Pivotal Paper of the Past: How Alzheimer's Disease got redefined (published 2021)
Alzheimer’s disease: Redefining pathophysiology with the goal of redirecting therapeutic intervention
Keywords: Lipid metabolism, neuroinflammation, lipid-associated microglia, disease-associated astrocytes, prion diseases
Executive summary
Alzheimer’s disease is proposed to be a multi-step process initiated by an inability to metabolize lipids adequately, that over time leads to adaptive responses that ultimately become detrimental. The first step in the cascade is microglial lipid accumulation and immune activation. Secondly, astrocytes are activated, disrupting normal function and driving amyloid beta accumulation. Failure to clear amyloid beta, and prionlike proliferation of pathologic proteins, including amyloid plaque and tau tangle formation, represent the end stage of the disease. A focus on early intervention; understanding mechanisms of CNS lipid dyshomeostasis; and identifying the key receptors, cytokines, and downstream messengers driving the destructive cascades are all expected to be critical to disease modification. In addition, establishing a deep neurologic reserve capacity, including increasing cognitive stimulation, maintaining vascular flow, and addressing the endocrine aging process, all have the potential to delay clinical presentation and slow progression of the disease.
Introduction
Though Alzheimer’s disease (AD), initially characterized over a century ago, is a global public health crisis inexorably on the rise, our ability to identify effective therapeutic interventions has been minimal. Throughout history, the “black box” nature of the brain only enabled understanding of the most obvious anatomical changes and basic biomarker assessments, leading to correlations that have been inappropriately linked to causation. In addition to limited and fragmented insights into the complex and interconnecting biologic pathways driving the disease, imprecision in diagnosis—specifically, grouping dementias despite dissimilarities—has contributed to slow progress. AD research has been frustrated by contradictory results due to the lack of laboratory methods capable of quantifying the complexity of a dynamic system where molecular activity may be either compensatory or pathologic at different time points. As a consequence, drug development has focused on the least metabolically dynamic and most pathologically apparent end-stage sequelae of the disease: amyloid plaques and tau tangles.
However, new methods of characterizing some of the dynamic actions and multiple phenoypes of microglia and astrocytes have emerged, and these, combined with observational data and genome-wide association studies, can characterize pathologic events earlier in the course of disease and redirect research toward a more productive and proactive path. Specifically, 3 areas of genetic correlation with AD—lipid regulation, immune regulation, and protein clearance—are promising areas of focus for targeted intervention. (Jansen 2019) Since microglia and astrocytes are the primary producers of APOE, the protein with the strongest genetic link to AD, they are predicted to have a critical and complementary role in pathophysiology. (Fernandez 2019) A greater appreciation of CNS cholesterol metabolism and lipid transport; CNS immunity; microglial-astroglial axis involvement; and microenvironmental factors that may accelerate or slow the progression of the disease may open the path to therapeutic innovation.
Cholesterol homeostasis and lipid-accumulating macrophages
The brain is highly dependent on cholesterol, and due to the blood-brain barrier it must produce its own, typically in astrocytes. APOE is the major transport mechanism of cholesterol exchange among neuronal and nonneuronal CNS cells, with the AD-associated APOE4 being the least effective carrier. Cholesterol production in adulthood serves to maintain neuronal protection through late life, including roles in neurosteroid biosynthesis, anti-infective functions, and responding to CNS injury. However, if there is a mismatch of production and efflux, the brain becomes oversaturated with cholesterol. Outside the CNS, elevated cholesterol accumulates in macrophages, which then undergo inflammatory responses; in the brain this occurs in the microglia, which have the same embryonic origin as macrophages. Microglia, mobile throughout the CNS and tight regulators of lipid and lipoprotein metabolism, are first responders that undergo an adaptive shift in an attempt to address the overload and maintain homeostasis. (Loving, 2020)
Lipid overload leads to formation of lipid droplet-accumulating microglia which resemble the foamy macrophages of atherosclerotic lesions. (Marschallinger, 2020) TREM2, which is responsible for cholesterol transport in the microglia, may have a role in switching microglia to a neurodegenerative phenotype. Cholesterol processing enzymes ACAT and SOAT become overactive, oxidizing cholesterol and creating these activated microglia, which trigger an inflammatory cascade. Lysosomes degrade lipids, but this process becomes dysfunctional in aged microglia. Droplets may form intracellular cholesterol crystals which further contributes to lysosomal dysfunction, inflammasome activation, and microglial activation. This activated state also induces a mitochondrial metabolic switch which promotes NF-kB and produces reactive oxygen species. (Lee, 2020) Ultimately, the capacity of microglia to function is eroded, and the ability to maintain lipid equilibrium is exceeded.
