Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer’s disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer’s Project’s meta-analysis, we identified clusters of genes that grouped into pathways involved in β-amyloid (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging (PET) in 168 individuals, and cerebrospinal fluid (CSF) Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.

To determine the relationship between amyloid burden and neural function in healthy adults at risk for Alzheimer's Disease (AD), we used multimodal imaging with [C-11]Pittsburgh compound B positron emission tomography, [F-18]fluorodeoxyglucose, positron emission tomography, and magnetic resonance imaging, together with cognitive measurement in 201 subjects (mean age, 60.1 years; range, 46–73 years) from the Wisconsin Registry for Alzheimer's Prevention. Using a qualitative rating, 18% of the samples were strongly positive Beta-amyloid (Ab+), 41% indeterminate (Aβi), and 41% negative (Aβ–). Aβ+ was associated with older age, female sex, and showed trends for maternal family history of AD and APOE4. Relative to the Aβ– group, Aβ+ and Aβi participants had increased glucose metabolism in the bilateral thalamus; Aβ+ participants also had increased metabolism in the bilateral superior temporal gyrus. Aβ+ participants exhibited increased gray matter in the lateral parietal lobe bilaterally relative to the Aβ– group, and no areas of significant atrophy. Cognitive performance and self report cognitive and affective symptoms did not differ between groups. Amyloid burden can be identified in adults at a mean age of 60 years and is accompanied by glucometabolic increases in specific areas, but not atrophy or cognitive loss. This asymptomatic stage may be an opportune window for intervention to prevent progression to symptomatic AD.

Objective: To examine whether engagement in physical activity might favorably alter the agedependent evolution of Alzheimer disease (AD)-related brain and cognitive changes in a cohort of at-risk, late-middle-aged adults.Methods: Three hundred seventeen enrollees in the Wisconsin Registry for Alzheimer's Prevention underwent T1 MRI; a subset also underwent 11 C-Pittsburgh compound B-PET (n 5 186) and 18 F-fluorodeoxyglucose-PET (n 5 152) imaging. Participants' responses on a self-report measure of current physical activity were used to classify them as either physically active or physically inactive based on American Heart Association guidelines. They also completed a comprehensive neuropsychological battery. Covariate-adjusted regression analyses were used to test whether the adverse effect of age on imaging and cognitive biomarkers was modified by physical activity.Results: There were significant age 3 physical activity interactions for b-amyloid burden (p 5 0.014), glucose metabolism (p 5 0.015), and hippocampal volume (p 5 0.025) such that, with advancing age, physically active individuals exhibited a lesser degree of biomarker alterations compared with the physically inactive. Similar age 3 physical activity interactions were also observed on cognitive domains of Immediate Memory (p 5 0.042) and Visuospatial Ability (p 5 0.016). In addition, the physically active group had higher scores on Speed and Flexibility (p 5 0.002) compared with the inactive group. Conclusions:In a middle-aged, at-risk cohort, a physically active lifestyle is associated with an attenuation of the deleterious influence of age on key biomarkers of AD pathophysiology. However, because our observational, cross-sectional design cannot establish causality, randomized controlled trials/longitudinal studies will be necessary for determining whether midlife participation in structured physical exercise forestalls the development of AD and related disorders in later life. Animal models of Alzheimer disease (AD) show that physical exercise represents an efficacious means for favorably altering not only cognitive trajectories but also underlying pathophysiologic processes, including b-amyloid (Ab) burden, tau phosphorylation, and neuronal loss.