See also Aging
Alzheimer’s Disease Neuroimaging Initiative
US Patents for transgenic mice models: U.S. Patent 5,387,742 U.S. Patent No. 5,602,299
NIH Neurosciences Blueprint. Alzorum
Diagnostic Tests: Quest (The calculated ratio of Beta-amyloid 40 and Beta-amyloid 42)
Companies: NeuralEM (electromagnetic treatment) Lilly (testing options)
See also Microglial cells under Immune Cells
Introduction:
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the main cause of dementia. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020)). The Alzheimer’s treatment space is projected to be worth 15.5 billion by 2031, according to hHealthcareAnalyst.
According to one estimate, over 55 million people globally are impacted by dementia, and between 60–70% of these individuals are living with Alzheimer’s disease.
AD is a progressive disease resulting in senile dementia. It is a progressive disease of the human central nervous system and manifested by dementia in the elderly, by disorientation, loss of memory, diffficulty with language, calculation, or visual spatial skills and by psychiatric manifestations. It is estimated that healthcare spending on Alzheimer’s disease and related age related dementials in 2012 is 200 billion in the US alone.
AD falls into 2 categories: late onset, which occurs in old age (65+ years) and early onset which develops before the senile period (between 35-60). In both types, the pathology is the same but the abnormalities tend to be more severe and widespread in cases beginning in early age.
Pathology and Biomarkers:
Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting nerve cells located within higher cortical centers that ultimately results in impaired cognition, including a gradual decline in memory, judgment, and communication. AD is characterized by at least 2 types of lesions in the brain, neurofibrillary tangles and senile plaques. The principal constituent of the plaques is a peptide called “Abeta or beta-amyloid peptide”.
AD shares features with other neurodegenerative disorders such as cerebral atrophy, neuron and synapse loss, accumulation of intracellular protein aggregates in neurons, and glial activation, but also other features more specific to AD such as the accumulation of extracellular proteins aggregates, called amyloid plaques. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))
AD is characterized by the presence within the brain of amyloid fibril containing neuritic plaques comprised of proteolytically derived 40-42 residue fragments of the amyloid precursor protein. Historically, Abeta fibrils have been deemed primarily responsible for neuronal dysfunction and death; however, more recent evidence indicates that oligomers, which includes soluble cross-lined beta-amyloid protein species (CAPS), are the most pathogenic Abeta conformers. (Nuallain, Biochemistry 2008, 47, 12254-12256).
AD is characterized by age-associated progressive memory decline. Two hallmarks of AD are amyloid beta and tau.
Amyloid Peptides: (e.g., Amyloid beta protein):
Neuropathological and genetic data strongly supports a primary role for amyloid peptides, particulary amyloid beta protein, which accumulate as senile plaques in brain parenchyma, in the pathogenesis of AD. The presence of circulating Abeta like antibodies in the peripheral blood of AD patients is known (Mruthinti, Neurobiology of Aging 25 (2004) 1023-1032).
Abeta peptide is a 4 kDa internal fragment of 39-43 amino acids of a larger transmembrane glycoprotein named amyloid precursor protein (APP). As a result of proteolytic processing of APP by different secretase enzymes, Abeta is primarily found in both a short form, 40 amino acids in lenght, and a long form, rangering from 42-43 amino acids in lenght. Several mutations within the APP protein have been correlated with the presence of AD.