Additional cholesterol-related direct CNS toxicity is also relevant at this point in AD pathology. Hippocampal neurogenesis is impaired in the presence of high cholesterol, and the blood-brain barrier (BBB) is weakened, potentially favoring pathological progression (Engel, 2019). Also, increased cholesterol at the plasma membrane increases BACE1-mediated APP cleavage, directly driving amyloid beta (Aβ) production, and notably APOE4 leads to more toxic cleavage fragments. (Zhang, 2019) Finally, excess cholesterol in microglia delays Aβ degradation. (Lee, 2010) APOE4 compounds this effect by competitively binding to LDLRP1, inhibiting Aβ clearance. (Stakos, 2020)
Therapeutic efforts to impact the course of AD with statins, which resulted in cognitive impairment, may have failed due to lack of specificity in location of the action. (Schultz 2018) However, there are a number of potentially actionable steps in this early, presymptomatic stage, including targeting enzymes (ACAT and SOAT) essential to the metabolic pathway; modulation of proteins (APOE, ABCA, CETP, PKSC9, LXR) critical to reverse cholesterol transport (Cantuti-Castelvetri, 2018; Murphy, 2012, Chew 2020); and targeting the activated microglial glycolysis energy metabolism pathway. (Lauro, 2020; Loving, 2020) Intervention in the immune activation process, by targeting CD33, TREM2, or APOE4 to prevent microglial “switching” of activation to a pro-inflammatory phenotype is potentially the most promising approach due to early and precise action. (Krasemann, 2017)
Endocrine aging and steroid homeostasis are also critical to consider and a potential target of intervention. Notably, PKSC9 is upregulated in AD brains, and could be an early biomarker of the disease, particularly in females where its regulation is under tighter genetic control. It is potentially upregulated as a signal of lipodopathy in an attempt to reduce cholesterol metabolism and redirect the LDLR to the lysosome, as a signal that the capacity to receive cholesterol is full. (Picard, 2019). Evaluating the interplay of sex hormones and vitamin D on CNS cholesterol levels, is promising, especially the apparent protective effect of estrogen against the development of AD when given within a critical window after menopause. (Rettberg, 2014)
Microglial activation, the immune cascade, and disease-associated astrocytes
In non-CNS analog conditions such as atherosclerosis and fibrotic lung disease, foam cell formation is associated with a pro-fibrotic state; therefore, it is possible that a similar pro-fibrotic switch occurs in the CNS. (Thomas, 2015; Hamby, 2006; Venosa 2019) This could be initiated by the macrophage-astrocyte axis.
Astrocytes are the protective structure-providing cells of the CNS critical to synapse formation, plasticity, and function. They serve to maintain the BBB, regulate blood flow via calcium signaling, and modulate tissue repair and fibrosis. In AD, they become activated, potentially as an evolutionarily-conserved attempt to contain an area of damage, that causes collateral damage due to expression of inflammatory mediators and neurotoxic activity. (Habib, 2020)
Astrocytes are activated by microglia via IL-1α, TNFα, and C1q. (Liddelow, 2017) This causes the astrocyte to lose its normal function and instead produce large amounts of inflammatory molecules, complement cascade proteins, and neurotoxic mediators, such as ROS and NO, that are destructive to synapses and have been reported in AD brains. Interestingly, TGF‐β, upregulated upon CNS injury, can augment astrocytic NO production by increasing the number of astrocytes capable of expressing NOS-2—thereby recruiting a latent population of cells that then increase numerically with disease progression. (Liddelow, 2017; Bialas, 2013; Balez, 2016) Activated astrocytes show aberrant regulation of calcium homeostasis, disrupting neuronal networks and vascular flow. (Kuchibhotla, 2008) Cytokines activate the neuroinflammatory JAK-STAT pathway, which is a hallmark of activated astrocytes. Under inflammatory conditions, glycolysis is promoted. Finally, the proinflammatory feedback loop involving TGF‐β and complement signaling contributes to amyloidosis, fibrosis, and cerebral amyloid angiopathy. (Caraci, 2011; Diniz 2017)
Perhaps most importantly, reactive astrocytes secrete Aβ and contribute to the overall amyloid burden of the brain. Reactive astrocytes have increased levels of the 3 necessary components for Aβ production, APP, BACE1, and gamma secretase, and even a small increase in Aβ production by astrocytes increases overall Aβ production by 40%—over time, eclipsing the amount produced by neurons. (Zhao, 2011; Frost, 2017)
Astrocytes, like microglia, initially work to defend from a CNS insult, yet ultimately reach a point where the defense becomes destructive. They become doubly-destructive by engaging in cross talk with activated microglia, thus mutually reinforcing the devastating pathways in the brain. (Perez-Nievas, 2018) Interestingly astrocytes expressing APOE4 reportedly secrete significantly more cholesterol than their APOE3+ counterparts (Lin, 2018)—further compounding the original problem of cholesterol overload.
