Abstract
Canine cognitive dysfunction (CCD) is a common neurodegenerative disorder among geriatric dogs, characterized by disorientation, interaction changes, sleep-wake cycle disturbances, house soiling, activity level changes, and anxiety. Canine cognitive dysfunction is currently underdiagnosed due to the lack of an objective and reliable diagnostic tool, and treatment options are severely limited. Importantly, CCD shares common pathological hallmarks of human Alzheimer disease, such as β-amyloid accumulation, τ protein phosphorylation, neuronal loss, and neuroinflammation. β-Amyloid deposits in Alzheimer disease and CCD appear in 2 main forms: extracellular amyloid plaques, which disrupt synaptic function and contribute to neurotoxicity, and cerebral amyloid angiopathy, where β-amyloid accumulates in the walls of cerebral blood vessels. Cerebral amyloid angiopathy leads to vascular dysfunction, chronic hypoxia, microhemorrhages, and neuroinflammation, further exacerbating cognitive decline. Research into these shared pathologies offers potential therapeutic targets that could benefit both canine and human patients suffering from these neurodegenerative disorders. In this article, we review the latest understanding of CCD pathology and discuss new advancements in diagnostic and therapeutic options as well as the outlook of the CCD disorder.
Canine cognitive dysfunction (CCD) is a neurodegenerative disorder that predominantly affects geriatric dogs. It is estimated that the prevalence of CCD is 8.1% in ages 8 to 11 years, 18.8% in ages 11 to 13 years, 45.3% in ages 13 to 15 years, and 67.3% in ages 15 to 17 years.1 Dogs with CCD typically show signs of disorientation, altered social interactions, altered sleep-wake cycles, loss of housetraining/other learned behaviors, altered activity levels, and increased anxiety (DISHAA).2 These behavioral signs are used for the clinical diagnosis of CCD. Additional symptoms include vision and olfactory impairment, tremors, and head ptosis.3
Despite its high prevalence, CCD is frequently underdiagnosed, particularly in its early stages, mainly due to the absence of reliable biomarkers.4 The current diagnosis of CCD relies heavily on behavioral questionnaires filled out by the caregivers that can be influenced by other confounding factors. Canine cognitive dysfunction shares substantial similarities in clinical features with human Alzheimer disease (AD), and both conditions are characterized by progressive cognitive decline, which manifests as disorientation, memory loss, and changes in behavior (Table 1).5 Cumulative evidence supports that both diseases share similar pathogenic mechanisms, which involve the accumulation of β-amyloid (Aβ) plaques and τ protein hyperphosphorylation in the brain, leading to neuroinflammation, neuronal loss, and synaptic dysfunction.6 In this article, we review the latest understanding of the pathology of CCD and recent advancements in the diagnosis and treatment of the disease.
Clinical signs associated with the progression of Alzheimer disease and canine cognitive dysfunction (CCD).5
| Severity | Alzheimer disease | CCD |
|---|---|---|
| Mild | Mild memory lapses and increased difficulty completing complex tasks | Increased anxiety, reduced interactions with owner, altered sleep patterns, and confusion with familiar routines |
| Moderate | Increased memory loss, personality changes, and disorientation and difficulty with regular tasks | Increased confusion and disorientation, reduced responsiveness, and occurrences of house soiling |
| Severe | Loss of cognitive functions, cannot identify familiar people and/or objects, and cannot perform basic tasks | Severe memory loss, loss of basic skills including house training, aimless wandering, vocalization, and significant sleep disturbance |
Neuropathology in CCD
Beta-amyloid plaques
Beta-amyloid is generated from the cleaving of amyloid precursor protein, and the aggregation of Aβ into senile plaques in the brain has long been the primary focal point in the pathogenesis of AD.7 The amyloid hypothesis theorizes that the plaques interfere with neuronal signaling and activate glial cells, specifically astrocytes and microglia, subsequently triggering neuroinflammation.8 In dogs, Aβ appears to play a similar critical role in CCD development. Cummings et al9 reported that Aβ deposition is a contributing factor to age-related CCD prior to the onset of neurofibrillary tangle (NFT) formation. Furthermore, Urfer et al10 quantitatively measured Aβ42 (a specific Aβ peptide isoform that is 42 amino acids long) levels in 3 areas of the companion dog brain (prefrontal cortex, temporal cortex, and hippocampus/entorhinal cortex) and CSF using a newly developed Luminex assay. They found significant positive correlations between Aβ42 and age in all 3 brain regions, and brain Aβ42 abundance in these regions was correlated with the CCD Scale (CCDS) score in a multivariate analysis. Additionally, Schmidt et al11 examined the frontal cortex, hippocampus, and entorhinal cortex of 24 dogs aged 10 years or older from various breeds, concluding that highly neurotoxic pyroglutamyl Aβ plaques are deposited in the dog hippocampus with significantly more pyroglutamyl Aβ plaques in small and medium dogs than in large dogs.
