Stephanie A. Schultz

Subjective memory complaints, cortical thinning, and cognitive dysfunction in middle-age adults at risk of AD

Subjective memory complaints (SMCs) represent an individuals perception of subtle changes in memory in the absence of objective impairment in memory. However, it is not fully known whether persons with SMCs harbor brain alterations related to Alzheimers disease (AD) or whether they indeed demonstrate poorer cognitive performance.

Effect of Cognitive Reserve on Age-Related Changes in Cerebrospinal Fluid Biomarkers of Alzheimer Disease.

IMPORTANCE Although advancing age is the strongest risk factor for the development of symptomatic Alzheimer disease (AD), recent studies have shown that there are individual differences in susceptibility to age-related alterations in the biomarkers of AD pathophysiology. OBJECTIVE To investigate whether cognitive reserve (CR) modifies the adverse influence of age on key cerebrospinal fluid (CSF) biomarkers of AD. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional cohort of 268 individuals (211 in a cognitively normal group and 57 in a cognitively impaired group) from the Wisconsin Registry for Alzheimers Prevention and the Wisconsin Alzheimers Disease Research Center participated in this study. They underwent lumbar puncture for collection of CSF samples, from which Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) were immunoassayed. In addition, we computed t-tau/Aβ42 and p-tau/Aβ42 ratios. Cognitive reserve was indexed by years of education, with 16 or more years taken to confer high reserve. Covariate-adjusted regression analyses were used to test whether the effect of age on CSF biomarkers was modified by CR. The study dates were March 5, 2010, to February 13, 2013. MAIN OUTCOMES AND MEASURES Cerebrospinal fluid levels of Aβ42, t-tau, p-tau, t-tau/Aβ42, and p-tau/Aβ42. RESULTS There were significant age × CR interactions for CSF t-tau (β [SE] = -6.72 [2.84], P = .02), p-tau (β [SE] = -0.71 [0.27], P = .01), t-tau/Aβ42 (β [SE] = -0.02 [0.01], P = .02), and p-tau/Aβ42 (β [SE] = -0.002 [0.001], P = .004). With advancing age, individuals with high CR exhibited attenuated adverse alterations in these CSF biomarkers compared with individuals with low CR. This attenuation of age effects by CR tended to be more pronounced in the cognitively impaired group compared with the cognitively normal group. There was evidence of a dose-response relationship such that the effect of age on the biomarkers was progressively attenuated given additional years of schooling. CONCLUSIONS AND RELEVANCE In a sample composed of a cognitively normal group and a cognitively impaired group, higher CR was associated with a diminution of age-related alterations in CSF biomarkers of AD. This suggests one pathway through which CR might favorably alter lifetime risk for symptomatic AD.

Occupational Complexity and Cognitive Reserve in a Middle-Aged Cohort at Risk for Alzheimer's Disease

Higher occupational attainment has previously been associated with increased Alzheimers disease (AD) neuropathology when individuals are matched for cognitive function, indicating occupation could provide cognitive reserve. We examined whether occupational complexity (OCC) associates with decreased hippocampal volume and increased whole-brain atrophy given comparable cognitive function in middle-aged adults at risk for AD. Participants (n = 323) underwent structural MRI, cognitive evaluation, and work history assessment. Three complexity ratings (work with data, people, and things) were obtained, averaged across up to 3 reported jobs, weighted by years per job, and summed to create a composite OCC rating. Greater OCC was associated with decreased hippocampal volume and increased whole-brain atrophy when matched for cognitive function; results remained substantively unchanged after adjusting for several demographic, AD risk, vascular, mental health, and socioeconomic characteristics. These findings suggest that, in people at risk for AD, OCC may confer resilience to the adverse effects of neuropathology on cognition.

AMYLOID BURDEN, CORTICAL THICKNESS, AND COGNITIVE FUNCTION IN THE WISCONSIN REGISTRY FOR ALZHEIMER'S PREVENTION

There is a growing interest in understanding how amyloid-β (Aβ) accumulation in preclinical Alzheimers disease relates to brain morphometric measures and cognition. Existing investigations in this area have been primarily conducted in older cognitively-normal (CN) individuals. Therefore, not much is known about the associations between Aβ burden, cortical thickness, and cognition in midlife. We examined this question in 109, CN, late-middle-aged adults (mean age=60.72±5.65 years) from the Wisconsin Registry for Alzheimers Prevention. They underwent Pittsburgh Compound B (PiB) and anatomical magnetic resonance (MR) imaging, and a comprehensive cognitive exam. Blinded visual rating of the PiB scans was used to classify the participants as Aβ+ or Aβ-. Cortical thickness measurements were derived from the MR images. The Aβ+ group exhibited significant thinning of the entorhinal cortex and accelerated age-associated thinning of the parahippocampal gyrus compared with the Aβ- group. The Aβ+ group also had numerically lower, but nonsignificant, test scores on all cognitive measures, and significantly faster age-associated cognitive decline on measures of Speed & Flexibility, Verbal Ability, and Visuospatial Ability. Our findings suggest that early Aβ aggregation is associated with deleterious changes in brain structure and cognitive function, even in midlife, and that the temporal lag between Aβ deposition and the inception of neurodegenerative/cognitive changes might be narrower than currently thought.

