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's disease (AD) in cognitively normal aging.Methods-Two hundred and 41 cognitively normal individuals, age 45 to 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 (Aβ 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 Aβ 42 appear to begin earlier (18.2% of those age 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There is a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Aβ 42 with increased numbers of APOE4 alleles. Individuals with an APOE2 have no increase in MCBP with age and have higher CSF Aβ 42 levels than individuals without an APOE2 allele. There is no APOE4 or APOE2 effect on CSF tau or ptau 181 . NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptInterpretation-Increasing cerebral Aβ deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Aβ deposition may first be lowered CSF Aβ 42 , followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.Keywords preclinical Alzheimer's disease; Alzheimer's biomarkers; Aβ; amyloid imaging (PIB); APOE The concept of preclinical Alzheimer's disease (AD) postulates that AD lesions accumulate in the brain for years prior to the appearance of cognitive deficits or symptoms of dementia. 1 This concept developed from observations that densities of senile plaques (SPs) and neurofibrillary tangles (NFTs), sufficient to meet histopathologic criteria for AD, frequently are present in brains of individuals whose cognition at death was normal 2 -9 or stable.10 , 11 Preclinical AD assumes that AD neuropathology in cognitively normal individuals results in progressive neuronal deterioration and eventually will culminate in the clinical syndrome of dementia of the Alzheimer type (DAT), although the time to DAT may be influenced by variables such as an individual's degree of cognitive and brain "reserve".12 -14 To date, however, it is not known whether DAT is inevitable in preclinical AD. It remains possible that certain individuals with presumptive preclinical AD may never develop DAT, no matter how long they live. These biomarkers for AD may identify nondemented individuals at risk for developing DAT. In persons with mild cognitive impairment (MCI),28 progression to a clinical diagnosis of DAT is predicted by CSF Aβ 42 and tau levels and PIB findings.29 -31 Limited studies in cognitively normal older adults show that reduced levels of CSF Aβ 42...

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

“…One strength of the current study is that participants with a history of antidepressant use did not differ in age, sex, and ApoE status from participants with no antidepressant exposure. Increasing age and ApoE genetic background are the strongest known risk factors for AD and plaque load (33,48); thus it was critical that these parameters were controlled. A limitation of the current study is that, because participants were excluded if their clinical dementia rating (CDR) was greater than zero, antidepressant-treated participants with potential dementia or mild cognitive impairment would have been excluded, producing a selection bias.…”

“…A total of 186 cognitively normal participants were recruited into a study for imaging Aβ plaques in late life by PET imaging (32,33). Participants underwent PET Aβ imaging with Pittsburgh Compound B (PIB) and past use of antidepressant drugs was also ascertained (Table 1).…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…This has now been shown to be the case as evidenced by amyloid-imaging studies with Pittsburgh compound B as well as CSF studies using CSF Ab42 in which a decrease has been shown to indicate brain amyloid deposition. Cognitively normal apoE4-positive middle-aged and elderly individuals are much more likely to have brain amyloid (Reiman et al 2009;Morris et al 2010) and low CSF Ab42 (Sunderland et al 2004;Morris et al 2010) than apoE4-negative individuals. Further, apoE2-positive individuals rarely develop fibrillar Ab as defined by a positive amyloidimaging scan (Morris et al 2010).…”

“…Cognitively normal apoE4-positive middle-aged and elderly individuals are much more likely to have brain amyloid (Reiman et al 2009;Morris et al 2010) and low CSF Ab42 (Sunderland et al 2004;Morris et al 2010) than apoE4-negative individuals. Further, apoE2-positive individuals rarely develop fibrillar Ab as defined by a positive amyloidimaging scan (Morris et al 2010). Whereas human data supports the idea that apoE isoforms result in differential susceptibilty to Ab aggregation in the brain, animal studies utilizing genetically modified mice that develop Ab deposition and express human apoE isoforms show more directly that human apoE isoforms have a strong effect on the time of onset of Ab aggregation as well as the amount, location, and conformation of Ab in the brain.…”

Effect of Mild Cognitive Impairment and APOE Genotype on Resting Cerebral Blood Flow and its Association with Cognition

“…The apolipoprotein (APOE) e4 allele is a wellknown susceptibility gene for the development of late-onset AD, occurs in B15% to 20% of the population, and is estimated to account for B40% of AD cases (Devanand et al, 2005;Saunders et al, 1993). The APOE e4 allele has been linked to AD neuropathology (e.g., increases in amyloid b deposition, dysregulation of tau phosphorylation), as well as small vessel arteriolosclerosis and microinfarcts of the deep nuclei in autopsy-confirmed patients with AD, suggesting that the allele also has deleterious effects on cerebral microvascular integrity (Mahley et al, 1996;Morris et al, 2010;Tiraboschi et al, 2004;Yip et al, 2005).…”