Nevertheless, contradictory findings have been reported, showing no statistically significant correlation between Aβ load and CCD symptoms.12 Ozawa et al12 reported that while Aβ deposits consistently increased with age, they did not correlate strongly with the CCDS score. In contrast, the increases of ubiquitin-positive granules, astrocytes, and microglia are significantly correlated with CCD. These results suggest that Aβ deposition may not be a direct pathogenic factor of CCD and that synaptic impairment, myelin disruption, and glial activation could be more critical to CCD pathogenesis.12
Tau Phosphorylation
Hyperphosphorylation of the τ protein and the subsequent formation of NFTs is another hallmark of AD. The τ hypothesis states that the formation of NFTs mediated by τ phosphorylation disrupts cytoplasmic functions and axonal transport, leading to neuronal death.13,14 Several studies13,15 have shown phosphorylated τ deposits, similar to human AD, in the brains of CCD-affected dogs. For instance, Abey et al15 examined 6 CCD brains and 6 controls. They showed that all CCD dogs displayed elevated S396 p-τ labeling throughout the circuit, and tauopathy was prominently observed particularly in the cingulate and temporal lobes, which is consistent with early Braak staging patterns in AD.15 Habiba et al13 investigated phosphorylated τ in the cortical and hippocampal regions of 5 CCD-affected and 2 nondemented aged dogs by using immunohistochemical and immunofluorescence analysis. Their result showed extensive deposition of intracellular phosphorylated τ in the hippocampal and frontal cortex region, replicating morphological and regional distribution similar to human AD pathology.13 Additionally, Hines et al16 examined τ phosphorylated at 2 different sites, Thr181 and Thr217, in canine brains, demonstrating that fibril formation of τ phosphorylated at Thr181 and intracellular accumulation of τ phosphorylated at Thr217 in the cortices and hippocampus of aged canines compared to young animals. Their study also showed that phosphorylated τ at Thr217 in the cortical brain regions of aging canines was specific to dogs with CCD.
Astrocyte and microglial cell activation and hippocampal atrophy
Emerging evidence suggests that inflammation is a central component during AD progression. This AD hypothesis proposes that accumulation of Aβ triggers the recruitment and activation of microglia and astrocytes, leading to the secretion of proinflammatory mediators and subsequent neuroinflammation. Specifically, activated microglial cells exhibit a phagocytic response and express nitric oxide synthase that contributes to neuronal damage.14 This inflammatory response is believed to play a crucial role in the progression of AD by exacerbating neuronal loss and cognitive decline. Similar activation of microglia and astrocytes has been observed in CCD dogs where levels of nitric oxide synthase are significantly elevated compared to cognitively unimpaired dogs, suggesting a parallel inflammatory mechanism between CCD and AD.17,18 This finding underscores the potential utility of CCD as a model for studying AD, providing insights into the inflammatory processes that may drive neurodegeneration in both species.
The hippocampus, a crucial region for learning and memory, undergoes rapid atrophy over the progression of AD.19 This atrophy is strongly associated with the cognitive decline seen in affected individuals. Similarly, dogs with CCD show significantly smaller hippocampal volumes when normalized to total brain volume compared to control dogs. However, the authors of the study caution that hippocampal volume alone is not a reliable diagnostic measure for CCD in individual dogs due to substantial overlap between the hippocampal volumes of dogs with and without CCD.20
Diagnostic Biomarkers
The current diagnosis of CCD relies predominantly on behavioral questionnaires filled out by the caregivers. The most commonly used questionnaires include the Canine Dementia Scale and CCD Rating (CCDR) scale. Both questionnaires focus on behavioral changes related to DISHAA and provide a rating of the severity of the dog’s cognitive deficit.5 There are several challenges to this questionnaire’s approach as it heavily depends on caregiver’s ability to accurately identify and recall subtle behavioral changes. Furthermore, some behavioral changes may not be related to CCD but could instead be triggered by other factors, such as environmental influences, like noise or air pollution, or by other illnesses.