Cardiorespiratory fitness attenuates the influence of amyloid on cognition

The aim of this study was to examine cross-sectionally whether higher cardiorespiratory fitness (CRF) might favorably modify amyloid-β (Aβ)-related decrements in cognition in a cohort of late-middle-aged adults at risk for Alzheimers disease (AD). Sixty-nine enrollees in the Wisconsin Registry for Alzheimers Prevention participated in this study. They completed a comprehensive neuropsychological exam, underwent 11C Pittsburgh Compound B (PiB)-PET imaging, and performed a graded treadmill exercise test to volitional exhaustion. Peak oxygen consumption (VO2peak) during the exercise test was used as the index of CRF. Forty-five participants also underwent lumbar puncture for collection of cerebrospinal fluid (CSF) samples, from which Aβ42 was immunoassayed. Covariate-adjusted regression analyses were used to test whether the association between Aβ and cognition was modified by CRF. There were significant VO2peak*PiB-PET interactions for Immediate Memory (p=.041) and Verbal Learning & Memory (p=.025). There were also significant VO2peak*CSF Aβ42 interactions for Immediate Memory (p<.001) and Verbal Learning & Memory (p<.001). Specifically, in the context of high Aβ burden, that is, increased PiB-PET binding or reduced CSF Aβ42, individuals with higher CRF exhibited significantly better cognition compared with individuals with lower CRF. In a late-middle-aged, at-risk cohort, higher CRF is associated with a diminution of Aβ-related effects on cognition. These findings suggest that exercise might play an important role in the prevention of AD.

Cardiorespiratory fitness alters the influence of a polygenic risk score on biomarkers of AD

Objective: To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers. Methods: Ninety-five individuals from the Wisconsin Registry for Alzheimers Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. β-Amyloid 42 (Aβ42), Aβ40, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Aβ42/Aβ40 and tau/Aβ42 ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRS×CRF term in the models, we examined whether these associations were modified by CRF. Results: A higher PRS was associated with lower Aβ42/Aβ40 (p < 0.001), higher t-tau/Aβ42 (p = 0.012), and higher p-tau/Aβ42 (p = 0.040). Furthermore, we observed PRS × CRF interactions for Aβ42/Aβ40 (p = 0.003), t-tau/Aβ42 (p = 0.003), and p-tau/Aβ42 (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF. Conclusions: In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD.

Relationships between cardiorespiratory fitness, hippocampal volume, and episodic memory in a population at risk for Alzheimer's disease

Cardiorespiratory fitness (CRF) has been shown to be related to brain health in older adults. In individuals at risk for developing Alzheimers disease (AD), CRF may be a modifiable risk factor that could attenuate anticipated declines in brain volume and episodic memory. The objective of this study was to determine the association between CRF and both hippocampal volume and episodic memory in a cohort of cognitively healthy older adults with familial and/or genetic risk for Alzheimers disease (AD).

Meeting physical activity recommendations may be protective against temporal lobe atrophy in older adults at risk for Alzheimer's disease

Physical activity (PA) is associated with brain health in older adults. However, it is unknown whether the current physical activity recommendations (PAR) impart substantive benefit. The objective of this study was to compare temporal lobe volumes between older adults who met PAR and those who did not.

BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention

Objective: To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. Methods: One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimers Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. Results: Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline (p = 0.033). Conclusions: In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics.

Moderate Physical Activity is Associated with Cerebral Glucose Metabolism in Adults at Risk for Alzheimer’s Disease

The objective of this study was to investigate the relationship between accelerometer-measured physical activity (PA) and glucose metabolism in asymptomatic late-middle-aged adults. Ninety-three cognitively healthy late-middle-aged adults from the Wisconsin Registry for Alzheimers Prevention participated in this cross-sectional study. They underwent 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and wore an accelerometer (ActiGraph GT3X+) to measure free-living PA. Accelerometer data yielded measures of light (LPA), moderate (MPA), and vigorous (VPA) intensity PA. FDG-PET images were scaled to the cerebellum and pons, and cerebral glucose metabolic rate was extracted from specific regions of interest (ROIs) known to be hypometabolic in AD, i.e., hippocampus, posterior cingulate, inferior temporal cortex, and angular gyrus. Regression analyses were utilized to examine the association between PA and glucose metabolism, while adjusting for potential confounds. There were associations between MPA and glucose metabolism in all ROIs examined. In contrast, LPA was not associated with glucose uptake in any ROI and VPA was only associated with hippocampal FDG uptake. Secondary analyses did not reveal associations between sedentary time and glucose metabolism in any of the ROIs. Exploratory voxel-wise analysis identified additional regions where MPA was significantly associated with glucose metabolism including the precuneus, supramarginal gyrus, amygdala, and middle frontal gyrus. These findings suggest that the intensity of PA is an important contributor to neuronal function in a late-middle-aged cohort, with MPA being the most salient. Prospective studies are necessary for fully elucidating the link between midlife engagement in PA and later life development of AD.