Alzheimer's disease and its treatment-yesterday, today, and tomorrow

Abstract

Alois Alzheimer described the first patient with Alzheimer's disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial neurodegenerative disorder with familial, life style and comorbidity influences impacting a global population of more than 47 million with a projected escalation by 2050 to exceed 130 million. In the USA the AD demographic encompasses approximately six million individuals, expected to increase to surpass 13 million by 2050, and the antecedent phase of AD, recognized as mild cognitive impairment (MCI), involves nearly 12 million individuals. The economic outlay for the management of AD and AD-related cognitive decline is estimated at approximately 355 billion USD. In addition, the intensifying prevalence of AD cases in countries with modest to intermediate income countries further enhances the urgency for more therapeutically and cost-effective treatments and for improving the quality of life for patients and their families. This narrative review evaluates the pathophysiological basis of AD with an initial focus on the therapeutic efficacy and limitations of the existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine. The hypothesis that amyloid-β (Aβ) and tau are appropriate targets for drugs and have the potential to halt the progress of AD is critically analyzed with a particular focus on clinical trial data with anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aβ will benefit the majority of subjects with AD that the anti-Aβ MABs are unlikely to be the "magic bullet". A comparison of the benefits and disadvantages of the different classes of drugs forms the basis for determining new directions for research and alternative drug targets that are undergoing pre-clinical and clinical assessments. In addition, we discuss and stress the importance of the treatment of the co-morbidities, including hypertension, diabetes, obesity and depression that are known to increase the risk of developing AD.

Keywords: Alzheimer’s disease; N-methyl-Daspartate receptor; acetylcholinesterase inhibitors; amyloid protein; donepezil; lecanemab; memantine; monoclonal antibody.

FIGURE 1

Flowchart of Alzheimer’s Dementia pathogenesis and targets for drug intervention. MAB, monoclonal antibody; BAC1, beta-secretase 1; NMDA-receptor, N-Methyl-D-Aspartate receptor; TK, tyrosine kinase; NK, natural killer. This figure was created with BioRender.com.

FIGURE 2

Depiction of a neuron illustrating key CSF biomarkers useful in diagnosing AD in addition to a potential synaptic biomarker candidate, neurogranin. Total tau (T-tau) shows the extent of neuronal damage but lacks specificity for AD. Phosphorylated Tau (P-tau) represents tau proteins with relatively AD-specific modifications. The CSF Aβ42 level is reduced in AD despite the concurrent increase in amyloid (Aβ) deposition in the brain, which is a characteristic of AD pathology. The Aβ42/40 ratio compensates for individual variabilities, thus offering a more standard measure of amyloid pathology. This figure was created with BioRender.com.

FIGURE 3

The Acetylcholine Hypothesis and role of AChE Inhibition: Decreased levels of acetylcholine (ACh) contribute to cognitive decline; however, the inhibition of acetylcholinesterase (AChE) with acetylcholinesterase inhibitors (AChEIs) prevents the breakdown of ACh, thus resulting in elevated synaptic ACh levels. The increase in available ACh is associated with improved cognitive function. AChE also interacts with the enzyme presenilin-1 PS-1, which plays a crucial role in Aβ production including the regulation of γ-secretase, and its association with AChE underscores a significant cholinergic-amyloid link in the pathophysiology of AD. Mutations in the PSENI gene result in the enhanced production of Aβ (Silveyra et al., 2008). It has been reported that AChE enhances both transcription and production of PS-1, decreasing γ-secretase activity and reducing the processing of APP (Campanari et al., 2014). Thus, the loss of the regulation of PS-1 by AChE and a subsequent increase in γ-secretase activity will increase Aβ. This figure was created with BioRender.com.

