Effect of APOE ε4 Genotype on Metabolic Biomarkers in Aging and Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) may have heterogeneous pathophysiological underpinnings, with risk factors including apolipoprotein ε4 (APOE4) genotype and insulin resistance. We hypothesized that distinct phenotypes exist within AD. We examined APOE4 and metabolic biomarkers in 338 subjects (n=213 nondemented (ND), n=125 AD). We further characterized steady state free fatty acid (FFA) levels in a subset of 45 participants who had also participated in a hyperinsulinemic-euglycemic clamp. Insulin resistance (HOMA-IR) was elevated in AD vs ND (p=0.04) and in APOE4 noncarriers vs.carriers (p<0.01). This was driven by increased fasting insulin in AD vs. ND (p<0.01) and in APOE4 non-carriers vs carriers (p=0.01). Fasting glucose was not different. In subjects who underwent a clamp, there was a group x genotype interaction on FFA levels during hyperinsulinemia (p=0.03). APOE4 non-carriers with AD had higher FFA levels, while APOE4 carriers with AD exhibited lower FFA levels. Metabolic dysfunction is overrepresented in individuals with AD dementia who do not carry the APOE4 allele. This suggests that important subsets of AD phenotypes may exist that diverge metabolically.

APOEgenotype affects metabolic and Alzheimer‐related outcomes induced by Western diet in female EFAD mice

“…Although obesity and associated metabolic impairments are established risk factors for the development of AD (16), the extent to which APOE genotype impacts this relationship continues to be determined. There are reports that obesity increases AD risk specifically in APOE4 carriers (51,52), however most studies find that the relationship between metabolic impairments and AD risk is strongest in APOE4 noncarriers (28,(53)(54)(55)(56)(57). For example, risk of AD was reported as increased by either being overweight or having type 2 diabetes specifically in APOE4 noncarriers (55).…”

“…Obesity is a key factor in driving metabolic dysfunction that, in turn, has been identified as a central mechanism by which obesity promotes neural impairment and development of AD (23,24). Accumulating evidence identifies roles of APOE in the regulation of obesity (25) and various aspects of metabolic function systemically and in brain (26)(27)(28). Interestingly, both APOE4 (29,30) and obesity (31) increase inflammation, which has been implicated in AD pathogenesis (32).…”

Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies

“…In the CSF, increased levels of insulin are associated with increased levels of total tau and phosphorylated tau among APOE*ε4 noncarriers 207 . Fasting plasma insulin levels and free fatty acid levels are also increased in APOE*ε4 non-carriers 208 .…”

The Aging Metabolome—Biomarkers to Hub Metabolites

“…[ 21 ] One of the exciting insights that has emerged from these longevity studies is the association between the APOE4 genotype and aging. [ 22,23 ] Subjects with APOE4 genotype have substantially decreased extreme longevity unlike subjects with E2E3 genotype. [ 24 ] Though increased risk of AD pathology conferred by the APOE4 genotype has been studied, the basal metabolomic differences on “normal” aging remain to be elucidated and represent a significant opportunity.…”