Potential therapeutic targets at this stage of the disease process include inhibition of cytokine signaling, antioxidants, targeting Aβ production enzymes, inhibiting JAK/STAT signaling, and compensating for the altered calcium metabolism (for example, by promoting CNS blood flow), restoring Aβ-degrading capabilities to CLU-less activated astrocytes, or working to restore glymphatic clearance of waste, including soluble Aβ (potentially via AQP-4 reactivation). (Valenza, 2020; Wojtas, 2020)
Impaired CNS clearance and proteinopathy
Fischer wrote in 1910 that plaques form as a result of abnormal deposits within the brain that induce a local inflammatory reaction, resulting in a synaptotoxic microenvironment not conducive to a neuronal regenerative response. Ever since then, amyloid plaques resulting from proteolytic fragments of amyloid precursor protein (APP) have been the areas of most focus in research and development. Intraneuronal neurofibrillary tangles, also of considerable research interest, consist of tau, a microtubule-associated protein. Hallmark toxic properties of Aβ require tau: therefore, Aβ is considered upstream, triggering tau, which then enhances Aβ toxicity in a feedback loop. (Bloom, 2014) Unfortunately, Aβ and tau targeting has not resulted in efficacious therapeutics despite considerable investment of time and resources.
A novel way of looking at AD is to view Aβ accumulation as the end stage of disease as opposed to the driver. (Osorio, 2019) Aβ has a role in protecting the body from infections, repairing leaks in the blood-brain barrier, promoting recovery from injury, and regulating synaptic function. (Brothers, 2018) Therefore, these proteins may actually represent the brain’s last resort at compensation after all the “upstream” efforts from microglia and astrocytes have failed. The core problem of proteins in the CNS is a lack of clearance, driven by the deficiencies of function arising from activated microglia and astrocytes. When microglia are triggered to differentiate into the activated form and phagocytic activity is reduced, proteins may accumulate. (Deczkowska, 2018) Similarly, activated astroglia are associated with less effective glymphatic clearance. When both factors fail, protein accumulation can advance unchecked.
Once this stage of disease is reached, acceleration is rapid. Both Aβ and tau have prionlike activity, creating misshapen proteins that propagate pathology throughout the brain and correlate with early disease onset and younger age at death. (Aoyagi, 2019) Aβ also serves as a self-reinforcing feedback loop by activating microglia and by altering calcium homeostasis in astrocytes causing them to withdraw neuronal support, which further contributes to the toxic protein takeover. (Nirzhor, 2018)
More critically, there is a link back to cholesterol homeostasis in the brain. The conversion of APP into Aβ is influenced by intracellular cholesterol: excess cholesterol increases its production. Also, microglia with excess intracellular cholesterol are slower to degrade Aβ. Finally, prions (including Aβ and tau) require cholesterol to seed and spread, and prion infection also influences the cholesterol pathway, increasing esterified cholesterol levels (produced by neurons through activation of SREBP2—not microglia) and further driving the cycle of disease. (Hannaoui, 2014; Gomez-Gutierrez, 2020)
The exception to this order of events is Down Syndrome-associated and familial AD, where PSEN or APP amplification or mutations produce Aβ prions which act as the initiating event that triggers cholesterol overproduction. After the initial prion response, the process of disease is the same though the course is faster due to greater time overlap of multiple pathologic processes.
