IMPORTANCE Presently, the clinical standard for reporting the results of an amyloid positron emission tomography scan is to assign a dichotomous rating of positive or negative for the presence of amyloid. In a 4-year longitudinal study, we investigated whether using a continuous measure of the magnitude of baseline amyloid burden would provide valuable information about the rate of future cognitive decline over the subsequent 4 years compared with a dichotomous measure in middle-aged and older adults.OBJECTIVE To examine whether a continuous, dose-response relationship between amyloid burden and cognitive decline was present among middle-aged and older adults.DESIGN, SETTING, AND PARTICIPANTS This cohort study included 174 participants from the Dallas Lifespan Brain Study who were 40 to 89 years old at the beginning of the study, were cognitively normal at baseline (a Mini-Mental State Examination score of 26 or higher) with no history of neurological or psychiatric disorders, and had completed amyloid imaging ([F-18]-florbetapir) at baseline and cognitive assessments at baseline and a 4-year follow-up. Continuous amyloid burden was measured as the mean cortical standardized uptake value ratio (SUVR) at baseline.MAIN OUTCOMES AND MEASURES Linear mixed models assessed the effect of increasing baseline amyloid over time (SUVR x time interaction) on episodic memory, reasoning, processing speed, vocabulary, and Mini-Mental State Examination performance. Age, sex, education, apolipoprotein epsilon 4, and the random effect of intercepts were included as covariates.RESULTS The mean (SD) age for all participants (n = 174) was 66.44 (11.74) years, and 65 participants (37%) were men. The primary analyses yielded significant SUVR x time interactions in episodic memory, processing speed, vocabulary, and Mini-Mental State Examination performance, but not in reasoning performance. Higher baseline SUVR projected greater cognitive decline over 4 years. When controlling for variance related to a dichotomized positive/negative classification, most effects on cognition remained. Dichotomized amyloid status alone yielded fewer significant effects of amyloid on cognitive decline than continuous SUVR. Among amyloid-positive participants, increasing baseline SUVR predicted an increasing decline in episodic memory, but other effects on cognition were more limited. Finally, higher baseline amyloid burden among middle-aged adults was related to changes in vocabulary, with the effect driven by 3 apolipoprotein e4 homozygotes.CONCLUSIONS AND RELEVANCE These results suggest that the magnitude of amyloid burden at baseline is associated with the rate of cognitive decline over 4 years and potentially provides important information about the rate of future cognitive decline that is not available from a dichotomous positive/negative categorization.

Autopsy and amyloid PET imaging studies have consistently demonstrated that amyloid pathology is present in many non-demented older adults. Consequently, it has become critical to differentiate normal age-related cognitive decline from decline due to AD pathology. To help disentangle these two processes, we examined the effects of age and amyloid deposition on 3.5-year longitudinal cognitive changes across multiple domains in healthy adults, using data from the Dallas Lifespan Brain Study. Participants (n=98, age=55-89) who completed amyloid imaging (f-18-Florbetapir) at baseline and cognitive assessments at baseline and 3.5-year follow-up were included. Linear Mixed Model analyses were performed with Age, Amyloid status (positive or negative at baseline), and Time (Baseline or Follow-up) as independent variables and construct-based measures of processing speed, fluid reasoning, episodic memory, and crystallized knowledge as dependent variables, while controlling for sex, education, and APOE4 status. All interaction terms were also tested. We found an Amyloid × Time interaction on episodic memory and crystallized knowledge, such that individuals who were amyloid positive at baseline showed significant decline on these measures over a 3.5-year interval, while amyloid negative individuals remained stable (Figure 1). Importantly, chronological age was not associated with decline in episodic memory or crystallized knowledge during this interval. In contrast, for processing speed and reasoning, we found greater rates of decline over the 3.5-year interval at older ages (Figure 2), regardless of amyloid status. Episodic memory declined in amyloid positive but not amyloid negative healthy older adults, showing specificity of decline to this behavioral hallmark of AD. Amyloid positive but not amyloid negative adults additionally declined in crystallized knowledge, while aging alone did not have this effect. These findings highlight the potential predictive power of declining crystallized knowledge as a marker of preclinical AD, as crystallized knowledge normally remains stable throughout the adult lifespan. In contrast, declining processing speed and reasoning were associated with old age but not baseline amyloid. This suggests that decline in processing speed and reasoning over a relatively short time span may be characteristic of normal aging rather than Alzheimer’s disease, though further analyses are needed, particularly with longitudinal change in amyloid. Episodic memory and crystallized knowledge decline over 3.5 years in initially amyloid positive subjects but remain stable in amyloid negative. Processing speed and reasoning exhibit greater rates of decline over 3.5 years in 75-89 year olds than 55-74 years olds.

