Alzheimer's disease
ICD-10 Code G30.0, G30.1, G30.8, G30.9
What is the clinical spectrum of Alzheimer's Disease?
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects cognitive function, mood, and behaviour. AD exists in various forms that present a high degree of clinical heterogeneity in phenotypes, age-at-onset, etiology, progression rates, biomarkers, and responses to treatments, both between and within these forms.
Sporadic AD represents about 95% of AD cases and is categorized as late-onset AD (LOAD), occurring after age 65. Commonly, LOAD has an amnestic presentation (memory loss, cognitive impairment) characterized by early deficits in episodic memory, with non-amnestic symptoms (language impairment, behavioural changes) occurring less frequently than in early onset AD. Early onset AD (EOAD) can be sporadic or familial and the individuals are commonly affected before age 65 with both typical amnestic and atypical impairments, that pursue a faster course than in LOAD.
The typical histopathology of AD is characterized by the presence of extracellular neuritic plaques (NP) featuring a core of amyloid beta-peptide (Aβ) deposits, intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated and misfolded tau protein aggregates, and neurodegeneration. Besides Aβ, other components of NP include dystrophic neurites (axons or dendrites), activated microglia, reactive astrocytes, and complement proteins that in AD state amplify neuroinflammation and loss of synapses.
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What do we know about the etiology of Alzheimer's Disease?
AD is a multifactorial condition associated with several risk factors, including age, cardiovascular disease, diabetes, traumatic head injury, depression, and genetic predisposition. It is a uniquely human disorder.
To date, 76 genome-wide significant loci associated with AD risk were identified. Familial EOAD are caused by autosomal dominant mutations with high penetrance in genes like APP (encoding the precursor of Aβ) and PSEN1 (encoding presenilin-1 γ-secretase subunit). Beyond rare variants involved in early-onset AD, familial AD (FAD) may involve common variants that have modest individual effects but which can be integrated in a polygenic risk score (PGS) to estimate the overall genetic risk, as well as rare variants with reduced penetrance. An example of a common variant strongly associated with familial LOAD is the APOE ε4 isoform of the APOE gene which codes for glycoprotein involved in lipid transport and modulates Aβ aggregation and clearance. About 70% of sporadic AD patients carry at least one APOE4 allele.
According to the prevalent amyloid hypothesis of AD pathogenesis, accumulation of pathological forms of Aβ produced by cleavage of the amyloid precursor protein (APP) by the β- and γ-secretase enzymes in the brain is the primary pathological process, occurring upstream of tau pathology. Nonetheless, the amyloid cascade hypothesis, according to which Aβ pathology is the exclusive or the primary driver of AD pathogenesis, is regarded with scepticism, since Aβ plaque burden does not necessarily correlate with the presence of AD nor the severity of AD symptoms, and since therapies that targeted various Aβ forms did not produce the desired effect of reversal of cognitive decline in AD patients. Consequently, researchers are increasingly investigating the contribution of the multitude of other pathological processes, such as neuroinflammation, mitochondrial dysfunction, and vascular damage.
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How similar are human and animal nervous systems?
Below are some of the examples of inter-species differences that impact the face, construct, and predictive validity of animal models of AD.
Species-specific differences in brain structure and function
Novel tools such as multi-omics, mathematical modelling, immunostaining and neuroimaging, that enable comparison of finer traits, have revealed human-specific features of brain anatomy, morphology and physiology that confer unique vulnerability to AD. These features include the presence of von Economo neurons, higher action potential threshold voltage, as well as distinct distribution, morphology, and transcriptional profiles of astrocytes and microglia.
Species-specific differences in aging mechanisms
Rodents, who have evolved for rapid reproduction within their short lifespan, do not recapitulate the interactive effects that progressively cumulate across the human lifespan. In additions, rodent-specific features of genetic background, immune system, metabolic rate, susceptibility to pathogens and host-pathogens interactions, glucose regulation, hypothalamic-pituitary-thyroid axis dynamics, stress response capacity etc. can have a protective effect against the effects of biological drivers of age-related decline to which humans are commonly vulnerable.