The amyloid hypothesis holds that the accumulation of amyloid-beta (Aβ) is responsible for Alzheimer’s disease. Proponents of this theory believe that when amyloid beta clumps together to form deposits in the brain, it triggers neurodegenerative processes that lead to the loss of memory and cognitive abilities that characterize the disorder. Despite the recent FDA approval of anti-amyloid antibodies for Alzheimer’s disease and new investment in the space, skepticism remains about the value of these first disease-modifying drugs and the validity of the amyloid hypothesis. (“Amyloid Hypothesis in Doubt as Newly Approved Drugs Hit Hurdles” Biospace, 2024)
While the exact role of Aβ in Alzheimer’s is up for debate, anti-amyloid antibodies without a doubt have some effect on the disease process. Legembi (see below) for example reduced clinical decline by 27% compared to placebo based on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessment in patients with mild-to-moderate Alzheimer’s, and Kisunla (see bloew) reduced decline by 29% on the CDR-SB. But “The effect is less than Aricept [an earlier Alzheimer’s drug], and yet they’re moving forward. If the theory was correct, if you remove the amyloid, some patients should get better. Thus while amyloid is “important” to the Alzheimer’s disease process, it is not the driver. Rather, amyloid accumulation may be a response to neural damage, given that antioxidant qualities found in amyloid-beta. With the currently approved anti-amyloid antibodies, the amount of drug that gets into your brain is also about 1%, which is not a very efficient way of treating Alzheimer’s disease. Several companies—including Denali Therapeutics, Voyager Therapeutics and Aliada—are developing technologies to improve on that number. Roche’s anti-amyloid antibody trontinemab is an example of a therapy attempting to get the antibody across the BBB. Developed using the company’s proprietary Brainshuttle platform, trontinemab can cross the BBB and achieve higher levels of brain exposure and broader distribution across the central nervous system. at this point, that Alzheimer’s will have to be treated with multiple drugs attacking multiple mechanisms that are related to the biology of aging. (“Amyloid Hypothesis in Doubt as Newly Approved Drugs Hit Hurdles” Biospace, 2024)
Amyloid Beta Oligomers and Fibrils: Amyloid beta fibrils are been found primarily responsible for neuronal dysfunction and death. In addition, oligomers that include soluble cross-linked beta amyloid protein species (CAPS) have also been found detrimental. (Nuallain, Biochemistry, 2008, 47, pp. 12254-12256).
In the brain, amyloid beta peptides tend to clump and aggregate, forming elongated structures known as amyloid fibrils. Over time, these fibrils accumulate into plaques, which are the pathological hallmarks of more than 50 neurodegenerative diseases, including Alzheimer’s disease.
Receptor for AGEs (RAGE): occur in AD brain within hippocampal pyramidal cells, cortical neurons, glial cells and white matter. Some evidence exists to suggest that RAGE permits the accumulation, supports the aggregate of Abeta, resulting in inflammation and cytotoxicity in neuronal cells. AD individuals are also known to express high levels of anti-RAGE IgGs as shown from purificaiton of RAGE from plasma samples. (Mruthinti, Neurobiology of Aging 25 (2004) 1023-1032).
Tau:
–hyperphosphorylation
Tau is a microtubule (MT) associated protein particularly abundant in neurons, where it mostly localizes to axonal regions. It regulates MT stability and the maintenance of axonal transport. Under physiological conditions, tau binding to MTs is coordinated by phosphorylation, requiring a precise interplay of a multitude of kinases and phosphatases. In pathological conditions such as AD and related neurodegeenrative disorders called tauopathies, increased phosphorylation of tau is associated with a decrease in its binding to microtubules. This in turn results in tau misolding and self-aggregation, eventually leading to the accumulation of insoluble, paired helical filaments and other filamentous structures. Tau pathological tau aggregation is a shared molecular mechanism in more than 20 neurodegenerative conditions, including AD. While tau in the normal brain contains 2-3 phosporylated residues per tau molecule, it is estimated to be about 3-fold hyper-phosphorylated in AD brain. Accumulating data indicates that phosphorylation alone is not sufficient for aggregation and might even serve a protective role. Several other post-translational modifications such as acetylation, ubiquitination, methylation and glycosylation among others appear to play regulatory roles as well with respect to rates of tau clearance and aggregation and thus contribute to tau pathology. (Steen, WO 2017/053739).
