APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging

Abstract

Objective: To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging.

Methods: Two hundred forty-one cognitively normal individuals, aged 45-88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta(42) (Abeta(42)), tau, and phosphorylated tau (ptau(181)). All individuals were genotyped for APOE.

Results: The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Abeta(42) appeared to begin earlier (18.2% of those aged 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Abeta(42) with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Abeta(42) levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau(181).

Interpretation: Increasing cerebral Abeta deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Abeta deposition may first be lowered CSF Abeta(42), followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.

Figure 1

Mean cortical binding potentials for Pittsburgh Compound-B (PIB) in 241 cognitively normal participants as a function of age at clinical assessment and of (A.) the presence (red squares) or absence (black squares) of the ε4 allele of Apolipoprotein E (APOE) or (B.) the presence (green squares) or absence (black squares) of the ε2 allele of APOE.

Figure 1

Mean cortical binding potentials for Pittsburgh Compound-B (PIB) in 241 cognitively normal participants as a function of age at clinical assessment and of (A.) the presence (red squares) or absence (black squares) of the ε4 allele of Apolipoprotein E (APOE) or (B.) the presence (green squares) or absence (black squares) of the ε2 allele of APOE.

Figure 2

Unadjusted associations with age at clinical assessment and the presence (red squares) or absence (black squares) of APOE4 in 168 cognitively normal participants for cerebrospinal fluid (CSF) measures of: A. amyloid-beta42 (Aβ₄₂); B. tau; and C. tau phosphorylated at the threonine 181 position (ptau₁₈₁).

Figure 2

Unadjusted associations with age at clinical assessment and the presence (red squares) or absence (black squares) of APOE4 in 168 cognitively normal participants for cerebrospinal fluid (CSF) measures of: A. amyloid-beta42 (Aβ₄₂); B. tau; and C. tau phosphorylated at the threonine 181 position (ptau₁₈₁).

Figure 2

Unadjusted associations with age at clinical assessment and the presence (red squares) or absence (black squares) of APOE4 in 168 cognitively normal participants for cerebrospinal fluid (CSF) measures of: A. amyloid-beta42 (Aβ₄₂); B. tau; and C. tau phosphorylated at the threonine 181 position (ptau₁₈₁).

Figure 3

Unadjusted associations with age at clinical assessment and the presence (green squares) or absence (black squares) of APOE2 in the CSF of 168 cognitively normal individuals for CSF measures of A. Aβ₄₂; B. tau; and C. ptau₁₈₁.

Figure 3

Unadjusted associations with age at clinical assessment and the presence (green squares) or absence (black squares) of APOE2 in the CSF of 168 cognitively normal individuals for CSF measures of A. Aβ₄₂; B. tau; and C. ptau₁₈₁.

Figure 3

Unadjusted associations with age at clinical assessment and the presence (green squares) or absence (black squares) of APOE2 in the CSF of 168 cognitively normal individuals for CSF measures of A. Aβ₄₂; B. tau; and C. ptau₁₈₁.

Figure 4

A. Frequency by age group for individuals with MCBP for PIB >0.18 (“PIB-positive”) in 241 cognitively normal individuals as a function of the presence (red bars) or absence (black bars) of APOE4. B. Frequency by age group for individuals with CSF Aβ₄₂ <500pg/mL (“CSF Aβ₄₂ positive”) in 168 cognitively normal individuals as a function of the presence (red bars) or absence (black bars) of APOE4.

Figure 4

A. Frequency by age group for individuals with MCBP for PIB >0.18 (“PIB-positive”) in 241 cognitively normal individuals as a function of the presence (red bars) or absence (black bars) of APOE4. B. Frequency by age group for individuals with CSF Aβ₄₂ <500pg/mL (“CSF Aβ₄₂ positive”) in 168 cognitively normal individuals as a function of the presence (red bars) or absence (black bars) of APOE4.