In human AD, Aβ42 clearance is reduced, and more Aβ42 is deposited in the brain. Consequently, lower plasma Aβ42 levels are observed in AD patients compared to their counterparts.21 Panek et al22 observed that plasma Aβ42 levels were negatively correlated with the Canine Dementia Scale, indicating that dogs with lower plasma Aβ42 levels exhibited greater severity of CCD. Nevertheless, conflicting findings have been reported as well. For instance, Phochantachinda et al23 explored the relationship between plasma Aβ42 levels, measured by ELISA, and CCDR scores in adult, aging, and CCDS dogs. They further used proteomics analysis to identify potential plasma biomarkers underlying CCD, showing that plasma Aβ42 levels considerably overlapped within the CCD and aging groups without a correlation with the CCDR score in the CCD group.23 In consistence, Schütt et al24 showed that plasma Aβ42 concentration levels in the CCD group were greater compared to the control. Additionally, Stylianaki et al25 examined the Aβ42 oligomer levels in CSF, which is generally considered to be more accurate than plasma readings. They did not find a statistically significant difference in the CSF Aβ42 levels between cognitively unimpaired geriatric dogs and geriatric dogs with severe cognitive impairment. However, they observed a significant reduction in CSF Aβ42 levels in geriatric dogs with mild cognitive impairment compared to controls. This finding suggests that CSF Aβ42 levels might be a more sensitive marker for early cognitive changes but are not consistent enough for diagnosing severe impairment.25
The inconsistent results regarding Aβ as a biomarker for CCD raise concerns about its reliability. Similarly, phosphorylated τ does not appear to be a promising candidate either as several studies26,27 showed no evidence of tauopathy or the formation of NFTs in dogs with CCD. Although dogs with CCD exhibit reduced hippocampal volume, the significant overlap between affected and unaffected dogs limits the utility of hippocampal atrophy as a reliable diagnostic marker.28 Testing for microglial cells or astrocyte activation may be a viable candidate, but further studies are warranted to fully assess its reliability.
Furthermore, Vikartovska et al26 conducted biochemical analysis in serum, showing slightly elevated liver enzyme parameters (AST and ALT) and significantly decreased sodium and chloride levels in mild-CCD dogs. They reported for the first time a significant increase of neurofilament light chain levels in the blood serum of dogs with mild CCD compared to both normally aging seniors and young control dogs. This novel finding suggests that neurofilament light chain could serve as a potential biomarker for early CCD detection.26
Prevention and Treatment
Prevention and therapeutic strategies for CCD include diet supplements, medication, and cell therapy for hippocampal restoration (Table 2).
Overview of therapeutic approaches evaluated for CCD, including pharmacological agents, dietary interventions, supplements, and physical therapies.
| Therapy | Target | Study design | Brief result | Reference |
|---|---|---|---|---|
| Antioxidants | Oxidative stress | 2.8-year feeding study in aged dogs with mitochondrial cofactors and antioxidants | Improved cognitive function but no reduction in neuron loss in the hippocampus | 29–31 |
| Cyanidin-3-O-glucoside | Aβ accumulation and cognitive dysfunction | 90-day feeding study with honeyberry extract | Significant reduction in cognitive dysfunction scores and serum Aβ levels in dogs with CCD | 23 |
| DHA and sphingolipids | Neuroprotection, neuroinflammation, and synaptogenesis | 6-month study with aged Beagles receiving lipid extract containing DHA and sphingolipids | Significant improvement in spatial learning and glutamate levels in the frontal lobe | 32–34 |
| BPB | Cognitive function and brain aging | 6-month study with dogs tested on spatial learning tasks | Significant improvement in performance on complex cognitive tasks, supporting cognitive health in aging dogs | 35–38 |
| MCT | Cognitive function and alternative energy source | 8-month feeding study with MCT-supplemented diet on aged dogs | Significant improvements in cognitive function | 39–41 |
| MCT and BPB combination | Cognitive function and brain aging | 90-day clinical study with senior dogs on MCT + BPB diet | Significant improvements in all 6 DISHAA signs of CDS in dogs fed 6.5% MCT + BPB diet | 42 |
| SAMe tosylate | Mental impairment and cognitive dysfunction | 2-month study with 36 dogs with CCD signs receiving SAMe or placebo | Significant improvement in activity, awareness, and cognitive function | 43 |
| Selegiline | Neuroprotection, dopaminergic and cholinergic function | 60-day clinical trial with 641 dogs on selegiline treatment | 77.2% of dogs showed improvement, particularly in disorientation and sleep-wake cycles | 44, 45 |
| Nicergoline | Sleep-wake cycle and learned behaviors | Observational study in 70% of dogs with CCD | Alleviated sleep-wake cycle and loss of learned behaviors | 46–48 |
| Cholinesterase inhibitors | Cholinergic function | Studies with phenserine, donepezil, and other inhibitors in dogs with CCD | Improved memory and cognitive function in dogs with CCD | 49–51 |