Since a large group of proteins indirectly execute the toxic downstream effects of Aβ accumulation, agents that target the insulin receptor, NMDA, adrenergic receptors, or calcium channel receptors have demonstrated benefit in alleviating the symptoms of end-stage disease. However, a future focus of intervention may be more rationally based on the mechanism of disease. Potentially, targeting APP processing to drive less-toxic splice variants in an earlier stage of plaque development could prove to be beneficial in slowing pathophysiologic changes by correcting the imbalance of synthesis and clearance. Antisense oligonucleotides targeting the prion-like proteins may have potential. Additionally, since >80% of AD patients show cerebral amyloid angiopathy due to Aβ deposits in vessels, targeting enhanced intracranial blood flow could prove to be somewhat valuable in alleviating symptoms. (Penke, 2020) Lastly, since a lack of ability to degrade misfolded proteins contributes to increased rate of accumulation, targeting the ubiquitin-proteasome degradation system, such as with PROTACs, may be a promising disease modifier in late-stage AD. (Al Mamun, 2020)
CNS protection and cognitive reservoir
AD is a series of complicated cellular metabolic and immunologic interactions, decoupled from the clinical appearance of symptoms which present much later in the course of disease. In addition to targeting the multiple mechanisms of disease directly, adopting neuroprotective behaviors and developing a high level of cognitive reserve should be emphasized in order to delay the development of, or compensate for, life-impacting symptoms.
A key consideration that is infrequently discussed is the cognitive reservoir. Like conditions such as renal failure or multiple sclerosis, it takes a long process of deterioration to finally reach the point of clinically-apparent disease. By enhancing the cognitive reservoir, the person with AD can cognitively compensate, remaining more resilient in spite of pathological progression. This explains the frequent finding of disconnection between autopsy pathology results and apparent functional level before death.
Neuroprotection may be promoted by optimizing the metabolic microenvironment in terms of regulating cellular energetics and metabolism, preventing oxidative injury, increasing vascular flow, and reducing glycosylation. Behaviors that have potential to offer cognitive protection include sleep hygiene, anti-inflammatory use in early stage of disease, physical activity, anti-insulinogenic diet, correcting sterol metabolism or deficiencies (specifically hypovitaminosis D and estrogen/androgen deficiencies), and cognitive training to enhance reserve. (Berkowitz, 2018) These potential protective factors are worth evaluating in retrospective or real-world analyses to in order to better characterize AD clinical onset prevention recommendations.
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COIL: A proposed redefinition of AD
Considering the interacting, progressive, mutually-reinforcing driver nature of the disease, an overarching descriptive term could be COIL: CNS Overactive Immuno-Lipometabolism.
The disease model of COIL could be envisioned as a series of cycles that are interconnected (Fig 1). Failures happen in a particular sequence of events (from microglial activation to astrocyte activation to proteinopathy), resulting in a connected chain that drives the disease inexorably forward. Each one of these cycles initially becomes overactive as a neuroprotective or compensatory mechanism, but as they fail, the next “gear” in the pathologic chain is triggered. Though protective lifestyle and microenvironmental factors promote cognitive reserve and delay onset of clinically-apparent symptoms, specific and targeted interventions is the only way to truly stop disease progression. (Fig 2)
Single-targeted intervention attempts must happen at the appropriate time early in disease, otherwise the magnitude of effect may not be enough to stop the inevitable sequence of events. Combination therapies that work together to address multiple points in the pathophysiology (for example, an immune modulator combined with a cholesterol efflux promoter) may be more effective due to the lengthy time course of disease development and multiple confounding factors. Biomarkers of early disease must be elucidated to serve as surrogate markers in order to expedite trial results for these early interventions. More specific imaging, including precision-targeted PET to enable detection of proteins that are upregulated early in the disease process, should be investigated.
Conversely, therapeutic agents targeted at the end stage of disease, such as amyloid- or tau-targeted agen
ts, have a very high burden of effect needed to stop the disease load which has already gained momentum: drug development targeted beyond the point of proteinopathy is unlikely to be of significant benefit.
The proposed redefinition of late-onset AD as COIL can have multiple advantages. Focusing attention on the earlier, “silent” stages of the disease allows for more potential therapeutic interventions—and perhaps more importantly, allows for time and personal empowerment to strengthen cognitive reserve and adopt neuroprotective behaviors. Additionally, by not just changing the textbook pathophysiologic cascade but by re-naming the disease we may be able to establish a clean break from the past century of failures, en
courage a new paradigm to drive research, establish clear delineation from other dementias, and remove the stigma of stagnation to uplift all those in the community fighting against this debilitating disease, from scientists to sufferers. The term COIL symbolically represents the cycles of pathology, the circuitous path of therapeutic development attempts, and aging itself: our “mortal coil,” a burden of life we must carry—or, with innovative therapeutic tools, evade.
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