Species-specific differences in genetics and gene expression regulation
The majority of GWAS-identified risk variants for AD reside in non-coding regions of the human genome - non-coding DNA and non-protein-coding genes - that have a crucial role in gene expression regulation. Many of these non-coding genomic regions show little evolutionary conservation between humans and model organisms, meaning that their sequence, structure, and regulatory function is likely to significantly diverge across species.
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Face validity - How well do animal models replicate the human disease phenotype?
Due to the technical complexity of replicating the interplay between dozens of sporadic AD mutations and environmental factors in mouse models, most animal research has instead focused on reproducing core pathological hallmarks shared by both sporadic and familial AD - abundant amyloid plaques, NFT, and neuronal loss. As a result, the pathophysiological landscape of sporadic AD - metabolic dysregulation, vascular dysfunction, chronic low-grade inflammation and oxidative damage - remains under-studied.
Amyloid beta injection-induced, chemical injection-induced and senescence-accelerated animal models do not recapitulate the key pathophysiological hallmarks of AD - widespread NFT and neurodegeneration. This is equally the case for genetically-induced animal models of AD via overexpression (APP/PSEN, 3xTg-AD, Tg2576, 5xFAD) and knock-in (NL, NL-F, NL-G-F, APP swe/PSEN1, APP^NL-F, APP^NL-G-F x PSEN1^P117L).
Indeed, out of over 200 experimentally-induced animal models of AD generated so far, none were able to fully recapitulate the disease phenotype. Several groups have attempted to model AD in species other than mice, including chicks, dogs, rats, guinea pigs, rabbits, dolphins, and non-human primates, but without obtaining a more human-relevant phenotype.
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Construct validity - How well do the mechanisms of disease induction in animals reflect the currently understood etiology of the human disease?
The strategy of experimental induction of AD in animals is mainly reliant on introduction of FAD mutations through genetic editing. Overexpression of mutated genes is not representative of mutations found in humans with FAD and sporadic AD, except perhaps for rare cases of familial EOAD in which the APP locus is duplicated. MAPT (tau) mutations inserted in certain mouse models, are not found in AD patients but in patients with frontotemporal dementia, a disorder with distinct mechanisms.
The newer generation knock-in (KI) AD mouse models that combine several AD-associated mutations by using simultaneous multi-locus editing still fall short of recapitulating human-specific gene structure and function, gene expression regulation, epigenetic modifications, post-transcriptional regulation, and modifier genes, limiting the mechanistic relevance to human pathology. Furthermore, mouse models that combine distinct double or triple APP mutations to enhance amyloid pathology, such as DKI NL-F and TKI NL-G-F mice, do not mimic the etiology of FAD, since in FAD patients these mutations are not cumulative but occur individually in separate families or individuals.
Amyloid beta injection-induced, chemical injection-induced and senescence-accelerated animal models do not mimic the genetic and non-genetic causes of FAD and sporadic AD. Animal models of AD are not representative of distinct disease mechanisms that are responsible for heterogenous EOAD and LOAD presentations. The complex interactions between internal and external risk factors that intervene in sporadic AD are not captured in animals, and even if they were, they would be heavily influenced by species-specific differences, producing pathomechanisms that are of doubtful relevance for humans.
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Behavioural test validity - how well do behavioural tests in animals translate to human behaviour?
Behavioural tests in rodent models of AD typically assess learning and spatial memory (Morris water maze, Barnes maze, Y-maze spontaneous alternation), fear-associated memory (contextual and cued fear conditioning), recognition memory (novel object recognition), exploration (rearing), anxiety (elevated plus maze, open field), depression (forced swim test), sociability and social interaction (three-chamber test).
Results of behavioural tests in animals for a given drug candidate are often presented as a promise of cognitive improvement in AD patients, despite the fact that it was demonstrated over and over again that reversal of cognitive decline was not observed in AD patients, revealing a profound disconnect between the faith in preclinical behavioural tests and the cruel reality of clinical failure. Even if robustness of individual behavioural tests was improved, these tests would still fail to recapitulate human-specific cognitive capacities, behavioural patterns and molecular underpinnings.
