Neuroimmune contributions to Alzheimer’s disease: a focus on human data

Abstract

The past decade has seen the convergence of a series of new insights that arose from genetic and systems analyses of Alzheimer’s disease (AD) with a wealth of epidemiological data from a variety of fields; this resulted in renewed interest in immune responses as important, potentially causal components of AD. Here, we focus primarily on a review of human data which has recently yielded a set of robust, reproducible results that exist in a much larger universe of conflicting reports stemming from small studies with important limitations in their study design. Thus, we are at an important crossroads in efforts to first understand at which step of the long, multiphasic course of AD a given immune response may play a causal role and then modulate this response to slow or block the pathophysiology of AD. We have a wealth of new experimental tools, analysis methods, and capacity to sample human participants at large scale longitudinally; these resources, when coupled to a foundation of reproducible results and novel study designs, will enable us to monitor human immune function in the CNS at the level of complexity that is required while simultaneously capturing the state of the peripheral immune system. This integration of peripheral and central perturbations in immune responses results in pathologic responses in the central nervous system parenchyma where specialized cellular microenvironments composed of multiple cell subtypes respond to these immune perturbations as well as to environmental exposures, comorbidities and the impact of the advancing life course. Here, we offer an overview that seeks to illustrate the large number of interconnecting factors that ultimately yield the neuroimmune component of AD.

Chemotherapy promotes astrocytic response to Aβ deposition, but not Aβ levels, in a mouse model of amyloid and APOE

“…Glial activation is one of the original defining aspects of the AD pathological changes ( Alzheimer et al, 1995 ). Recent AD genetics ( Podlésny-Drabiniok et al, 2020 ) and detailed neuropathological analyses ( Perez-Nievas et al, 2013 ; Haage and De Jager, 2022 ) support the hypothesis that inflammation may contribute to risk of the onset of AD and to the progression to cognitive impairment. There may be CNS astrocytic pathways promoted by chemotherapy in response to the denser Aβ accumulations.…”

Genetic insights into the association between inflammatory bowel disease and Alzheimer’s disease

“…Greater genetic risk for IBD has a negative impact on the accumulation of tau proteinopathy, prioritizing a set of IBD risk alleles among which there may be a protective effect in relation to AD. This is an intriguing observation that will require more extensive dissection of IBD's polygenic architecture to understand what aspect may help to reduce the accumulation of tau proteinopathy, which has been clearly implicated as a target of microglia in human AD (51,52). This exercise integrating GWAS results with pertinent myeloid QTL data therefore offers an important insight that the many myeloid pathways implicated in IBD susceptibility should probably be deprioritized in relation to AD, focusing our attention on other pathways, particularly those that are more specific for the microglial context.…”

The emerging mechanism behind viral infections and extracellular vesicles hypotheses leading to neuroinflammation and Alzheimer's disease pathology

“…All these manifestations have been related to aging and Alzheimer's disease (AD). AD is currently the most common type of dementia, affecting more than 60 million people worldwide with an expected increase in the coming years 1,2 . Symptoms associated with AD and its related disorders are mainly due to hallmarks deposition including extracellular amyloid‐beta (Aβ) aggregations and intracellular tau proteins ending with severe brain damage 3 .…”