Amyloid and APOE ε4 interact to influence short-term decline in preclinical Alzheimer disease.
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ABSTRACT: Objective
To examine whether β-amyloid (Aβ) and APOE ε4 status independently contribute or interact to influence longitudinal cognitive decline in clinically normal older individuals (CN).Methods
Data from 490 CNs were aggregated across 3 observational cohort studies (Harvard Aging Brain Study, Alzheimer's Disease Neuroimaging Initiative, and Australian Imaging Biomarkers and Lifestyle Study of Ageing; median age = 75.0 years, 255 female), and the contributions of APOE ε4 and Aβ on longitudinal change over a median of 1.49 years were examined. Cognitive decline was assessed with the Mini-Mental State Examination (MMSE) and Logical Memory (immediate and delayed recall scores).Results
High Aβ participants were more likely to be APOE ε4+ than low Aβ participants. CNs who were both high Aβ and APOE ε4+ showed greater decline in Logical Memory immediate recall (p < 0.087), Logical Memory delayed recall (p < 0.024), and MMSE (p < 0.034) compared to all other groups (low Aβ/APOE ε4-, low Aβ/APOE ε4+, and high Aβ/APOE ε4-). No other pairwise contrast was significant for any cognitive measure.Conclusions
Clinically normal individuals who are APOE ε4+ and have high Aβ showed the highest cognitive decline. These results suggest that Aβ and APOE ε4 are not redundant contributors of decline in aging but rather interact to promote decline during the short follow-up period examined in this study. Longer follow-up periods will be essential to fully elucidate the influence of Alzheimer disease risk factors on cognitive decline in aging.
SUBMITTER: Mormino EC
PROVIDER: S-EPMC4035706 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC7518559 | biostudies-literature
Project description:Importance:Older age, high levels of ?-amyloid (A?), and the presence of the apolipoprotein E (APOE) ?4 allele are risk factors for Alzheimer disease (AD). However, the extent to which increasing age, A?, and ?4 are associated with memory decline remains unclear, and the age at which memory decline begins for A?-positive ?4 carriers and noncarriers has not been determined. Objective:To determine the association of age, A? level, and APOE ?4 with memory decline in a large group of cognitively healthy older adults. Design, Setting, and Participants:This longitudinal observational study included cognitively healthy older adults (age >60 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study from March 31, 2006, through March 31, 2017; of 1583 individuals enrolled, 1136 refused or were excluded owing to other criteria (eg, having mild cognitive impairment or AD). Participants underwent A? imaging in research clinics in Perth and Melbourne and more than 72 months of follow-up (at 18-month intervals). The association of age with memory was fitted to a quadratic model. Age was treated as a continuous, time-dependent variable. Exposures:?-Amyloid imaging using positron emission tomography, genotyping for APOE ?4, and longitudinal neuropsychological assessments of episodic memory during the 72-month follow-up. Main Outcomes and Measures:Episodic memory composite score. Results:Of the 447 participants, 203 (45.4%) were men and 244 (54.6%) were women; mean (SD) age was 72.5 (6.6) years. Equal proportions of female participants were observed in each A?-?4 group (24 of 51 A?-positive ?4 noncarriers [47.1%] ; 35 of 64 A?-negative ?4 carriers [54.7%]; 40 of 72 A?-positive ?4 carriers [55.6%]; and 145 of 260 A?-negative ?4 noncarriers [55.8%]). Adults with A? findings (mean [SD] age, 74.4 [6.8] years) were approximately 4 years older than those negative for A? (mean [SD] age, 69.8 [6.1] years). Memory decline diverged significantly from A?-negative ?4 noncarriers at an earlier age in A?-positive ?4 carriers (64.5 years) than in A?-positive ?4 noncarriers (76.5 years), such that by 85 years of age, A?-positive ?4 carriers performed approximately 1.5 SD units worse on the episodic memory composite than A?-negative ?4 noncarriers and approximately 0.8 SD units worse than A?-positive ?4 noncarriers. Memory performance of A?-negative ?4 carriers did not differ from that of the A?-negative ?4 noncarriers (estimate [SE], 0.001 [0.001]; t?=?0.526; P?=?.77). Conclusions and Relevance:Prior work has shown that A? and ?4 combine to influence memory decline in nondemented older adults. Results of this study indicate that increasing age may further exacerbate these effects. The estimates provided may be used to determine the risk of memory decline associated with A? and ?4 at each age.
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Project description:Recommendations for the diagnosis of preclinical Alzheimer disease (AD) have been formulated by a workgroup of the National Institute on Aging and Alzheimer's Association. Three stages of preclinical AD were described. Stage 1 is characterized by abnormal levels of ?-amyloid. Stage 2 represents abnormal levels of ?-amyloid and evidence of brain neurodegeneration. Stage 3 includes the features of stage 2 plus subtle cognitive changes. Stage 0, not explicitly defined in the criteria, represents subjects with normal biomarkers and normal cognition. The ability of the recommended criteria to predict progression to cognitive impairment is the crux of their validity.Using previously developed operational definitions of the 3 stages of preclinical AD, we examined the outcomes of subjects from the Mayo Clinic Study of Aging diagnosed as cognitively normal who underwent brain MRI or [(18)F]fluorodeoxyglucose and Pittsburgh compound B PET, had global cognitive test scores, and were followed for at least 1 year.Of the 296 initially normal subjects, 31 (10%) progressed to a diagnosis of mild cognitive impairment (MCI) or dementia (27 amnestic MCI, 2 nonamnestic MCI, and 2 non-AD dementias) within 1 year. The proportion of subjects who progressed to MCI or dementia increased with advancing stage (stage 0, 5%; stage 1, 11%; stage 2, 21%; stage 3, 43%; test for trend, p < 0.001).Despite the short follow-up period, our operationalization of the new preclinical AD recommendations confirmed that advancing preclinical stage led to higher proportions of subjects who progressed to MCI or dementia.
| S-EPMC3348848 | biostudies-other
Project description:.BackgroundGenetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer's disease.ObjectiveThe aim of this study was to assess whether the association was present in cognitively normal older adults.MethodsLongitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study.ResultsNo independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E (APOE) ɛ4 and rs11023139 in individuals with high amyloid-β burden. APOE ɛ4/rs11023139-A carriers declined significantly faster than APOE ɛ4/rs11023139-G_G carriers in measures of global cognition (p = 0.011) and verbal episodic memory (p = 0.020).ConclusionThese results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ4 cognitively normal older adults with a high neocortical amyloid-β burden.
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