UC San Diego

Historically, a clinical diagnosis of Alzheimer’s disease could only be confirmed upon the discovery of β-amyloid plaques and tau tangles post-mortem. Today, biomarkers (imaging and biofluid measurements of β-amyloid, tau, and neurodegeneration) are being used to define the disease in vivo. Chapter 1 of this dissertation examines the long-term performance of baseline cognitive, neuroimaging, and cerebrospinal fluid biomarker-assisted prognoses in patients with mild cognitive impairment. Concordant atrophy, memory impairment, and abnormal β-amyloid and tau was associated with the highest risk for conversion to dementia, while individuals with concordant negative risk remained stable for up to 11 years. These results suggest that baseline biomarker-assisted predictions of decline to dementia are stable over the long term, and that combinations of complementary biomarkers can improve the accuracy of these predictions. Though individuals with mild cognitive impairment are still in the prodromal stages of clinical Alzheimer’s disease, converging evidence suggests the pathologic changes underlying Alzheimer’s disease begin up to 15 years before cognitive impairment. Chapter 2 of this dissertation tests whether the combination of the polygenic and age-specific risk for Alzheimer’s disease can predict elevated β-amyloid in clinically unimpaired individuals in order to enroll these individuals into preclinical Alzheimer’s disease trials. Alzheimer’s disease incidence rates and a polygenic hazard score were used to create a gene- and age-defined ADAge. The ADAge-enrichment screening method identified clinically unimpaired individuals with elevated β-amyloid and lowered screening costs in real-world preclinical Alzheimer’s disease trial data. These results demonstrate the utility of ADAge enrichment as a more efficient and cost-effective means to enroll clinically normal individuals with elevated β-amyloid in clinical trials. Clinically, distinctions between Alzheimer’s disease and related dementias are suboptimal and complicated by shared genetic risk factors and frequent co-pathology. Chapter 3 of this dissertation analyzes the utility of polygenic risk assessments for Alzheimer’s disease, dementia with Lewy bodies, and Parkinson’s disease to differentiate between individuals with distinct underlying pathologies. Polygenic scores were specifically associated with either dementia with Lewy bodies or Alzheimer’s disease pathology, indicating that an assessment of genetic risk may be useful to clinically distinguish between Alzheimer’s disease and dementia with Lewy bodies.