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Predictive validity – How well do animal models predict safety and efficacy of therapies in patients?
Preclinical research using animal models of AD has consistently failed to produce significant benefits for patients. At least 200 unique compounds were validated in AD animal models in the past two decades. The genetically-induced APP/PSEN, 3xTg-AD, Tg2576 and 5xFAD mouse models have been the backbone of AD drug testing, contributing to the very high failure rate of 99.6% in clinical trials.
Current treatments for AD include symptomatic therapies, that ease the symptoms of AD without addressing its underlying causes (cholinesterase inhibitors and partial NMDA antagonists), and therapies that focus on the underlying causes (aducanemab, lecanemab, and donanemab immunotherapy).
Out of the three immunotherapies targeting Aβ, only lecanemab is currently authorized for use in the EU and only in patients with early AD who carry one or no copies of the APOE4 gene, as to minimize the risk of ARIA in these particularly susceptible AD populations. Due to high frequency of ARIA with serious events, even in non-APOE4 carriers, the EMA issued a negative opinion on the marketing authorization for donanemab in March 2025.
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Ethical validity - How well do animal experiments align with human ethical principles?
Preclinical - Animal research is unethical in essence by human standards, since it involves physical constraint, psychological suffering and deprivation of freedom, social interactions, natural environment, and life purpose. In addition to this baseline, experiments inflict severe clinical harm in animals.
Clinical- Statistics consistently show that clinical success rates of drugs developed and tested in animals is very low, raising the question of whether it is ethical to put the health of patients at risk.
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Intrinsic validity - How well do animal models capture the clinical heterogeneity of the human disease?
Animal models do not recapitulate the clinical heterogeneity in Alzheimer’s disease phenotypes, age-at-onset, etiology, progression rates, and responses to treatments.
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Extrinsic validity - How well does animal experimentation generate reliable and reproducible outcomes?
Contributing factors include flawed experimental design, variation in animal strains and experimental conditions, and lack of transparency on methodology and results of animal studies. In spite of significant investment in dissemination, various incentives and training of animal researchers, the ARRIVE - Animal Research: Reporting of In Vivo Experiments - guidelines remain poorly implemented and the majority of animal experiments is irreproducible. While in vitro methods are not immune to issues of reproducibility, the moral weight of irreproducible animal studies is not the same.
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Key takeaways
Alzheimer’s disease (AD) is a highly debilitating progressive neurodegenerative disorder affecting cognitive function and behaviour. Its prevalence is projected to triple worldwide by 2050, posing a major societal and health care burden.
Critical inter-species differences between animals and humans in brain structure, cognition, behaviour, aging mechanisms, genetics, and gene expression regulation preclude faithful recapitulation in animals of symptoms of this uniquely human disorder.
Due to decades old reliance on animal research to study AD pathogenesis, the exact mechanisms of AD remain unclear.
The failure rate in clinical trials of treatments developed and validated in animal models of AD is as high as 99.6%. To date, none of the treatments tested in AD animal models were able to halt or reverse cognitive decline in AD patients.
A switch from animal-based to human-based research is urgently needed to better understand the cellular and molecular derivers of AD and develop effective therapies adapted to heterogenous disease subtypes.
How is Human-Based In Vitro Testing the Answer to Advance Biomedical Research into Alzheimer's Disease
The following section explores the creative ways in which researchers can leverage human-based in vitro technologies to better understand the mechanisms of AD, identify new therapeutic targets and test efficacy of drug candidates. The list of over 20 suggestions and examples of strategies adopted by researchers includes modelling of heterogenous AD subtypes using AD patient iPSC-derived brain tissues, analysis of the functional impact of sporadic AD-associated genetic variants by parallel editing of multiple loci in human iPSC-derived organoids, investigation of pathways responsible for aging of human neurons through accelerating aging experiments, studying of the mechanisms by which comorbidities affect AD pathogenesis by employing multi-organ-on-chip systems and testing of the ability of compounds to inhibitor aβ and tau aggregation by real-time tracking of aggregation kinetics in FAD and sporadic patient-derived brain organoids.
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