Alzheimer’s disease (AD) predominantly occurs as a late onset (LOAD) form involving neurodegeneration and cognitive decline with progressive memory loss. Risk factors that include aging promote accumulation of AD pathologies, such as amyloid-beta and tau aggregates, as well as inflammation and oxidative stress. Homeostatic glial states regulate and suppress pathology buildup; inflammatory states exacerbate pathology by releasing pro-inflammatory cytokines. Multiple stresses likely induce glial senescence, which could decrease supportive functions and reinforce inflammation. In this perspective, we hypothesize that aging first drives AD pathology burden, whereafter AD pathology putatively induces glial senescence in LOAD. We hypothesize that increasing glial senescence, particularly local senescent microglia accumulation, sustains and drives perpetuating buildup and spread of AD pathologies, glial aging, and further senescence. We predict that increasing glial senescence, particularly local senescent microglia accumulation, also transitions individuals from healthy cognition into mild cognitive impairment and LOAD diagnosis. These pathophysiological underpinnings may centrally contribute to LOAD onset, but require further mechanistic investigation.

Lewy body‐involving diseases (LBD) are commonly associated with Parkinson's disease (PD) featuring voluntary movement inhibition, due to dopaminergic neuron dysfunction in the substantia nigra. PD is clinically tracked through Lewy bodies (LB), composed of insoluble α‐synuclein aggregates sequestered with organelles, particularly inside neurons. However, α‐synuclein pathology also appears in incidental LBD, Parkinson's disease dementia, and dementia with LB (DLB). Incomplete explanations address how these clinical pathologies interrelate, LBD etiology variability, and frequently overlapping α‐synuclein and Alzheimer's disease (AD) pathologies. We hypothesize that (1) chronic environmental insult exposure and (2) senescence(‐like) neuron accumulation contribute toward initiating and sustaining LBD; individual cell vulnerability determines either cell reactivity, death, or senescence in response to environmental insults. We predicate that parkinsonian and other neurodegenerative symptoms over LBD progression involve (3) co‐occurring AD pathologies, wherein dementia symptomology develops when synergistic glial senescence, tau hyperphosphorylation, and possible α‐synuclein aggregation reach into regions involved in AD progression.Highlights: Senescence burden is predicted to explain α‐synucleinopathy progression. Senescence and cell death are hypothesized to occur in α‐synucleinopathies. Sub‐apoptotic stress is proposed to induce senescence in α‐synucleinopathies. Neuronal senescence likely first spreads α‐synucleinopathies to new regions. Glial senescence likely underlies Parkinson's disease and Alzheimer's disease overlap.

Alzheimer's disease (AD) involves cognitive decline, possibly via multiple concurrent pathologies associated with iron accumulation. To investigate if iron accumulation in AD is more likely due to pathological iron‐rich compartments, or a compensatory response of iron within oligodendrocytes to disease progression, we sought to quantify iron‐rich staining (via Perl's diaminobenzidine; DAB). Healthy wild‐type (WT) and APP^Swe‐PS1Δe9 (APP‐PS1; amyloid‐beta overexpressing) male mice were examined during middle age, at 14 months. The frontal cortex, a brain region affected over the course of dementia progression, was investigated. Iron‐rich compartments were found across genotypes, including oligodendrocytes and immune cells at the blood–brain barrier, and exclusively amyloid plaques in the APP‐PS1 genotype. A semi‐automated approach was employed to quantify the staining intensity of iron‐rich compartments with light microscopy. Mouse frontal cortex of each genotype was also assessed qualitatively and ultrastructurally with scanning electron microscopy, to novelly discern and confirm iron‐rich staining (via Perl's DAB). We found parenchymal iron staining corresponding to oligodendrocytes, pericytes, astrocytes, microglia and/or infiltrating macrophages, and amyloid plaques; increased iron deposition and clustering were detected in middle‐aged male APP‐PS1 versus WT frontal cortex, supporting that AD pathology may involve greater brain iron levels and local clustering. Unexpectedly, iron‐rich cells were enriched at the central nervous system (CNS) interface and perivascular space in control and APP‐PS1 mouse models, with ultrastructural examination revealing examples of these cells loaded with many secretory granules containing iron. Together, our results provide novel exploration and confirmation of iron‐rich cells/compartments in scanning electron microscopy and reinforce literature that iron deposition is relatively increased in AD over healthy cognitive aging and involves greater local clusters of iron burden. Increased iron burden along the aging trajectory, regardless of cognitive status, may also be attributed to novelly discovered iron‐rich cells secreting granules along the CNS border. image

Alzheimer’s disease (AD) predominantly occurs as a late-onset form (LOAD), involving neurodegeneration and cognitive decline with progressive memory loss. Over time, risk factors and aging promote accumulation of well-known AD pathologies in oxidative stress, amyloid-beta and tau protein pathology, as well as inflammation. Homeostatic glial functions regulate and suppress these AD pathologies; however, other glial states involve increased pro-inflammatory cytokine release and further pathology accumulation. Different stresses can additionally induce cellular senescence, or an irreversible differentiation process resulting in decreased supportive functions and increased, pro-inflammatory cytokine release. While these pathophysiological underpinnings all contribute to LOAD, they require temporal and mechanistic integration. This perspective hypothesizes that when individuals have threshold senescent glia accumulation, they transition from healthy cognition into mild cognitive impairment and LOAD diagnosis. Particularly, senescent microglia are predicted to represent a final threshold required for the tau pathology burden and spreading that corresponds to sustained neurodegeneration and dementia severity. We first explore age-related decline in glia that promote increases in AD pathologies, and then discuss emerging evidence linking oxidative stress, neurons containing tau pathology, and amyloid-beta to microglia, oligodendrocyte progenitor cell, and astrocyte senescence. Our hypothesis proposes that senescent astrocytes and oligodendrocyte progenitors pressure microglia to phagocytose neurons containing tau pathology. The resulting senescent microglia would form neuritic plaques and induce paracrine senescence transitioning into a progressive clinical dementia presentation. This predictive hypothesis can potentially account for why medications used to treat LOAD fail, as previous treatments have not reduced senescent glial burden. It is also coherent with the predominant hypotheses surrounding LOAD, generates testable hypotheses about LOAD, and increases rationale in testing senolytics as targeted treatments for LOAD arrest and reversal.

Iron is essential in all cells, but paradoxically accumulates in various regions across neurodegenerative diseases including Multiple Sclerosis, Alzheimer’s disease, traumatic brain injuries, frontotemporal dementia, Amyotrophic Lateral Sclerosis, stroke, and Lewy bodies associated with Parkinson’s. Furthermore, neurodegenerative pathologies frequently co-exist or compound; when such pathologies threshold into clinical progression across (overlapping) neurodegenerative diseases remain unexplained. We propose a new unifying theory: localized iron accumulation facilitates chronic neurodegeneration, wherein location-specific and temporal iron accumulation result in individual and concurrent neurodegenerative diseases. Excess ferrous iron can trigger ferroptosis, while ferric iron stored in ferritin involves cellular senescence: complementary and self-sustaining processes promoting oxidative stress, mitochondrial and endolysosomal dysfunction, and other hallmarks involved in chronic neurodegeneration. Finally, our proposed ferroptotic-senescence axis novelly accounts for both singular and compound proteinopathies. Our theory highlights important, novel priorities for diagnostics to screen for concurrent neurodegenerative diseases, and therapeutics for targeting iron-driven cell death and senescence.