Associations between 5‐lipoxygenase activating protein (FLAP) genetic variation rs9551963 and Alzheimer’s disease phenotypes

Abstract

AbstractBackgroundLeukotrienes are inflammatory mediators, synthesized by 5‐lipoxygenase and its activating protein (FLAP), and their activity may play a role in Alzheimer’s disease (AD). In AD mouse models, inhibition of FLAP improved memory and reduced amyloid (Aβ) deposition. Single nucleotide polymorphisms (SNPs) of ALOX5AP, which encodes FLAP, have been implicated in ischemic stroke in humans. However, there is limited research on the relationship between ALOX5AP and AD. This longitudinal study investigated associations between the ALOX5AP SNP rs9551963 A/C and various AD phenotypes.MethodParticipants from the Alzheimer’s Disease Neuroimaging Initiative (phases GO, 2, and 3) diagnosed with AD, mild cognitive impairment (MCI), or clinically normal cognition (CN) were categorized as minor allele carriers (AC, CC) or non‐carriers (AA) of rs9551963. Mini Mental State Exam (MMSE) and Rey Auditory Verbal Learning Test (RAVLT) % forgetting were selected to assess cognition. Cerebrospinal fluid biomarkers and MRI brain volumetric data were also considered. Interactions between rs9551963 genotype and time (baseline, month 24, and month 48) were measured in mixed models. All models controlled for age, sex, and APOE e4 status; education and baseline intracranial volume were additional controls in cognitive and volumetric analyses respectively.ResultMinor allele carriers in the AD‐MCI Aβ‐positive group had worse decline on the MMSE (F1,297 = 5.33, p = 0.022, n = 521), and smaller volumes of whole brain (F1,146 = 7.13, p = 0.008, n = 408) and hippocampus (F1,132 = 6.38, p = 0.013, n = 377) over time that were not seen in other subgroups. In the AD subgroup, Aβ‐positive carriers had greater increases in RAVLT % forgetting scores (F1,135.5 = 6.19, p = 0.014, n = 158) and greater whole brain volume loss (F1,27.6 = 5.67, p = 0.024, n = 132), over time. These associations were not seen in Aβ‐negative participants.ConclusionMinor allele carriers of the ALOX5AP SNP rs9551963 who were Aβ‐positive showed greater loss of cognitive status and memory, and more hippocampal and whole brain atrophy, over time. These findings suggest a possible effect of leukotriene synthesis in the progression of AD.