated tau levels, which suggests that this biomarker construct does not represent amyloid-independent tauopathy. At the group level, individuals with SNAP did not show cognitive decline but did show a diminished practice effect. SNAP is likely heterogeneous, with a subset of this group at elevated risk for short-term decline. Future refinement of biomarkers will be necessary to subclassify this group and determine the biological correlates of ND markers among A?- CN individuals.

SUBMITTER: Mormino EC

PROVIDER: S-EPMC5266522 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Heterogeneity in Suspected Non-Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals.

Mormino Elizabeth C EC Papp Kathryn V KV Rentz Dorene M DM Schultz Aaron P AP LaPoint Molly M Amariglio Rebecca R Hanseeuw Bernard B Marshall Gad A GA Hedden Trey T Johnson Keith A KA Sperling Reisa A RA

JAMA neurology 20161001 10

<h4>Importance</h4>A substantial proportion of clinically normal (CN) older individuals are classified as having suspected non-Alzheimer disease pathophysiology (SNAP), defined as biomarker negative for β-amyloid (Aβ-) but positive for neurodegeneration (ND+). The etiology of SNAP in this population remains unclear.<h4>Objective</h4>To determine whether CN individuals with SNAP show evidence of early Alzheimer disease (AD) processes (ie, elevated tau levels and/or increased risk for cognitive de ...[more]

PMID: 27548655

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Project description:ImportanceThere 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.ObjectiveTo examine patterns of neurodegeneration in individuals with SNAP compared with their Aβ+ counterparts.Design, setting, and participantsA 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 measuresParticipants 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+]).ResultsThe 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 relevanceIn 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.

Project description:ImportanceThe Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity to evaluate factors associated with elevated brain amyloid.ObjectiveTo investigate the association of elevated amyloid with demographic and lifestyle factors, apolipoprotein E (APOE), neuropsychological testing, and self- and study partner reports of cognitive function.Design, setting, and participantsThis cross-sectional study included screening data in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected from April 2014 to December 2017 and classified by amyloid status. Data were was analyzed from 2018 to 2019 across 67 sites in the US, Canada, Australia, and Japan and included 4486 older individuals (age 65-85 years) who were eligible for amyloid PET (clinically normal [Clinical Dementia Rating = 0] and cognitively unimpaired [Mini-Mental State Examination score, ≥25; logical memory IIa 6-18]).Main outcomes and measuresScreening demographics, lifestyle variables, APOE genotyping, and cognitive testing (Preclinical Alzheimer Cognitive Composite), self- and study partner reports of high-level daily cognitive function (Cognitive Function Index). Florbetapir amyloid PET imaging was used to classify participants as having elevated amyloid (Aβ+) or not having elevated amyloid (Aβ-).ResultsAmyloid PET results were acquired for 4486 participants (mean [SD] age, 71.29 [4.67] years; 2647 women [59%]), with 1323 (29.5%) classified as Aβ+. Aβ+ participants were slightly older than Aβ-, with no observed differences in sex, education, marital or retirement status, or any self-reported lifestyle factors. Aβ+ participants were more likely to have a family history of dementia (3320 Aβ+ [74%] vs 3050 Aβ- [68%]) and at least 1 APOE ε4 allele (2602 Aβ+ [58%] vs 1122 Aβ- [25%]). Aβ+ participants demonstrated worse performance on screening Preclinical Alzheimer Cognitive Composite results and reported higher change scores on the Cognitive Function Index.Conclusions and relevanceAmong a large group of older individuals screening for an Alzheimer disease (AD) prevention trial, elevated brain amyloid was associated with family history and APOE ε4 allele but not with multiple other previously reported risk factors for AD. Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function. These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials aimed at slowing cognitive decline during the preclinical stages of AD.

Project description:Background: Suspected non-Alzheimer disease pathophysiology (SNAP) refers to the subjects who feature negative β-amyloid (Aβ) but positive tau or neurodegeneration biomarkers. It accounts for a quarter of the elderly population and is associated with cognitive decline. However, the underlying pathophysiology is still unclear. Methods: We included 111 non-demented subjects, then classified them into three groups using cerebrospinal fluid (CSF) Aβ 1-42 (A), phosphorylated tau 181 (T), and total tau (N). Specifically, we identified the normal control (NC; subjects with normal biomarkers, A-T-N-), SNAP (subjects with normal amyloid but abnormal tau, A-T+), and predementia Alzheimer's disease (AD; subjects with abnormal amyloid and tau, A+T+). Then, we used the static amplitude of low-frequency fluctuation (sALFF) and dynamic ALFF (dALFF) variance to reflect the intrinsic functional network strength and stability, respectively. Further, we performed a correlation analysis to explore the possible relationship between intrinsic brain activity changes and cognition. Results: SNAP showed decreased sALFF in left superior frontal gyrus (SFG) while increased sALFF in left insula as compared to NC. Regarding the dynamic metric, SNAP showed a similarly decreased dALFF in the left SFG and left paracentral lobule as compared to NC. By contrast, when compared to NC, predementia AD showed decreased sALFF in left inferior parietal gyrus (IPG) and right precuneus, while increased sALFF in the left insula, with more widely distributed decreased dALFF variance across the frontal, parietal and occipital lobe. When directly compared to SNAP, predementia AD showed decreased sALFF in left middle occipital gyrus and IPG, while showing decreased dALFF variance in the left temporal pole. Further correlation analysis showed that increased sALFF in the insula had a negative correlation with the general cognition in the SNAP group. Besides, sALFF and dALFF variance in the right precuneus negatively correlated with attention in the predementia AD group. Conclusion: SNAP and predementia AD show distinct functional impairment patterns. Specifically, SNAP has functional impairments that are confined to the frontal region, which is usually spared in early-stage AD, while predementia AD exhibits widely distributed functional damage involving the frontal, parietal and occipital cortex.

Dataset Information

Heterogeneity in Suspected Non-Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals.

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Heterogeneity in Suspected Non-Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals.

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