| Senolytic agents and NAD+ precursors | Cellular aging, neuroinflammation, and neuronal degeneration | Experimental study on dogs with CCD | Significant improvements in CCD scores by removing senescent cells | 52, 53 |
| Calcium dysregulation (apoaequorin and tacrolimus) | Intracellular calcium, oxidative stress, and neuroinflammation | Experimental studies with dogs and rats | Significant cognitive improvements and reduced amyloid deposition with calcium-targeted treatments | 54–56 |
| Cell therapy (skin-derived neuroprecursors) | Synaptic restoration and neuron regeneration | Pilot study with microinjections of skin-derived neuroprecursors into hippocampus | 4 of 5 dogs showed symptom reversal and increased hippocampal synaptic density | 57 |
| Physical activity | Cognitive function and symptom progression | Observational study with 11,574 dogs, including 287 with CCD | Higher physical activity associated with lower severity of CCD symptoms and slower progression | 58–60 |
| RD2 | Aβ oligomers and memory deficits | Clinical trial with cognitively impaired Beagles receiving RD2 | Improved short-term memory and cognition in Beagles, suggesting a potential therapy for CCD | 61 |
For each therapy, the table outlines the physiological targets, study design, and key findings.
Aβ = β-amyloid. BPB = Brain protection blend. DHA = Docosahexaenoic acid. DISHAA = Disorientation, interaction changes, sleep–wake cycle disruption, house soiling, activity changes/anxiety. MCT = Medium-chain triglyceride. RD2 = Rational design 2. SAMe = S-adenosylmethionine.
Diet and supplements
Antioxidants—Oxidative stress is considered a primary factor in brain aging and AD, and consequently, the use of exogenous antioxidants to mitigate oxidative damage has become a prominent focus in antiaging research.29,30 Cotman et al31 conducted a 2.8-year feeding study in which aged dogs were given a diet supplemented with mitochondrial cofactors and antioxidants (such as vitamin E, vitamin C, grape pomace, and carrot granules). They found that the specialized diet dramatically improved the ability of aged dogs to learn more difficult tasks in comparison to those fed the control diet. Interestingly, despite these cognitive improvements, the specialized diet did not reduce neuron loss in the hilus of the hippocampus compared to age-matched control dogs.31 These findings suggest that while a combination of exogenous antioxidants and mitochondrial cofactors may enhance cognitive function in older dogs, they are insufficient to prevent irreversible neuron loss. In another study, Lee et al23 examined the impact of dietary flavonoids in pet foods on dogs with CCD. After 90 days of feeding the pet food containing cyanidin-3-O-glucoside, the primary component of honeyberries, they observed a significant reduction in both cognitive dysfunction scores and serum Aβ levels, suggesting that dietary flavonoids can effectively improve cognitive dysfunction scores and reduce serum Aβ levels in dogs.23
Docosahexaenoic acid and sphingolipids—Docosahexaenoic acid (DHA) is the main omega-3 polyunsaturated fatty acid in the brain, and it plays a crucial role in neuroprotection, neuroinflammation, and synaptogenesis.32 Docosahexaenoic acid has been shown to suppress the Aβ signaling pathway, reducing the production and accumulation of Aβ deposits in the brain.33 Araujo et al34 investigated the effectiveness of a novel lipid extract containing porcine brain–derived sphingolipids in combination with DHA in alleviating cognitive deficits on aged Beagles with CCD. Over a 6-month period, the Beagles receiving the lipid extract supplement showed significantly improved performance on challenging spatial discrimination and reversal learning tasks compared to those given a placebo. Magnetic resonance spectroscopy further revealed a significant increase in frontal lobe glutamate and glutamine levels in the supplemented group, suggesting physiological changes linked to the DHA and sphingolipids diet supplement. These findings indicate that the lipid extract may help counteract age-related cognitive deficits in dogs.34
Brain protection blend—Previous studies32,35 have confirmed that antioxidants improve cognitive performance by combating oxidative stress, and DHA is crucial for brain health and function. Additionally, L-arginine (a precursor to nitric oxide) plays a vital role in learning and memory processes, and vitamins B6 and B12 are particularly important for maintaining cognitive function.36,37 Leveraging these components, Pan et al38 developed the brain protection blend (BPB), which combines antioxidants, DHA-containing fish oil, l-arginine, and B vitamins to enhance cognitive function in older dogs. Over a 6-month study, dogs were tested on spatial learning tasks, including landmark discrimination and egocentric discrimination. The BPB-supplemented group exhibited significantly better performance on the landmark discrimination task and 2 egocentric discrimination reversal tasks compared to the control group, indicating that the benefits of BPB are particularly evident with task complexity.38 These findings suggest that long-term BPB supplementation could improve cognitive function and support nutritional strategies to address age-related cognitive decline.