FIGURE 4

The excitatory neurotransmitter glutamate plays an essential role in synaptic plasticity, a process that refers to the ability of synapses to strengthen, or weaken, in response to neuronal activity. Glutamate-mediated synaptic plasticity involves two key processes: long-term potentiation (LTP) and long-term depression (LTD) (Riedel et al., 2003; Abraham et al., 2019). In brief, LTP requires the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) and N-methyl-D-aspartate receptors (NMDAR). Activation of the NMDAR is initially prevented due to intracellular Mg2+ blocking the cation channel, however, when glutamate activates the AMPAR this results in the entry of Na+ and depolarization of the neuron (Step 1 in Figure 5) and removal of the Mg2+ block (Step 2 in Figure 5), allowing activation of the NMDAR and the intracellular entry of both Na+ and Ca2+ (Vargas-Caballero and Robinson, 2004; Blanke and VanDongen, 2009). The increase in intracellular Ca2+ initiates a signaling cascade that involves the enzyme calcium/calmodulin-dependent protein kinase II (CaMKII) and triggers the translocation of intracellular AMPARs to the postsynaptic membrane (Step 4a in Figure 4) and phosphorylates AMPAR (Step 4b in Figure 4) (see Sumi and Horada, 2020, for details of the signaling pathway). Collectively, these events result in the strengthening of the neuronal signal and ultimately lead to the development of LTP and memory formation and learning (Wang, 2017), including changes in gene transcription that affect receptor density and result in changes in neuron function. However, the excessive release and presence of glutamate in the neuronal synapse results in elevated levels of intracellular calcium and prolonged cell depolarization (Choi, 1987). This, in turn, results in the generation of increased levels of reactive oxygen species (ROS), causing neuronal damage and cell death (Savolainen et al., 1995). Excess levels of glutamate promote microglia-mediated neuroinflammation, further damaging adjacent neurons (Qin and Crews, 2012; Lee V. M. et al., 2021). This supports the argument that the combination of microglia-mediated inflammation and oxidative stress results in neural damage, synaptic dysfunction and impairment of LTP leading to AD. Elevated Aβ is also associated with hyperactivity of NMDA-mediated currents and neurotoxicity, thus providing a link between the role of Aβ plaques and defective glutaminergic neurotransmission (Harkany et al., 2000; Domingues et al., 2007). This figure was created with BioRender.com.

FIGURE 5

Non-amyloidogenic and amyloidogenic pathways and β-secretase (BACE-1) inhibition. This figure illustrates the non-amyloidogenic (A) and amyloidogenic (B) pathways of amyloid precursor protein (APP) processing. Light green circle represents normal PSEN-1 protein at the γ-secretase complex. Dark brown circle represents mutated PSEN-1 protein at the γ-secretase complex, which increases production of longer and aggregation-prone beta amyloids. Aβ42 is rich in hydrophobic amino acids such as isoleucine, phenylalanine, and valine. Specifically, the hydrophobic side chains at the positions 41 and 42 increase the propensity of Aβ42 to aggregate (Kim and Hecht, 2005). This promotes the formation of the β-sheet structures characteristic of aggregated amyloid proteins. In a normal physiologic state (Figure 5A), APP is processed by α-secretase and then by β-secretase (Butterfield et al., 2013). However, when there is reduced α-secretase together with increased β-secretase activity, the amyloidogenic pathway is induced (Figure 5B). As Aβ42 increases, aggregates of Aβ form monomers that then develop into small oligomer clusters that form more stable Aβ fibrils, highly ordered crossed beta-sheet structures that align perpendicular to the fibril axis forming an extended rigid fiber (Chen et al., 2017). As more and more Aβ proteins are produced, the fibrils form a tighter and more stable structure due to the hydrophobic interactions between the amino acids side chains that stabilize into a senile plaque in the extracellular space (Chen et al., 2017). BACE-1 inhibitors (purple) target beta-secretase, reducing activity along the amyloidogenic pathway. This eventually results in the decrease in the production of the amyloid-beta (Aβ) peptides associated with Alzheimer’s disease. This figure was created with BioRender.com.