Neurofibrillary tanges (NFTs), consisting of paired helical filaments (PHFs) or straight filaments due to the polymerization of tau protein into fibrillar intracellular aggregates, are a definining neuropathological feature of AD. In AD, the severity of tau pathology, assessed according to the Braak staging for NFTs, is a stronger correlate and predictor of cognitive outcomes than amyloid beta plaques, another neuropathological hallmark of AD. (“Phospho-tau serine-262 and serine-356 as biomarkers of pre-tange soluble tau assemblies in Alzheimer’s diease” Nature Medicine, 31 (2025).
—-Specific patterns of hyperphosphorylation
——T205 and T181:
Barthelemy (US 17/015,985, published as US 2020/0400689; see also US Patent applicaiton No: 17/368403 published as US 2021/0341495) discloses a method for selecting a therapeutic agent that prevents amyloid deposit and reduces amyloid plaque load or targets neurofibrillary tangles based on a specific tau phosphorylation pattern. In one embodiment, a therapeutic agent is administered when the isolated tau sample from a subject contains tau phosphorylation at T181 or p217 at about 1.5 dstand deviations above and tauphosphorylation at T205 that is below about 1.5 standard deviations.
Russel “Comprehensive quantitative profiling of Tau and phosphorylated Tau peptides in cerebrospinal fluid by mass spectrometry provides new biomarker candidates” J of Alzheimer’s disease, 55 (2017) 303-313) disclsoes that aberrant tau phosphorylation is a hallmark in AD and that cerebrospinal fluid (CSF) levels of total tau and tau phosphorylated at threonine resiude 181 (pThr181) are established ore biomarkers for AD.
Vasan (US 2008/0220449) discloses diagnosing, stratifying and monitoring the progression or regression of AD which includes detecting in a sample a level of at least phosphorylated tau pT217, soluble tau oligomer, tau-amyloid-beta 1-42 complex and a combination thereof and comparing the level form the sample to a reference level. Vasan discloses that other biomarkers for AD utilize the ratio of p-tau to Abeta1-42 as a sensitive marker for discriminating patients with AD form healthy controls and that changes in lvels of tau and Abeta-142, pTau 181 over teh baseline were much higher between groups than in the same groups during the progression of the disease.
——Ser202/Thr205/Ser208: Tris buffered soline-soluble tau aggregates from autopsy verified AD brain tissues includes the core ques-tau258-368. In neuropatholgoical assessments, antibodies agaisnt the phosphorylation sites serine-262 and serine-356 within the STA core almost exclusively stained granula (prefibrillar) tau aggregates in pre-NFTs while antibodies agaisnt phosphorylation at serine-202 and threonine-205 and threonine 231, outside the STA core, stained the entire spectrum of tau aggregates in pre-NFTs and Mature NFTs, dystrophic neurites nad neuropil threads in the hippocampus. Targeting ealry stage STAs is a potentially effective approach to develop anti-tau diagnostics and therapies. (“Phospho-tau serine-262 and serine-356 as biomarkers of pre-tange soluble tau assemblies in Alzheimer’s diease” Nature Medicine, 31 (2025).
Despres (PNAS, “Identificaiton of the Tau phosphorylation pattern that drives its aggregation” 2017, 114(34)) discloses using in vitro kinase assays combeind with NMR spefctroscopy to show that the combined phosphorylation at the Ser202/Thr205/Ser208 sites, together with absence of phosphorylation at the Ser262 sites, yeild a Tau sample that readily forms fibers, as observed by thioflavin T fluorescence and electron microscopy.
——Ser262/Ser356:
–Tau kinases and their inhibitors
Multiple protein kinases such as GSK-3 (a serine/threonine kinase), CDK5, Akt and PKA can phosphorylate tau. (Xu, US 2009/0233993). Glycogen synthase kinase 3 (GSK-3) may have a key role in the pathogenesis of both sporadic and familiarl AD. It has been reported that GSK-3beta induces hyperphosphorylation of tau. Chronic lithium (a GSK-3 inhibitor) treatment in double transgenic mice overexpression GSK-3beta and tau has shown to prevent tau hyperphosphorylation and neurofibrillary tangle formation. Cao (US11,065,225)
The thousand-and-one amino acid kinases (TAOKs) 1 and 2 phosphorylate tau on more than 40 residues in vitro.. TAOKs are phosphorylated and active in AD brains actions displaying tau patholoy and active TAOKs co-localise with both pre-tange
le and tangle structures. TAOK inhibitors can reduce tau phosphorylation on T123 and T427 and also on additional pathological sites. Such TAOK inhibitors also have been shown to decrease tau phosphorylation in differentiated primary cortical neurons. ((Giacomini, Acta Neuropathologica Communications (2018) 6: 37).
