APOE and BDNF polymorphisms moderate amyloid β-related cognitive decline in preclinical Alzheimer’s disease

Abstract

Accumulation of β-amyloid (Aβ) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ɛ4 carrier[ɛ4+], ɛ4 non-carrier[ɛ4−]) and brain-derived neurotrophic factor (BDNFVal/Val, BDNFMet) in the extent to which they moderate Aβ-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aβ neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aβ positron emission tomography neuroimaging was used to classify participants as Aβ− or Aβ+. Relative to Aβ−ɛ4−, Aβ+ɛ4+ individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40–1.22), while Aβ+ɛ4− individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aβ−ɛ4− and Aβ−ɛ4+ groups. Among Aβ+ individuals, ɛ4+/BDNFMet participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ɛ4−/BDNFVal/Val participants (d=0.90–1.02). At least two genetic loci affect the rate of Aβ-related cognitive decline. Aβ+ɛ4+/BDNFMet individuals can expect to show clinically significant memory impairment after 3 years, whereas Aβ+ɛ4+/BDNFVal/Val individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aβ− and Aβ+ ɛ4− groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.

BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

“…We have also reported that in preclinical sporadic Alzheimer's disease, the APOE "4 allele increases the rate of memory decline and brain volume loss associated with high amyloid-b (Dore et al, 2013;Lim et al, 2014aLim et al, , 2015c. We have also observed that amyloid-b + older adults who carry both the APOE "4 and BDNF Met 66 allele show greater memory decline than those who carry either one by itself (Lim et al, 2015b). Reanalysis of the current data taking into account APOE "4 did not indicate any effect of APOE or any interaction between APOE and BDNF on cognition (Table 3).…”

“…We also explored the extent to which carriage of the BDNF Met 66 allele was associated with domains of cognition beyond episodic memory, neuronal function in the precuneus and CSF biomarkers of amyloid-b 1-42 and phosphorylated tau (p-tau 181 ). Finally, while the apolipoprotein E (APOE) "4 allele does not increase severity of clinical presentation in ADAD (Ryman et al, 2014), we observed previously additive effects of the BDNF Met 66 and APOE "4 alleles on amyloid-b-related cognitive decline in preclinical sporadic Alzheimer's disease (Lim et al, 2015b). Therefore, we also explored the extent to which APOE acts independently, or with BDNF, to impact disease processes in ADAD.…”

Association of Brain-Derived Neurotrophic Factor (BDNF) Gene Snps G196A and C270T with Alzheimer’s Disease: A Meta-Analysis

“…After careful review, finally, 39 potential studies were included. According to our inclusion criteria, four studies have not been included for estimating OR and 95% CI because they did not reported genotypic frequency of patients and healthy controls [28,29]. Finally, 39 eligible studies involving 9409 cases and 9522 controls were enrolled in the pooled analyses.…”

The Roles of Genetics in Aβ related Alzheimer's Diseases

“…In the mice blood-brain barrier (BBB) model, it has been shown that Apo-E allele undermines the clearance of neurotoxic Aβ peptides (destructive effects: Apo-E4 is greater than that of the Apo-E3 and Apo-E2) [47]. In this context, Aβ peptides bind to Apo-E4, resulting in a rapid removal of free Aβ 1-40 / Aβ .…”

“…3, using the florbetapir (18F-FDG) positron emission tomography (PET) imaging technique, it has been shown that the APOE alleles in chromosome 19 and butyrylcholinesterase (BCHE) can be regarded as Aβ peptide deposition regulator [47]. In cognitively normal AD patients, the cortex glucose metabolism rate (CMRgI) is significantly reduced for Apo-E ε4 carrier [ε4 +], especially in the front frontal lobe, parietal lobe, temporal lobe and posterior cingulate regions [48][49][50][51][52].…”