Alzheimer’s disease progresses due to brain cell deterioration and death. Its phenotypic risks are the age of onset, hippocampal volume, and cortical area and volume. Vascular brain injury (VBI), neurofibrillary tangles, neuritic plaques, and cerebrospinal fluid (CSF) levels are also problematic. This study evaluates the CSF levels of Aβ42, tau, and ptau181, along with various other such risk factors.

The study group comprises 26431 AD cases and controls. Polygenic risk scores(PRS) are computed using logistic regression and two-sample Mendelian randomization(MR) techniques. They evaluated and inferred the causal effects of risk factors on the AD phenome.

The PRS for an increase in education (exposure variable) and diastolic BP reduced AD risk. MR study causally associated education with lower AD. It is also associated with delayed AAOS and increased cortical surface area and thickness. Diastolic BP and pulse pressure increase VBI risk. At the same time, total and LDL cholesterol levels increase neuritic plaques. The other associations were total cholesterol with decreased hippocampal volume and smoking with decreased cortical thickness. Also, type 2 diabetes led to early AAOS, while sleep duration was linked to cortical thickness.

The MR and PRS examinations are comprehensive and supportive. They affirm the causal role of education, BP, smoking, diabetes, and cholesterol levels with the AD phenome.