Reagan (US 2009/0104628) discloses a method for measuring phosphorylation of proteins such as tau at specific serine, threonine or tyrosine residues by subjecting the protein to a reaction mixture that includes a phosphokinase which allows the creation of a phosoryalted form of the protein which is then contacted with an antibody specific for the phosphorylation site(s).
Role of Microglia:
Genome-Wide Associattion studies from large European and American consortia identified common genetic polymorphisms at loci harboring genes with microglia-specific expression pattern in the CNS, such as ABC7, CD33 and members of the MS4A genes cluster as genetic determinants of AD risk. The identification of TREM2 R47H and its strong effect size on AD risk association marked a turning point in establishing microglia as a central play in AD pathogenesis. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))
–ADGRG1: is a key receptor that enable protective action of microglia. When microglia lack this receptor, plaque builds up quickly, cuasing memory loss and brain damage. But when the receptor is present, it appears to keep Alzheimer’s symptoms under control. ADGRG1 is one of hundreds of G prtoein coupled recepros.
–APOE:
While APOE is predominantly expressed by astrocytes in the healthy brain, it is dramatically upregulated by microglia upon inflammation or injury. Genome-Wide Association studies from large European and American consortia identified common genetic polymorphisms at loci harboring gnes with microglia-specific epxrewssion pattern in the CNS, such as ABC7, CD33 and members of the MS4A genes cluster as genetic determinatns of AD risk. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))
–TREM2:
TREM2 is an imune receptor expressed in the myeloid lineage, primarily tissue resident macrophages, including microglia and osteoclasts. TREM2 is a cell surface receptor containing one immunoglobulin domain with no intracellular signaling motifes. Instead TREM2 binds sto the adaptor protin DAP12/TYROBP and to a less extent to DAP10. DAP12 has an immunoreceptor tyrosin-based activating motif (ITAM) that acts as a signal transducer and DAP12 is also essential to traffice TREM2 to the cell surface. A variety of tREM2 ligands have been identified, including phospholipids, bacterial surface antigens as well as the AD risk genes APOE and APOJ/CLU. Ligand binding to tREM2 clusters the receptor, which induces DAP12 phosphorylation at the ITAM, recruitment and phosphorylation of SYK and subsequent activation of a downstream signaling cascade that has primarily been studied in osteoclasts, DCs and somewhat in microglia. TREM2 ligation idncues recruitment of SHIP1 and PI3K, which signals through mTOR, as well as activaiton and nuclear transport of beta-cartenin and rapid calcium influx and phosphyrlation of ERK1/2 Human genetics has shown a central role for microglia in AD etiology. The identification of TREM2 as a genetic risk factor marked a turning point in AD genetics. TREM2 R47H was a rare nonsynonymous coding mutation in a known gene, known to be exclusively expressed in microglia in the brain. Mutations in TREM2 and DAP12/TYROBP, its binding partner, were known to cause Nasu-Hakola disease, which is characterized by early onset dementia (among other patholgies in the periphery) and the strong effect size of the mutation that tripled diease risk was proof of its importance. The most prevalent TREM2 mutation associated with AD is the R47H missense mutation. While this variant does not appear to modulate TREM2 expression, maturation or localization, it does reduce ligand binding and ligand mediated TREM2 signaling, suggesting that it is a hypomorphic mutation. Furthermore, people carrying two copies of different TREM2 hypomorphic or loss of funciton mutations develop early onset neurodegenerative diseases, such as leukodystrophy, called Nasu-Hakola Disease or Frontotemperoal dementia. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))
–CD33:
