Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-ε4 significantly increases AD risk, APOE-ε3 is the most common gene variant, and APOE-ε2 protects against AD. However, the underlying mechanisms of APOE-ε4 on AD risk remains unclear, with APOE-ε4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-ε3/3 (n = 9) or APOE-ε4/4 (n = 10) participants with AD pathology and APOE-ε3/3 (n = 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-ε4/4-AD individuals compared to APOE-ε3/3-AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-ε3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-ε4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.

Background and Objectives:Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is present in ∼25% of older persons’ brains and is strongly associated with cognitive impairment. Hippocampal sclerosis (HS) pathology is often comorbid with LATE-NC, but the clinical and pathological correlates of HS in LATE-NC are not well understood.Methods:In this retrospective autopsy cohort study, data derived from the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data Set, which included neurological status, medical histories, and neuropathologic results. All autopsies were performed in 2014 or later. Among participants with LATE-NC, those who also had HS pathology were compared with those without HS with regard to candidate risk factors or common underlying diseases. Statistical significance was set at nominal p<0.05 in this exploratory study.Results:A total of 408 participants were included (n=221 were LATE+/HS-; n=145 were LATE+/HS+, and n=42 were LATE-/HS+). Most of the included LATE-NC+ participants were severely impaired cognitively (83.3% demented). Compared to HS- participants, LATE-NC+ participants with HS trended towards having worse cognitive status and scored lower on the “Personal Care” and “Orientation” domains (both p=0.03). Among LATE-NC+ participants with Braak NFT Stages 0-IV (n=88), HS+ participants were more impaired in the “Memory” and “Orientation” domains (both p=0.02). There were no differences (HS+ compared with HS-) in the proportion with clinical histories of seizures, stroke, cardiac bypass procedures, diabetes, or hypertension. The HS+ group lacking TDP-43 proteinopathy (n=42) were relatively likely to have had strokes (p=0.03). Comparing LATE-NC+ participants with or without HS, there were no differences in Alzheimer’s disease neuropathologies (Thal Aβ phases or Braak NFT stages) or Lewy body pathologies. However, the HS+ group was less likely to have amygdala-restricted TDP-43 proteinopathy (LATE-NC Stage 1) and more likely to have neocortical TDP-43 proteinopathy (LATE-NC Stage 3); p<0.001. LATE-NC+ brains with HS also tended to have more severe Circle of Willis atherosclerosis and arteriolosclerosis pathologies.Discussion:In this cohort skewed toward severely demented participants, LATE-NC+HS pathology was not associated with seizures or with Alzheimer’s-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy, and with more severe non-Aβ vessel wall pathologies.

Background: Obesity increases the risk for human abdominal aortic aneurysms (AAAs) and enhances Ang II (angiotensin II)–induced AAA formation in C57BL/6J mice. Obesity is also associated with increases in perivascular fat that expresses proinflammatory markers including SAA (serum amyloid A). We previously reported that deficiency of SAA significantly reduces Ang II–induced inflammation and AAA in hyperlipidemic apoE-deficient mice. In this study. we investigated whether adipose tissue-derived SAA plays a role in Ang II–induced AAA in obese C57BL/6J mice. Methods: The development of AAA was compared between male C57BL/6J mice (wild type), C57BL/6J mice lacking SAA1.1, SAA2.1, and SAA3 (TKO); and TKO mice harboring a doxycycline-inducible, adipocyte-specific SAA1.1 transgene (TKO-Tg fat ; SAA expressed only in fat). All mice were fed an obesogenic diet and doxycycline to induce SAA transgene expression and infused with Ang II to induce AAA. Results: In response to Ang II infusion, SAA expression was significantly increased in perivascular fat of obese C57BL/6J mice. Maximal luminal diameters of the abdominal aorta were determined by ultrasound before and after Ang II infusion, which indicated a significant increase in aortic luminal diameters in wild type and TKO-TG fat mice but not in TKO mice. Adipocyte-specific SAA expression was associated with MMP (matrix metalloproteinase) activity and macrophage infiltration in abdominal aortas of Ang II–infused obese mice. Conclusions: We demonstrate for the first time that SAA deficiency protects obese C57BL/6J mice from Ang II–induced AAA. SAA expression only in adipocytes is sufficient to cause AAA in obese mice infused with Ang II.