The effect of increased genetic risk for Alzheimer's disease on hippocampal and amygdala volume

Abstract

Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging is an early marker of Alzheimer’s disease (AD). Whether genetic risk factors for AD exert an effect on these subcortical structures independent of clinical status has not been fully investigated. We examine whether increased genetic risk for AD influences hippocampal and amygdala volumes in case-control and population cohorts at different ages, in 1674 older (aged >53 years; 17% AD, 39% mild cognitive impairment [MCI]) and 467 young (16–30 years) adults. An AD polygenic risk score combining common risk variants excluding apolipoprotein E (APOE), and a single nucleotide polymorphism in TREM2, were both associated with reduced hippocampal volume in healthy older adults and those with MCI. APOE ɛ4 was associated with hippocampal and amygdala volume in those with AD and MCI but was not associated in healthy older adults. No associations were found in young adults. Genetic risk for AD affects the hippocampus before the clinical symptoms of AD, reflecting a neurodegenerative effect before clinical manifestations in older adults.

APOE*E4Is Associated with Gray Matter Loss in the Posterior Cingulate Cortex in Healthy Elderly Controls Subsequently Developing Subtle Cognitive Decline

“…Consistent with previous reports in elderly controls, 15,18,20 no APOE genotyping-related effect was identified in the hippocampus and mesial temporal cortex in subjects with both sCON and dCON. In agreement with previous observations in this field, these observations indicate that the APOE*E4 allele detrimental effect in terms of structural changes and clinical progression becomes evident only in elderly individuals with significant cognitive deterioration (MCI) or clinically overt symptoms of dementia (early AD).…”

“…[15][16][17] Although higher cortical amyloid ␤ load and decreased metabolism in the above-mentioned areas were reported in the APOE*E4 allele, crosssectional MR imaging studies failed to identify consistent GM decreases associated with this genotype in elderly controls (for a review see Fouquet et al 44 ). The finding in the current investigation that APOE*E4 was related to GM loss in only the subsequently deteriorating but not in the cognitively stable groups might explain these partially conflicting results of previous studies, which typically do not include detailed neuropsychological assessment and follow-up.…”

“…However, negative data were also reported. 15,18,20 In younger APOE*E4 carriers, the results are also more ambiguous. Some studies demonstrated reduced GM in middle-aged 21 and young APOE*E4 carriers 22,23 compared with the other APOE allele carriers, whereas others reported no APOE*E4 effect throughout adulthood.…”

“…3,4 Cross-sectional structural MR imaging studies indicated reduced gray matter in elderly APOE*E4 carriers including healthy controls, subjective memory impairment, mild cognitive impairment (MCI), and AD. [5][6][7][8][9][10][11][12][13][14] In MCI and AD, the APOE*E4-related GM decrease seems to affect areas involved in AD pathology, notably the hippocampus, amygdala, and mesial temporal cortex [14][15][16][17] but also the left occipital, frontal, and anterior cingulate cortices. 14,18 In healthy elderly controls, the APOE*E4 effect on brain structure is less clear.…”

No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

“…Including the full polygenic score significantly improved prediction over use of APOE alone where including both APOE and PRS gave AUC = 78.2% [31]. Examples of the AD PRS based on the IGAP discovery analysis demonstrating genetic overlap with other traits include neuroimaging measures of subcortical brain volumes, plasma C-reactive protein, and lipids [32,33]. Finally, to confirm our findings using an alternative method, we used SNP effect concordance analysis (SECA) with only the discovery datasets, to examine whether SNPs found to be associated with the serum iron measures are enriched within associated SNPs with AD risk, and vice versa.…”