CD33 is a member of the Siglec family of sialic acid binding receptors. It carries an immunoreceptor tyrosin-based inhibitory motif (ITIM). Siglects generally function by engaging specific sialidated glycans on either neighboring cells (trans) or the same cell (cis ) and when engaged, they block the activity of ITAM carrying receptors by recruiting SH2 domain phosphatases that induce dephosphorylation of SYK. CD33 was identified as an AD risk gene by GWAS analysis. SNPs that reduce CD33 expression are associated witih a reduced AD risk and reduced CD33 expression correlates with reduced Abeta pathology in human AD patient brains. Later on, the functional SNP was identified to cause alternative splicing of CD33 that removes its ligand binding domain and reduces cell surface expression. Genome-Wide Association studies from large European and American consortia identified common genetic polymorphisms at loci harboring genes with microglia-specific epxression pattern in the CNS, such as ABC7, CD33 and members of the MS4A genes cluster as genetic determinatns of AD risk. (Rhinn, “Shifting paradigms: The central role of microglia in Alzheimer’s disease” Neurobiology of Disease 143 (2020))
–Galectin-3 (Gal-3):
A growing body of evidence supports the role of inflammatory mechanisms in the development of AD and the importance of myeloid cells. Gal-3 has been assocaited with AD apthology and with microglial activation. (Venero, “Galectin-3, a rising star in modulating microglia activaiton under conditions of neurodegeneration” (2022)
Sortilin-related receptor 1 (SORL1): encodes a large, multi-domain containing, membrane-bound receptor involved in endosomal sorting of proteins between the trans-Golgi network, endosomes and the plasma membrane. It is genetically associated with Alzheimer’s disease (AD), the most common form of dementia. SORL1 is a unique gene in AD, as it appears to show strong associations with the common, late-onset, sporadic form of AD and the rare, early-onset familial form of AD.
SORL1, a transmembrane protein, functions as a receptor for various ligands, including APOE, tau, and APP. It plays a role in protein sorting and trafficking, particularly in neurons. SORL1’s interaction with these ligands and its involvement in endolysosomal pathways have implications for diseases like Alzheimers.
SORL1 is located on chromosome 11q23.2-24.2 in humans and is widely expressed in the brain. It is particulary highly expressed in neurons of the hippocampus and some nuclei of the brainstem and Purknije cells, and has slightly weaker expression in neurons of the thalamus and the hypothalamus. It is also expressed in other tissue types such as the testes, ovaries, thyroid and lymph nodes.
The full-lenght transcript of SORL1 endoces about 250 kDa membrane bound protein which primarily localizes in the endosomal and Golgi compartments. Nascent SORL1 prtoeins are generated in the ER and then transported through the trans-Golgi network (TGN) and eventually to the cell surface. They are initially inactive due to the pro-peptide at the NY2 temrinal which is removed by furin-medaited cleavage in the TGN due to the RRKR furin recognition sequence. This allows the receptor to be directed to the cells suface where it can be utilized with in a signaling pathway or enter a trafficking endocytosis if it is internalized by clathrin-medaited endocytosis eploying the chaperone clathrin adaptor protein 2 (AP2). Alternative splicing occurs for SORL1, with at least 5 protein-coding transcripts arising from the gene in humans according to the ENSEMBL databse. The shortest alternative splice product, SORL1-06 has a transcription initiation site in intron 30 and is epxressed highly in the hippocampus and temepral lobe, moderately in the entorhinal cortex and frontal cortex and is undetectable in the tested or kidney. (Oardelli, “Sorting out the role of the Sortilin-related receptor 1 in Alzheimer’s disease” J Alzheimer’s Disease Reports 4 (2020) 123-140).
SORL1 can modulate the distribution of AbetaPP within cells. Overexpression of SORL1 results in an accumulation of AbetaPP in the Golgi and prevents it from being sorted to the late endosomal membranes where some Abeta is produced. (Oardelli, “Sorting out the role of the Sortilin-related receptor 1 in Alzheimer’s disease” J Alzheimer’s Disease Reprots 4 (2020) 123-140).