FIGURE 6

Impact of hyperphosphorylated tau on Microtubule Stability. This figure illustrates the detrimental effect of hyperphosphorylated tau proteins on microtubules. In the normal state (A), tau stabilizes microtubules via a balance between negatively and positively charged residues in their monomers (Mukrasch et al., 2007; Jho et al., 2010). In the absence of any pathological conditions, the balance between these positively and negatively charged molecules keeps tau proteins attached to microtubules where they assist in essential molecular transport. However, when tau becomes hyperphosphorylated in the diseased state (B), via the src family tyrosine kinase, fyn (Lee et al., 2004), tau proteins become less and less positive weakening the electrostatic force between tau and microtubules (Fischer et al., 2009). This results in microtubule disintegration impairing ubiquitin proteasome-mediated autophagic clearance of Aβ (Cowan et al., 2010; Weng and He, 2021). In addition, tau neurofibrillary tangles within the neuron physically obstruct the movement of cellular components along the microtubules; the density of neurofibrillary tangles and severity of the pathology correlate with the level of cognitive impairment (Cowan et al., 2010; Nelson et al., 2012). In the normal state (A), tau stabilizes microtubules, which are essential for cellular structure and transport. However, when tau becomes hyperphosphorylated in the diseased state (B), it loses its stabilizing ability, resulting in microtubule disintegration. This disruption compromises cellular structure and function, contributing to the pathogenesis of Alzheimer’s disease. Figures C and D compare the role of tau in the normal brain (C) with the AD brain (D). D shows microtubule disintegration, neurofibrillary tangle formation, and amyloid plaque deposition and accumulation. This figure was created with BioRender.com.

FIGURE 7

The Vascular Hypothesis. The Blood-Brain Barrier and ApoE4: There are many waste products in the interstitial space, including Aβ and tau proteins and neurofibril tangles. With normal cerebral vascular function and pulsatile blood flow, the direction of CSF flow is from the periarterial space to the interstitial space to perivenous space. While the interstitial fluid crosses the AQP4 channel on the astrocytes of the perivenous space, the waste products in the interstitial space get carried along to the perivalvular space and to the lymphatic system. However, for subjects with vascular abnormalities, such as due to atherosclerosis, the decreased pulsatile blood flow drives CSF flow from the periarterial to interstitial to perivenous space, thus resulting in accumulation of beta amyloid and tau protein in the interstitial space. The presence of amyloid plaques in turn causes additional vascular dysfunction by damaging nearby blood vessels and disrupting the regulation of blood flow in the brain (Thomas et al., 1996). Subjects who carry the ApoE4 genotype have a reduced ability to clear Aβ, which then accumulates in brain microvessels and parenchyma (Martel et al., 1997), and is then associated with reduced cerebral blood flow and metabolism across multiple cortical regions, increasing the risk of hypoxic brain injury (Small et al., 1995; Mielke et al., 1998; Kim et al., 2013). In addition, cognitively normal ApoE4 carriers show significant age-related deficits in cerebral perfusion as they age, which increases the risk of AD (Thambisetty et al., 2010; Liu et al., 2013). Carrying the ApoE4 also heightens the risk of pericyte dysfunction thereby reducing the critical role of pericytes in maintaining the integrity of the blood brain barrier (BBB) thereby allowing Aβ and other inflammatory molecules to penetrate the CNS, inducing neuroinflammation and accelerating AD in part via inhibition of the anti-inflammatory effects of the TREM2-DAP12 complex on microglia (Armulik et al., 2010; Nishitsuji et al., 2011; Halliday et al., 2016; Fitz et al., 2021; Iannucci et al., 2021; Zhou et al., 2023). Data from ApoE4 carriers shows that the breakdown in the BBB starts in the medial temporal lobe, which is the part of the brain critical for cognitive function (Montagne et al., 2020). In consequence, inflammation and oxidative stress associated with both vascular dysfunction and Aβ worsen the damage caused by each factor, creating a feedback loop that accelerates AD progression. This figure was created with BioRender.com.

FIGURE 8

This figure depicts two potential pathways whereby viruses may trigger Alzheimer’s Disease (AD) pathology. (A). The direct invasion of the virus into the Central Nervous System (CNS) or the induction of systemic inflammation by peripheral viral infection, even in the absence of direct CNS invasion. Both routes converge in the development of neuroinflammation, increased Aβ production, tau hyperphosphorylation, and neurodegeneration, collectively resulting in AD symptomatology. (B). The virus utilizes extracellular vesicles (EVs) as a protective mechanism, allowing it to evade the immune system by encapsulating itself within EVs during its transit into the CNS. In addition, EVs serve as carriers for viral proteins, viral nucleic acids, and pro-inflammatory cytokines, and avoid detection by the immune system, before passing through the BBB to enter the CNS and cause infection and neuroinflammation (Yates et al., 2019; Horn and Maclean, 2021; Liu et al., 2021). The injection of EVs containing proinflammatory mediators into mice has been shown to increase activation of astrocytes and microglia, and thus supports a link between viral infections, EVs and neuroinflammation (Li et al., 2018). This figure was created with BioRender.com.