Medium-chain triglycerides—Poor cerebral glucose metabolism, resulting from disruptions in the insulin signaling pathway, is commonly observed in aging rodents, monkeys, humans, and dogs.39 This impairment means the brain cannot effectively utilize glucose, leading to insufficient energy for neuronal signaling and overall brain function. As an alternative energy source, ketones can be utilized by the brain when glucose is inadequate. Research has shown that increasing ketone availability can enhance cognitive function in cognitively impaired individuals.40 Pan et al41 examined the impact of dietary supplementation with medium-chain triglycerides (MCTs), which can help the body produce ketones for energy, on the cognitive function of aged dogs. The treatment group fed a diet supplemented with 5.5% MCT over an 8-month period was subjected to landmark discrimination learning, egocentric visuospatial function, and attention. The result demonstrated that the MCT-supplemented group performed significantly better in most cognitive tests compared to the control group, with the most notable improvements seen in more challenging tasks.41 Additionally, the MCT group had significantly elevated levels of β-hydroxybutyrate, a ketone body.41 These findings indicate that long-term MCT supplementation can enhance cognitive function in aged dogs by providing the brain with an alternative energy source. Moreover, the combination of MCT and BPB was tested in a clinical study42 involving 87 senior dogs with CDS, which were divided into 3 diet groups, with 29 dogs/group: control, 6.5% MCT plus BPB, and 9% MCT plus BPB. After 90 days, the diet of 6.5% MCT plus BPB led to significant improvements in all 6 DISHAA signs associated with CDS, whereas the control group improved in only 4 signs.42 This study confirms the effectiveness of MCT and BPB in managing CDS, supporting that targeting brain aging risk factors can enhance cognitive function in dogs.
S-adenosylmethionine tosylate supplementation—Rème et al43 evaluated the effectiveness of oral S-adenosylmethionine (SAMe) tosylate (Novifit tablets; Virbac) as a dietary aid for managing age-related mental impairment in dogs. Thirty-six dogs over 8 years old with CCD signs were divided into 2 groups: 1 received 18 mg/kg SAMe tosylate (17 dogs), and the other received placebo tablets (19 dogs) for 2 months, with no concurrent behavioral treatments. Behavior and locomotion difficulties were evaluated using a 14-item questionnaire. Dogs treated with SAMe tosylate showed significantly greater improvements in activity and awareness compared to the placebo group at both 4 and 8 weeks.43 The overall mental impairment score reduced by over 50% in 41.2% of SAMe tosylate–treated dogs versus 15.8% of placebo-treated dogs at week 8. S-adenosylmethionine tosylate was safe and effective in improving age-related mental decline in dogs.43
Medication
Selegiline, also known as L-deprenyl, is currently the only FDA-approved drug for the treatment of CCD. Campbell et al44 reported a clinical trial involving selegiline hydrochloride administered at doses of 0.5 to 1.0 mg/kg once daily for 60 days in 641 dogs with CCD. By the end of the study, 77.2% of the dogs showed an overall improvement, with only minor adverse effects. The response to the treatment varied by symptom, with improvements ranging from 67.8% in activity or sleep-wake cycle to 77.8% in disorientation and interaction with family members.44 As a type B monoamine oxidase inhibitor, selegiline improves CCD by contributing to neuroprotective effects on dopaminergic, noradrenergic, and cholinergic neurons in dogs.6,45
Nicergoline, an α-adrenergic antagonist, has been used to treat cognitive, affective, and behavioral disorders of older people in over 50 countries for more than 3 decades, and recent findings suggest its potential for AD treatment.46,47 At present, nicergoline is also recommended for dogs with CCD. Seksel48 reported that nicergoline has alleviated sleep-wake cycle alteration and loss of learned behaviors in 70% of cases.