Aberrant Lipid Metabolism:
When AD was first described by Alois Alzheimer, he observed “adipose inclusions” and “lipid granules” in the glia of his deceased patient. It is now well established that aberrant lipid metabolism occurs in AD brains. Lipids in the brain include glycerophospholipis, sphin-golipids and cholesterol. These lipids play important roles such as in the structure of the myelin sheath which insulates axons and in formation of the plasma membrane. Cholesterol is one of the most well studied lipis and its homeostasis is implicated in AD. (Oardelli, “Sorting out the role of the Sortilin-related receptor 1 in Alzheimer’s disease” J Alzheimer’s Disease Reprots 4 (2020) 123-140).
Insulin Resistance/Deficiency:
It has been propsoed that AD may reprsent a “type 3 diabets” and that insulin resistance/deficiency underlies AD pathology. The insulin signaling patway has been shown to b e perturbed in AD brains. Since insulin signaling stimulates glucose metabolism, this could partly explain the aberrant glucose metabolism observed in AD brains in FDG-PET studies. SORL1 has been shown to act as a sorting receptor for the insulin receptor in adipocytes. It directs internalized insulin receptor back to the cell surface, preventing lysosomal catabolism and thereby amplifying insulin signals. Loss of SORL1 activiy could decrease the amount of insulin receptor at the cell surface and perturb the insulin signaling pathway. (Oardelli, “Sorting out the role of the Sortilin-related receptor 1 in Alzheimer’s disease” J Alzheimer’s Disease Reprots 4 (2020) 123-140).
Abnormal Glucose Metabolism:
Among the many ways neuroscientists think AD may strip away brain function is by disrupting the glucose metabolism needed to fuel the healthy brain. In essence, declining metabolism robs the brain of energy, leading to impariments in thinking and memory.
Inhibiting IDO1: Studies in mice suggest that a type of drug developed for treating cancer may be useful for AD. Blocking an enzyme called indoleamine-2,3-dioxygenase 1 (IDO1) in mouse models of AD restored metabolism in brain astrocytes and rescued memory and brain funciton. Kyneurenine regualtes production of the energy molcuel lactate, which nourishes the brain’s nuerons and helps maintain healthy synapses. IS01 is the rate limiting enzyme in the converison of tryptophan to kynurenine. A hypothesis is that increases in IDO1 and kyneurenine triggered by accumulation of amyloid ant tau proteins disrupts healthy brain metabolism and leads to cognitive delcine. Inhibiting this enzyme with compoudns that have previously investigated in human clinical trails for cancer could treat early stages of AD and potentially other neurodegenerative diseases under the hypothesis.
Aberrant Iron Content:
Iron content is increased in both living and post-mortem AD brains relative to controls. Iron dyshomeostasis may also be linked to many of the pathologies observed in AD such as mitochondrial dysfunction, fascular pathologies, changes in energy metabolism and inflmmation. (Oardelli, “Sorting out the role of the Sortilin-related receptor 1 in Alzheimer’s disease” J Alzheimer’s Disease Reports 4 (2020) 123-140).
Abberant Estrogen Production:
One hypothesis to explain the female bias observed in AD indidence is the reduced estrogen levels in females due to menopause. Estrogens have been shown to have neuroprotective effects in the rain and its adminsitration reduces the severtiy of lesions in the brain after with permanet or transient ischemia. This is relevant to AD as hypoxia/reduced blood flow is eivdent in AD grains. SORL1 epxression appears to be sitmulated by estrogens. (Oardelli, “Sorting out the role of the Sortilin-related receptor 1 in Alzheimer’s disease” J Alzheimer’s Disease Reprots 4 (2020) 123-140).
Aberant Synaptic Connectivity and Function:
In normal aging, cognitive function and memory dwidle. Data indicates that this age related functional decline is due in large part to changes in synaptic connectivity and function, rather than neuron loss. Loss of synapses is a common early patholoy across age related neurodegenerative conditions like amyotrophic lateral sclerosis and AD.
