Advancements in Immunity and Dementia Research: Highlights from the 2023 AAIC Advancements: Immunity Conference.

The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell-mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated.

Three major effects of APOE on Aβ immunotherapy induced ARIA.

The targeting of amyloid-beta (Aβ) plaques therapeutically as one of the primary causes of Alzheimer's disease (AD) dementia has been an ongoing effort spanning decades. While some antibodies are extremely promising and have been moved out of clinical trials and into the clinic, most of these treatments show similar adverse effects in the form of cerebrovascular damage known as amyloid-related imaging abnormalities (ARIA). The two categories of ARIA are of major concern for patients, families, and prescribing physicians, with ARIA-E presenting as cerebral edema, and ARIA-H as cerebral hemorrhages (micro- and macro-).

Assessment of neurovascular uncoupling: APOE status is a key driver of early metabolic and vascular dysfunction.

Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection.

Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology.

Soluble Biomarkers of Cerebrovascular Pathologies.

Vascular contributions to cognitive impairment and dementia (VCID) is an all-encompassing term that describes cognitive impairment due to cerebrovascular origins. With the advancement of imaging and pathological studies, we now understand that VCID is often comorbid with Alzheimer disease. While researchers in the Alzheimer disease field have been working for years to establish and test blood-based biomarkers for Alzheimer disease diagnosis, prognosis, clinical therapy discovery, and early detection, blood-based biomarkers for VCID are in their infancy and also face challenges.

Assessment of Neurovascular Uncoupling: Status is a Key Driver of Early Metabolic and Vascular Dysfunction.

Background: Alzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein ε4 () being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection.

Methods: PET imaging was used to assess metabolism-perfusion in both sexes of aging C57BL/6J, and h mice, and were verified by transcriptomics, and immunopathology.

Alzheimer's disease and inflammatory biomarkers positively correlate in plasma in the UK-ADRC cohort.

Introduction: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia.

Methods: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer's Disease Research Center cohort. We evaluated six Alzheimer's disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform.

Vascular Considerations for Amyloid Immunotherapy.

Purpose Of Review: Amyloid beta (Aβ) plaque accumulation is a hallmark pathology contributing to Alzheimer's disease (AD) and is widely hypothesized to lead to cognitive decline. Decades of research into anti-Aβ immunotherapies provide evidence for increased Aβ clearance from the brain; however, this is frequently accompanied by complicated vascular deficits. This article reviews the history of anti-Aβ immunotherapies and clinical findings and provides recommendations moving forward.

ε4 and exercise interact in a sex-specific manner to modulate dementia risk factors.

Introduction: Apolipoprotein E () ε4 is the strongest genetic risk factor for Alzheimer's disease and related dementias (ADRDs), affecting many different pathways that lead to cognitive decline. Exercise is one of the most widely proposed prevention and intervention strategies to mitigate risk and symptomology of ADRDs. Importantly, exercise and ε4 affect similar processes in the body and brain.

The Genotype Drives Distinct Gene Signatures in the Cortex of Young Mice.

Introduction: Restrictions on existing mouse models have impacted research toward understanding the strongest genetic risk factor contributing to Alzheimer's disease (AD) and dementia, , by hindering observation of a key, common genotype in humans - . Human studies are typically underpowered to address allele risk as the genotype is rare, which leaves human and mouse research unsupported to evaluate the genotype on molecular and pathological risk for AD and dementia.

Methods: As a part of MODEL-AD, we created and validated new versions of humanized and mouse strains that, due to unrestricted breeding, allow for the evaluation of the genotype.

Corrigendum: Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2R47H.

[This corrects the article DOI: 10.3389/fnagi.2021.

Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H.

Late-onset Alzheimer's disease (AD; LOAD) is the most common human neurodegenerative disease, however, the availability and efficacy of disease-modifying interventions is severely lacking. Despite exceptional efforts to understand disease progression legacy amyloidogenic transgene mouse models, focus on disease translation with innovative mouse strains that better model the complexity of human AD is required to accelerate the development of future treatment modalities. LOAD within the human population is a polygenic and environmentally influenced disease with many risk factors acting in concert to produce disease processes parallel to those often muted by the early and aggressive aggregate formation in popular mouse strains.

Genetic basis of susceptibility to low-dose paraquat and variation between the sexes in Drosophila melanogaster.

Toxicant resistance is a complex trait, affected both by genetics and the environment. Like most complex traits, it can exhibit sexual dimorphism, yet sex is often overlooked as a factor in studies of toxicant resistance. Paraquat, one such toxicant, is a commonly used herbicide and is known to produce mitochondrial oxidative stress, decrease dopaminergic neurons and dopamine (DA) levels, and decrease motor ability.

A novel mouse model expressing human forms for complement receptors CR1 and CR2.

Background: The complement cascade is increasingly implicated in development of a variety of diseases with strong immune contributions such as Alzheimer's disease and Systemic Lupus Erythematosus. Mouse models have been used to determine function of central components of the complement cascade such as C1q and C3. However, species differences in their gene structures mean that mice do not adequately replicate human complement regulators, including CR1 and CR2.

Transcriptional profiling predicts running promotes cerebrovascular remodeling in young but not midlife mice.

Background: The incidence of dementia and cognitive decline is increasing with no therapy or cure. One of the reasons treatment remains elusive is because there are various pathologies that contribute to age-related cognitive decline. Specifically, with Alzheimer's disease, targeting to reduce amyloid beta plaques and phosphorylated tau aggregates in clinical trials has not yielded results to slow symptomology, suggesting a new approach is needed.

Meox2 Haploinsufficiency Accelerates Axonal Degeneration in DBA/2J Glaucoma.

Purpose: Glaucoma is a complex disease with major risk factors including advancing age and increased intraocular pressure (IOP). Dissecting these earliest events will likely identify new avenues for therapeutics. Previously, we performed transcriptional profiling in DBA/2J (D2) mice, a widely used mouse model relevant to glaucoma.