Developing Topics.

Abstract

Alzheimer's disease (AD) is associated with the accumulation of neuropathological beta-amyloid (Ab) plaques, which is thought to be caused by an imbalance between Ab overproduction and dysfunctional Ab clearance. Both animal and human studies have shown that increased cerebrospinal fluid (CSF) levels of Ab peptides, especially Ab-40 and Ab-38 due to their high solubility, may be indicative of overall Ab dysregulation in preclinical AD, years before pathological Ab plaques begin to aggregate. The apolipoprotein E (APOE) e4 allele, which is the strongest genetic risk factor for AD, has been linked to impaired Ab clearance and disruption of the amyloid precursor protein (APP) pathway that is responsible for Ab production. However, the association between early Ab dysregulation and other genetic risk variants remains understudied. Thus, we aimed to explore whether genetic risk for AD is related to early markers of Ab overproduction by examining associations between polygenic risk scores (PRS) and CSF Ab-40 and Ab-38 in an AD-vulnerable population. We selected 88 non-demented Veterans (Age: M = 68.22, SD = 3.75 years) from the Alzheimer's Disease Neuroimaging Initiative-Department of Defense (ADNI-DOD) database with available genetic markers and CSF measures for Ab-40 and Ab-38. Genetic propensity for AD was assessed using genome-wide PRS, both with and without the APOE region, employing a p-value threshold < 0.01. CSF Ab concentrations were measured using a 2D-UPLC-tandem mass spectrometry method outlined by ADNI-DOD. Partial spearman's correlations related PRS to CSF Ab-38 and Ab-40 levels adjusting for age. CSF Ab-40 levels were positively associated with PRS for AD (rhopartial = 0.22, p = 0.037). When variants in the APOE region were excluded from the score, the relationship between CSF Ab-40 and PRS remained significant (rhopartial = 0.23, p = 0.035). The relationship between PRS for AD and CSF Ab-38 levels was not significant, regardless of whether APOE regions were included in the score (all p's > 0.1). Genetic risk for AD may lead to early Ab overproduction, as evidenced by elevated CSF Ab levels, particularly Ab-40. Other genetic variants, in addition to APOE, may play an integral role in disrupting the APP pathway and dysregulating Ab production.