Spinogenix is developing synaptic regenerative small molecuels that effectively penetrate the blood brain barrier and that can regenerate glutamatergic synapses. Its elad candiate for neurodegenerative and neuropsychiatric disorders is SPG302. In preclindial studies, SPG302 was shown to improve cognition and motor behaviors in multiple animal models of neurodegenerative disorders, including a model of cervical spinal cord injury. SPG302 is currenlty in Phase I studies in amyotrophic lateral sclerosis and AD.
–GAP-43 in cerebrospinal fluid (CSF) are associated with Alzheimer’s disease (AD) and can be a useful biomarker for research and diagnosis. GAP-43 is a presynaptic protein, and its increased presence in CSF suggests synaptic dysfunction, a key feature of AD.
While not a standalone diagnostic test, GAP-43, along with other biomarkers like amyloid and tau proteins, can be used in conjunction with clinical assessments and neuroimaging to improve the accuracy of AD diagnosis and monitor disease progression.
Microglial Activation:
Several studies conducted on autopsy tissues of AD patients and controls showed that microglial activation was observed in AD brains with microglial activation significantly higher within amiloid-beta plaques compared with plaque-free cortical areas. Cosiderable evidence ahs found that microglia proote the uptake and degradation of amyloid-beta. However, some studies have also found that the phagocytosis of amyloid-beta by microglia promoted plaque development. Microglia limit amyloid-beta assocaited tau seeding and spreading in AD mouse models.
Role of Chemokines:
Chemokines are small molecule proteins (8-14 kDa) involved in attraction and activation of microglia and may induce a leadage of the blood-brain barrier (BBB) to allow infiltration of peripheral immne cells. Chemokines may be released by neurons, astroctyes or microglia, and all these cell types can express certain chemokine receptors.
Chemokines are subdivided into four groups on the basis of a relative position of two N-terminal residues of 4 conserved cysteines. One and three amino acids separate the first and second cysteines in the CXC and CX3C whereas 2 cysteines are adjacent to each other in the CC subfamily. CXC and CC are the largest groups, while CX3C includes only one member, CX3CL1/fractalkine (expressed by neurons under physiological conditions), in which the first two cysteines are separated by 3 amino acids. This chemokine exists in both soluble and membrane bound forms. The best known function of chemokines is regulation of migration of various cells in the body. Chemokines exert their biological activity by binding to cell surface receptors that belong to the superfamily of G protein-coupled receptors. Although multiple chemokines can often bind to the same receptor and a single chemokine can bind to several receptors, the chemokine-chemokine receptor interactions are almost always restricted within a single subclass. To date, six CXC receptors have been identified, named from CXCR1 to CXCR6 and 11 CC receptors, from CCR1-CCR11, along with a single receptor for CX3CL1 and 1 for lymphotactinalpha/beta, called CX3CR1 (interacts with fractalkine) and XCR1. CCR2 receptors are expressed on immune cells and can be activated by pro-inflammatory chemokines, including CCL2. There is accumulating evidence for involvement of the CCL2/CCR2 axis in pathogenesis of AD. (Zawilska, “Role of chemokines in the development and progression of Alzheimer’s disease” J. Mole Neuroscience 72: 1929-19541 (2022).
Neurofilament light chain (NfL) is a biomarker for neurodegeneration, including Alzheimer’s disease, though it is not specific to Alzheimer’s. Elevated NfL levels in blood or cerebrospinal fluid (CSF) suggest neuronal damage, and higher levels are often seen in individuals with Alzheimer’s, especially as the disease progresses.
Diagnostics/Detection:
Amyloid PET imaging:
Amyloid PET is a well established biomarker that is widely used in clincial trails and observational studies to detmerine brain amyloid plaque burden. (Bateman, “Validation of plasma amyloid-ß 42/40 for detecting Alzheimer Disease amyloid plaques” American Academy of Neurology, 2021).
