Project Summary/Abstract The proposed study will clarify whether accelerated biological aging at midlife predicts higher levels of preclinical AD biomarkers, as measured using a highly reliable plasma beta-amyloid (Aβ) marker. We will study 750 individual twins age 40-64 from the Louisville Twin Study (LTS) to test the hypothesis that accelerated aging contributes to Aβ accumulation and changes in cognitive functioning in midlife. We will locate and recruit the twins, conduct in-person cognitive functioning and physical assessments at the University of Louisville, and collect 50cc of blood from each twin to quantify biological age, plasma-Aβ, and to genotype them. Our ability to recruit twins to participate for a new phase of study is demonstrated in our 2018 Midlife Pilot Study, in which we collected cognitive ability, physical measurements, and blood to construct a biological aging measure. Preliminary results suggest that biological age is a better predictor of episodic memory than global functioning, consistent with prior research. The LTS is the only twin study capable of linking accelerated aging, Aβ accumulation, and cognitive functioning at midlife to cognitive functioning in early life, as other comparable longitudinal twin study samples are currently too young. We will address two research questions: 1) Do individuals with genetic and environmental predispositions for accelerated aging have greater Aβ accumulation and perform worse cognitively in midlife?; and 2) How do early life developmental characteristics influence biological aging, Aβ, and midlife cognitive functioning? To address these questions, we will complete the following specific aims: Quantify several markers of biological aging to test whether accelerated aging predicts Aβ accumulation and lower cognitive functioning at midlife by collecting biological, cognitive, memory, and functional ability data from LTS twins age 40-64 (Aim 1); Determine whether Aβ accumulation mediates effects of accelerated aging on diminished cognitive functioning, adjusting for confounding genetic and environmental factors (Aim 2); Evaluate effects of early life characteristics on accelerated aging, Aβ accumulation, and cognitive functioning in midlife, adjusting for confounding genetic and environmental factors (Aim 3). The proposed research is significant because it will specify causal effects of accelerated aging in midlife on Aβ accumulation and cognitive functioning, using blood-based aging measures to predict Aβ accumulation, and will investigate causal effects of early life developmental mechanisms on accelerated aging, Aβ accumulation, and cognitive functioning at midlife. The proposed work is innovative because of the novel application of a lifespan twin study, the capability of strengthening causal conclusions about the effects of accelerated aging on AD biomarkers in midlife when randomization is impossible; and because it will establish new standards for plasma-Aβ data collection in l...