Autopsy and amyloid PET imaging studies have consistently demonstrated that amyloid pathology is present in many non-demented older adults. Consequently, it has become critical to differentiate normal age-related cognitive decline from decline due to AD pathology. To help disentangle these two processes, we examined the effects of age and amyloid deposition on 3.5-year longitudinal cognitive changes across multiple domains in healthy adults, using data from the Dallas Lifespan Brain Study. Participants (n=98, age=55-89) who completed amyloid imaging (f-18-Florbetapir) at baseline and cognitive assessments at baseline and 3.5-year follow-up were included. Linear Mixed Model analyses were performed with Age, Amyloid Status (positive or negative at baseline), and Time (Baseline or Follow-up) as independent variables and construct-based measures of processing speed, fluid reasoning, episodic memory, and crystallized knowledge as dependent variables, while controlling for sex, education, and APOE4 status. All interaction terms were also tested. We found an Amyloid×Time interaction on episodic memory and crystallized knowledge, such that individuals who were amyloid positive at baseline showed significant decline on these measures over a 3.5-year interval, while amyloid negative individuals remained stable (Figure 1). Additionally, we did not detect an effect of age on decline in episodic memory or crystallized knowledge. In contrast, for processing speed and reasoning, we found greater rates of decline over the 3.5-year interval at older ages (Figure 2), regardless of amyloid status. Episodic memory declined in amyloid positive but not amyloid negative healthy older adults, showing specificity of decline to this behavioral hallmark of AD. Amyloid positive but not amyloid negative adults additionally declined in crystallized knowledge, while aging alone did not have this effect. These findings highlight the potential predictive power of declining crystallized knowledge as a marker of preclinical AD, as crystallized knowledge normally remains stable throughout the adult lifespan. In contrast, declining processing speed and reasoning were associated with old age but not baseline amyloid. This suggests that decline in processing speed and reasoning over a relatively short time span may be characteristic of normal aging rather than Alzheimer’s disease, though further analyses are needed, particularly with longitudinal change in amyloid. Episodic memory and crystallized knowledge decline over 3.5 years in initially amyloid positive subjects but remain stable in amyloid negative. Processing speed and reasoning exhibit greater rates of decline over 3.5 years in 75-89 year olds than 55-74 year olds.

Importance: Identifying risk factors for increased beta-amyloid (A beta) deposition is important for targeting individuals most at risk for developing Alzheimer disease and informing clinical practice concerning prevention and early detection.Objective: To investigate risk factors for A beta deposition in cognitively healthy middle-aged and older adults. Specifically, we hypothesized that individuals with a vascular risk factor such as hypertension, in combination with a genetic risk factor for Alzheimer disease (apolipoprotein E epsilon 4 allele), would show greater amyloid burden than those without such risk.Design: Cross-sectional study.Setting: General communityParticipants: One hundred eighteen well-screened and cognitively normal adults, aged 47 to 89 years. Participants were classified in the hypertension group if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic, as measured across 7 occasions at the time of study.Intervention: Participants underwent A beta positron emission tomography imaging with radiotracer fluorine 18-labeled florbetapir. Participants were genotyped for apolipoprotein E and were classified as epsilon 4(+) or epsilon 4(-).Main Outcome Measure: Amyloid burden.Results: Participants in the hypertension group with at least 1 e4 allele showed significantly greater amyloid burden than those with only 1 risk factor or no risk factors. Furthermore, increased pulse pressure was strongly associated with increased mean cortical amyloid level for subjects with at least 1 e4 allele.Conclusions and Relevance: Vascular disease is a prevalent age-related condition that is highly responsive to both behavioral modification and medical treatment. Proper control and prevention of risk factors such as hypertension earlier in the life span may be one potential mechanism to ameliorate or delay neuropathological brain changes with aging.