Aβ42/Aβ40:
Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD and identify those at risk for future dementia due to AD. Thea ssay has been developed commercially (PrecivityAD by C2N Diagnostics) and is being used by physicains in the clinic to detect amyloid plaques and assit in diagnosis of AD dementia. (Bateman, “Validation of plasma amyloid-ß 42/40 for detecting Alzheimer Disease amyloid plaques” American Academy of Neurology, 2021).
—-The AD-Detect Test for Alzheimer’s Disease (Quest Diagnostics): is a blood test for Alzheimer’s disease, measures A-beta 42 and A-beta 40 biomarkers (a biological marker of a molecule found in the body that may be used in evaluating a disease state) in the blood and provides the A-beta 42/40 ratio. The ratio between these two molecular biomarkers may help to detect risk of Alzheimer’s disease in an individual.
Tau217/β-amyloid 1-42 Plasma Ratio:
—-The Lumipulse G pTau 217/β-amyloid 1-42 Plasma ratio (Fujirebio Diagnostics, Inc) measures two proteins, pTau 217 and beta-amyloid 1-42, found in human plasma, a component of blood, and calculates the numerical ratio fo teh levels of the two proteins. This ratio is correlated to the presence or absence of amyloid plaques in the pateint’s brain, reducing the need for a PET scan.
During review of the test, the FDA evaluated data from a multi-center clinical study of 499 individual plasma samples form adults who were cognitively imparied. The samples were tested by the Lumipulse test and compared with amyloid PET scan or CSF test resutls. 91.7% of individuals with the lumipulse positive results had the prsence of amyloid plaques by PET scan or CSF test result and 97.3% of individauls with engative resutls had a negative amyloid PET scan or CSF test result. Less than 20% of the 499 pateints tested reeived an indeterminate Lumipulse G pTau217/beta-Amyloid 1-42 plasma ratio result. The FDA reviewd the Lumipulse test through the 510k premarket notificaiton pathway. The test was granted breakthrough device designation.
Other markers:
Rai (US 2012/0295281) discloses many different biomarker including IGF-1, IGF-II, a-beta-40, abeta-42, alpha amylase, IL-1 beta and TNF-alpha as predictive of AD and Parkinson’s disease. The ‘281 publicaiton discloses that levels of abeta-42 increased in AD patients with a questionalbe AD diagnosis and with mild AD and increases further as the severity of AD intensifies. In various embodiments, the sensitivity acheived by the use of defined sets of AD biomarkers such as three biomarkers (Abeta-40, Abeta-42 and IGF-II). in one embodiment a field test kit has a set of test strips configured to produce a fluorescence level proportional to a level present on the test strip for each biomarker and a reading device.
Treatment: (See outline)
Models:
Neurons presenting hallmarks of AD:
Sun et al. developed a microRNA-based direct reprogramming approach using fibroblasts from individuals with late-onset Alzheimer’s disease ()LOAD). The authors generated neurons presenting the major hallmarks of the disease, including depositions of the proteins Aβ and tau and dysregulation of age-associated transposable elements. Preventing transposable element dysregulation rescued neurodegeneration and reduced Aβ deposition. Sun et al. “Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming” Science, 2024.
Transgenic (Tg) mouse models: In studies on the pathogenesis of AD, varous transgenic mouse models are used. They usually harbor human mutations responsible for familial AD, including variants of APP, presenilin 1 (PS1), and microtubule-associated protein tau (MAPT). The most commonly used Tg murine AD models are the following:
–Tg2576 line carrying teh double Swedish mutation (K670N and M661L) at the beta-secretase clevage site. These mice display an increase of APP production with consequent overproduciton of Abeta40 and Abeta42 and plaques formation in the frontal, temperol and entorhinal cortices, hippocampus, presubiculu and cerebellum at about 11-13 months of age. They can also display hyhyperphosphorylated tau at old age.
–rTg4510 line expressing human tau P301L.
–App/PS1 line containing human transgenes for APP and PS1 mutation, buoth under control of the Thy1 promoter.