Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer’s Disease Across Distinct Brain Regions

Alzheimer’s disease (AD) is a neurodegenerative disease with a complex etiology influenced by confounding factors such as genetic polymorphisms, age, sex, and race. Traditionally, AD research has not prioritized these influences, resulting in dramatically skewed cohorts such as three times the number of Apolipoprotein E (APOE) ε4-allele carriers in AD relative to healthy cohorts. Thus, the resulting molecular changes in AD have previously been complicated by the influence of apolipoprotein E disparities. To explore how apolipoprotein E polymorphism influences AD progression, 62 post-mortem patients consisting of 33 AD and 29 controls (Ctrl) were studied to balance the number of ε4-allele carriers and facilitate a molecular comparison of the apolipoprotein E genotype. Lipid and protein perturbations were assessed across AD diagnosed brains compared to Ctrl brains, ε4 allele carriers (APOE4+ for those carrying 1 or 2 ε4s and APOE4– for non-ε4 carriers), and differences in ε3ε3 and ε3ε4 Ctrl brains across two brain regions (frontal cortex (FCX) and cerebellum (CBM)). The region-specific influences of apolipoprotein E on AD mechanisms showcased mitochondrial dysfunction and cell proteostasis at the core of AD pathophysiology in the post-mortem brains, indicating these two processes may be influenced by genotypic differences and brain morphology

Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer’s Disease Across Distinct Brain Regions

Alzheimer’s disease (AD) is a neurodegenerative disease with a complex etiology influenced by confounding factors such as genetic polymorphisms, age, sex, and race. Traditionally, AD research has not prioritized these influences, resulting in dramatically skewed cohorts such as three times the number of Apolipoprotein E (APOE) ε4-allele carriers in AD relative to healthy cohorts. Thus, the resulting molecular changes in AD have previously been complicated by the influence of apolipoprotein E disparities. To explore how apolipoprotein E polymorphism influences AD progression, 62 post-mortem patients consisting of 33 AD and 29 controls (Ctrl) were studied to balance the number of ε4-allele carriers and facilitate a molecular comparison of the apolipoprotein E genotype. Lipid and protein perturbations were assessed across AD diagnosed brains compared to Ctrl brains, ε4 allele carriers (APOE4+ for those carrying 1 or 2 ε4s and APOE4– for non-ε4 carriers), and differences in ε3ε3 and ε3ε4 Ctrl brains across two brain regions (frontal cortex (FCX) and cerebellum (CBM)). The region-specific influences of apolipoprotein E on AD mechanisms showcased mitochondrial dysfunction and cell proteostasis at the core of AD pathophysiology in the post-mortem brains, indicating these two processes may be influenced by genotypic differences and brain morphology

SNPs associated with ILC (P<5×10⁻⁸) or LCIS (P<0.05) in a pooled lobular analysis (GLACIER and BCAC).

<p>SNPs associated with ILC (P<5×10⁻⁸) or LCIS (P<0.05) in a pooled lobular analysis (GLACIER and BCAC).</p

rs11977670, chromosome 7:139942304 G>A, and association ILC in populations of European ancestry.

<p>rs11977670, chromosome 7:139942304 G>A, and association ILC in populations of European ancestry.</p

Forest plot for rs11977670.

<p>Forest plot for rs11977670.</p

SNPs showing differential lobular and ductal associations with breast cancer risk in BCAC subjects (ER+ tumours only).

<p>SNPs showing differential lobular and ductal associations with breast cancer risk in BCAC subjects (ER+ tumours only).</p

Association with risk of breast cancer for rs11977670 stratified by breast cancer tumour subtypes (Pooled analysis, BCAC, GLACIER, UK PHASE II).

<p>Association with risk of breast cancer for rs11977670 stratified by breast cancer tumour subtypes (Pooled analysis, BCAC, GLACIER, UK PHASE II).</p

Lobular cancer study design.

<p>Lobular cancer study design.</p