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Association of ?-Amyloid and Apolipoprotein E ?4 With Memory Decline in Preclinical Alzheimer Disease.

ABSTRACT: 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.

SUBMITTER: Lim YY

PROVIDER: S-EPMC5933393 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Association of β-Amyloid and Apolipoprotein E ε4 With Memory Decline in Preclinical Alzheimer Disease.

Lim Yen Ying YY Kalinowski Pawel P Pietrzak Robert H RH Laws Simon M SM Burnham Samantha C SC Ames David D Villemagne Victor L VL Fowler Christopher J CJ Rainey-Smith Stephanie R SR Martins Ralph N RN Rowe Christopher C CC Masters Colin L CL Maruff Paul T PT

JAMA neurology 20180401 4

<h4>Importance</h4>Older age, high levels of β-amyloid (Aβ), and the presence of the apolipoprotein E (APOE) ε4 allele are risk factors for Alzheimer disease (AD). However, the extent to which increasing age, Aβ, and ε4 are associated with memory decline remains unclear, and the age at which memory decline begins for Aβ-positive ε4 carriers and noncarriers has not been determined.<h4>Objective</h4>To determine the association of age, Aβ level, and APOE ε4 with memory decline in a large group of ...[more]

PMID: 29356823

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Project description:As Alzheimer disease (AD) research moves to intervene in presymptomatic phases of the disease, we must develop outcome measures sensitive to the earliest disease-related changes.To demonstrate the feasibility of a cognitive composite outcome for clinically normal elderly participants with evidence of AD pathology using the ADCS Preclinical Alzheimer Cognitive Composite (ADCS-PACC). The ADCS-PACC combines tests that assess episodic memory, timed executive function, and global cognition. The ADCS-PACC is the primary outcome measure for the first clinical trial in preclinical AD (ie, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study).With the ADCS-PACC, we derive pilot estimates of amyloid-related decline using data from 2 observational studies conducted in North America and another conducted in Australia. The participants analyzed had normal cognition and mean ages of 75.81, 71.37, and 79.42 years across the 3 studies.For the 2 studies that collected data on A? levels (ADNI and AIBL), we estimate decline in a preclinical AD "A?-positive" placebo group and compare them with an "A?-negative" group. For the study that did not include data on A? levels (the ADCS Prevention Instrument [ADCS-PI] study), we grouped participants by the presence of APOE-?4 and by clinical progression.In ADNI, A?-positive participants showed more decline than did A?-negative participants with regard to the ADCS-PACC score at 24 months (mean [SE] difference, -1.239 [0.522] [95% CI, -2.263 to -0.215]; P?=?.02). In AIBL, the mean (SE) difference is significant at both 18 months (-1.009 [0.406] [95% CI, -1.805 to -0.213]; P?=?.01) and 36 months (-1.404 [0.452] [95% CI, -2.290 to -0.519]; P?=?.002). In the ADCS-PI study, APOE-?4 allele carriers performed significantly worse on the ADCS-PACC at 24 months (mean [SE] score, -0.742 [0.294] [95% CI, -1.318 to -0.165]; P?=?.01) and 36 months (-1.531 [0.469] [95% CI, -2.450 to -0.612]; P?=?.001). In the ADCS-PI study, cognitively normal participants who progress from a global Clinical Dementia Rating score of 0 are significantly worse on the ADCS-PACC than cognitively normal participants who are stable with a global Clinical Dementia Rating score of 0 at months 12, 24, and 36 (mean [SE] ADCS-PACC score, -4.471 [0.702] [95% CI, -5.848 to -3.094]; P?<?.001). Using pilot estimates of variance and assuming 500 participants per group with 30% attrition and a 5% ? level, we project 80% power to detect effects in the range of ??=?0.467 to 0.733 on the ADCS-PACC.Analyses of at-risk cognitively normal populations suggest that we can reliably measure the first signs of cognitive decline with the ADCS-PACC. These analyses also suggest the feasibility of secondary prevention trials.

Project description:Importance:The accumulation of aggregated ?-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging. Objective:To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content. Design, Setting, and Participants:Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including ?-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals. Main Outcomes and Measures:Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction. Results:The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/?-amyloid 42, suggesting that phosphorylated tau 181/?-amyloid 42 levels modulate age-related changes in myelin water fraction. Conclusions and Relevance:These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease's course and lead to new markers of efficacy for prevention and treatment trials.

Project description:An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD and MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy and adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function.

Project description:ImportancePositron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Observing their progressive accumulation in the brains of clinically normal older adults is critically important to understand the pathophysiologic cascade leading to AD and to inform the choice of outcome measures in prevention trials.ObjectiveTo assess the associations among Aβ, tau, and cognition, measured during different observation periods for 7 years.Design, setting, and participantsProspective cohort study conducted between 2010 and 2017 at the Harvard Aging Brain Study, Boston, Massachusetts. The study enrolled 279 clinically normal participants. An additional 90 individuals were approached but declined the study or did not meet the inclusion criteria. In this report, we analyzed data from 60 participants who had multiple Aβ and tau PET observations available on October 31, 2017.Main outcomes and measuresA median of 3 Pittsburgh compound B-PET (Aβ, 2010-2017) and 2 flortaucipir-PET (tau, 2013-2017) images were collected. We used initial PET and slope data, assessing the rates of change in Aβ and tau, to measure cognitive changes. Cognition was evaluated annually using the Preclinical Alzheimer Cognitive Composite (2010-2017). Annual consensus meetings evaluated progression to mild cognitive impairment.ResultsOf the 60 participants, 35 were women (58%) and 25 were men (42%); median age at inclusion was 73 years (range, 65-85 years). Seventeen participants (28%) exhibited an initial high Aβ burden. An antecedent rise in Aβ was associated with subsequent changes in tau (1.07 flortaucipir standardized uptake value ratios [SUVr]/PiB-SUVr; 95% CI, 0.13-3.46; P = .02). Tau changes were associated with cognitive changes (-3.28 z scores/SUVR; 95% CI, -6.67 to -0.91; P = .001), covarying baseline Aβ and tau. Tau changes were greater in the participants who progressed to mild cognitive impairment (n = 6) than in those who did not (n = 11; 0.05 SUVr per year; 95% CI, 0.03-0.07; P = .001). A serial mediation model demonstrated that the association between initial Aβ and final cognition, measured 7 years later, was mediated by successive changes in Aβ and tau.Conclusions and relevanceWe identified sequential changes in normal older adults, from Aβ to tau to cognition, after which the participants with high Aβ with greater tau increase met clinical criteria for mild cognitive impairment. These findings highlight the importance of repeated tau-PET observations to track disease progression and the importance of repeated amyloid-PET observations to detect the earliest AD pathologic changes.

Project description:ImportanceAlzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression.ObjectiveTo evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals.Design, setting, and participantsThis prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses.ExposuresBaseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort.Main outcomes and measuresThe primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion.ResultsAmong 171 Aβ-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time.Conclusions and relevanceIn this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.

Dataset Information

Association of ?-Amyloid and Apolipoprotein E ?4 With Memory Decline in Preclinical Alzheimer Disease.

Publications

Association of β-Amyloid and Apolipoprotein E ε4 With Memory Decline in Preclinical Alzheimer Disease.

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