Previous studies have found that cortical responses to different stimuli become less distinctive as people get older. This age-related dedifferentiation may reflect the broadening of the tuning curves of category-selective neurons (broadening hypothesis) or it may be due to decreased activation of category-selective neurons (attenuation hypothesis). In this study, we evaluated these hypotheses in the context of the face-selective neural network. Over 300 participants, ranging in age from 20 to 89 years, viewed images of faces, houses, and control stimuli in a functional magnetic resonance imaging session. Regions within the core face network and extended face network were identified in individual subjects. Activation in many of these regions became significantly less face-selective with age, confirming previous reports of age-related dedifferentiation. Consistent with the broadening hypothesis, this dedifferentiation in the fusiform face area (FFA) was driven by increased activation to houses. In contrast, dedifferentiation in the extended face network was driven by decreased activation to faces, consistent with the attenuation hypothesis. These results suggest that age-related dedifferentiation reflects distinct processes in different brain areas. More specifically, dedifferentiation in FFA activity may be due to broadening of the tuning curves for face-selective neurons, while dedifferentiation in the extended face network reflects reduced face- or emotion-selective activity.

Beta-amyloid (Aβ) protein deposition is a marker of Alzheimer's Disease (AD) and a key component in theories of disease pathogenesis. Interestingly, research has shown that at least 20% of cognitively normal elderly evidence Aβ neuropathology; whether amyloid necessarily leads to dementia is an open question. Identification of the most salient risk factors which increase the likelihood for beta-amyloid deposition is an important part of targeting individuals who are most at risk and will promote an understanding of the modifications most likely to prevent neuropathological changes associated with AD. Therefore, we tested the hypothesis that individuals with vascular risk factors such as hypertension would show greater amyloid burden than those without such risk. We further hypothesized that vascular risk, in combination with a known genetic risk factor (APOE-ε4 allele), would show even greater amyloid deposition. Participants (117 well-screened and cognitively normal adults, ages 47-89 underwent Aβ PET imaging with radiotracer 18F-Florbetapir. Participants were genotyped for Apolipoprotein E and were classified as ε4+ or ε4-. Participants were classified in the Hypertension group if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 systolic/90 diastolic. Results revealed a significant Genetic Risk X Hypertension interaction, where participants with both hypertension and at least one e4 allele, showed significantly greater amyloid burden than those with only one risk factor or no risk factors. Secondary analyses showed that increases in pulse pressure were strongly associated with increases in mean cortical amyloid, especially in the genetic risk group. Thus, genetic risk alone did not confer a significantly higher risk for amyloid pathology, suggesting that it is important to consider genetic risk in the context of health factors. Vascular disease is a prevalent age-related condition that is highly responsive to both behavioral modification and medical treatment. Proper control and prevention of vascular risk earlier in the lifespan may ameliorate or delay future cognitive decline in older age.

Beta-amyloid (Aß) is a key component of Alzheimer's disease pathology, and previous reports suggest that ∼25% of cognitively healthy older adults have increased levels of amyloid. Relatively little is known about the cognitive consequences of amyloid deposition in healthy adults, or the magnitude of its effects on cognition. In the present study, we examined the relationship of amyloid burden to cognitive function in a large lifespan sample of healthy adults, beginning at age 30 up to age 89. We hypothesized that amyloid would exert a negative effect on cognition, but expected that a substantial amount of age-related decline would remain, even after effects due to amyloid deposition were controlled. 137 highly educated (mean 16.40 years), healthy adults (age 30-89, mean MMSE 29.28) screened against history of cardiovascular, neurological or psychiatric conditions were scanned on a Siemens ECAT HR scanner 50 min after injection of 370 MBq bolus of 18F-AV-45(Florbetapir) to image beta-amyloid deposition. PET data were spatially normalized to an AV-45 template and SUVRs extracted from 8 ROIs (normalized to cerebellum). Two cognitive tests measured each of four domains: processing speed, working memory, fluid reasoning and crystallized intelligence. In the full sample (controlling forage), as amyloid burden increased, decreases were observed in processing speed, working memory, and fluid reasoning but not crystallized intelligence. A subgroup of 25 individuals aged 60+ with marked amyloid elevation (exceeded the 95% CI) showed strong associations between level of amyloid and cognitive function: in these subjects, higher amyloid burden was associated with decreased speed (r = -.59), working memory (r = -.63), and reasoning (r = -.54), but not crystallized ability. Despite these effects, when we removed these subjects from the sample, strong age-related decline was still observed in low amyloid participants.