title: Effect of APOE and CD33 on Cognitive Decline.
abstract: OBJECTIVE
  An Alzheimer's disease (AD) diagnosis is preceded by a long period of cognitive decline. We previously demonstrated increased risk of decline among individuals possessing one or more APOE ε4 alleles together with a family history of AD. The objective of this study is to investigate the possibility that such an increased risk might be due to AD risk genes with small effects in combination with APOE.
  
  
  METHODS
  Participants in the Health and Retirement Study (HRS) over the age of 65, who contributed DNA, and had two or more evaluations with an abbreviated version of the modified Telephone Interview for Cognitive Status (TICS-m) were eligible for the study (n = 7451). A genetic risk score (g-score) was derived using AD risk genes' meta-analyses data, assigning risk according to the number of risk alleles and summed over all the risk genes. Trajectories of cognitive function were modeled in four groups of Caucasian participants with and without one or more APOE ε4 alleles and either a high or low g-score: APOE ε4-/low g-score; APOE ε4-/high g-score; APOE ε4+/low g-score; and APOE ε4+/high g-score. Post hoc analyses evaluated interactions between individual genes and APOE.
  
  
  RESULTS
  Individuals in the APOE ε4+/high g-score group exhibited the greatest cognitive decline over time (p<.0001). This risk appeared to be greater than the sum of the effects of either high g-score or APOE ε4 alone. When gene interactions were individually tested with APOE, a statistically significant interaction with CD33 was discovered (p = 0.04) although the interaction was no longer significant when adjusted for multiple comparisons.
  
  
  CONCLUSIONS
  Individuals with multiple AD risk genes in addition to having one or more APOE ε4 alleles are at greater risk of cognitive decline than individuals with either APOE ε4 or a high genetic risk score. Among those with one or more APOE ε4 alleles, having one or more copies of the CD33 C (risk) allele may further increase the risk of cognitive decline.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America; Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Hayden
authors.affiliation: Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Neurology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lutz
authors.affiliation: Department of Biostatistics, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Maragatha
authors.initials: M
authors.lastname: Kuchibhatla
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Germain
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America; Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Neurology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Plassman
mesh_terms: D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics*; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; D063268:Sialic Acid Binding Ig-like Lectin 3