Complex, late-onset diseases such as Alzheimer’s Disease (AD) are influenced by a multitude of heterogeneous factors, including genetic predispositions, environmental effects, lifestyle choices, and chronic physiological conditions. AD, recognized increasingly as a heterogeneous disorder, presents with varied manifestations in its prodromal stage, accompanied by diverse comorbidities, and a range of onset and progression patterns. Concurrently, the molecular heterogeneity underlying AD is also becoming better documented, revealing the involvement of specific cell-types and cellular programs. However, the integration of the expanding molecular markers with environmental and lifestyle factors remains a challenge.
Our research focuses on the following key questions and aims: (1) To integrate AD/dementia-related genetic markers with descriptors of early-life adversities, environmental factors, inflammation, and metabolomic profiles, particularly lipidomic markers, to identify prodromal signatures and complex markers of dementias and AD using UK Biobank data; (2) To stratify patients with subjective or mild cognitive impairment, dementia, and AD using these integrated signatures; (3) To explore the role of related multimorbidities in the signatures; (4) To delineate healthy aging process by utilizing biological aging clocks; (5) To validate these signatures using independent cohorts and animal experiments from the AD-focused SOLID project.