Both AD and CCD are characterized by cholinergic hypofunction, with reduced levels of acetylcholine and butyrylcholine.49 Cholinesterase hydrolyzes these cholinergic neurotransmitters, so cholinesterase inhibitors should upregulate their levels. Of the 4 FDA-approved drugs for AD, 3 are cholinesterase inhibitors.50 Studies49,51 have shown that treating dogs with cholinesterase inhibitors, such as phenserine, donepezil, and a novel butyrylcholinesterase inhibitor, improved memory and cognitive functions. The fourth FDA-approved drug for AD, memantine, is an N-methyl-d-aspartate receptor inhibitor. Overactivation of N-methyl-d-aspartate receptors has been shown to increase reactive oxygen species production and the formation of Aβ.62 Although memantine has yet to be tested for CCD, it has been studied for treating canine compulsive disorders and was well tolerated by the dogs.63
Senescence is characterized by DNA damage, shortened telomeres, and overall cellular aging. Normally, senescent cells are cleared by immune cells; however, this process is impeded by aging and in conditions such as AD and CCD. The removal of senescent cells has been shown to reduce amyloid and τ pathologies, neuronal degeneration, and neuroinflammation.52 A recent study53 has demonstrated that dogs treated with a combination of senolytic agents (compounds that promote the death of senescent cells) and NAD+ precursors exhibit significant improvements in CCDR scores.
Intracellular calcium dysregulation is a common feature observed in both AD and CCD.54,55 This dysregulation is associated with increased oxidative stress, neuroinflammation, and the activation of glial cells.54 Treatment with the calcium-buffering protein apoaequorin has resulted in significant improvements in cognitive task performance in dogs, even surpassing the benefits observed from administering the FDA-approved drug selegiline.55 Additionally, disruption of intracellular calcium levels also upregulates calcineurin signaling in AD, leading to synaptic loss, Aβ production, and overall cognitive decline. A study56 shows that treating aging dogs with tacrolimus, a calcineurin inhibitor, reduced age-related deficits to memory and Aβ deposition as measured by CSF biomarkers. This suggests that targeting calcium dysregulation and calcineurin signaling could be a promising therapeutic strategy for mitigating cognitive decline in both AD and CCD.
Other treatments
The effect of cell therapy has been investigated in dogs. Valenzuela et al57 explored a novel cell therapeutic approach for treating CCD in older dogs. Six dogs diagnosed with CCD received microinjections of 250,000 autologous skin-derived neuroprecursors into the hippocampus. The result indicated that despite 1 adverse event, 4 out of 5 dogs experienced improvements, with 2 achieving full reversal of symptoms lasting up to 2 years.57 Postmortem analysis revealed significantly higher hippocampal synaptic density and neuron intensity compared to untreated dogs. Similar results were replicated in an aged rat model, showing reversal of memory deficits and synaptic depletion.57 The study suggests that the cell therapy of the skin-derived neuroprecursors could potentially restore neurosynaptic function in CCD dogs.
Physical activities were previously shown to significantly protect against cognitive decline in AD, and similar research has been conducted for CCD as well.58,59 Bray et al59 investigated the connection between physical activity and cognitive health in companion dogs in 11,574 dogs aged 6 to 18 years, including 287 dogs diagnosed with CCD. Using owner-reported data on cognitive health, physical activity, health conditions, training history, and dietary supplements, they found that higher physical activity levels were significantly associated with lower severity of cognitive dysfunction symptoms, slower symptom progression, and reduced likelihood of CCD diagnosis. Additionally, Yarborough et al60 reported that, when controlling for factors such as age, health status, and breed type, inactive dogs were 6.47 times more likely to develop CCD compared to highly active dogs. These findings suggest that regular physical activity is a crucial component in mitigating the risks of CCD in dogs.
Given the significant overlap in the pathogenesis of AD and CCD, treatments developed for AD may also apply to CCD. For example, an all D-enantiomeric peptide named RD2 is a novel drug candidate for AD that is under clinical development. It specifically targets and disassembles Aβ oligomers by breaking down Aβ monomers. A recent study61 that administered RD2 to cognitively impaired Beagles has reported improvements in short-term memory and cognition. While most therapeutic efforts for AD have focused on Aβ, even the most promising compounds have failed to show definitive therapeutic efficacy in clinical trials. Consequently, the focus is shifting toward tauopathy-targeted approaches, including monoclonal antibodies, like gosuranemab, tilavonemab, semorinemab, and zagotenemab, and vaccines (eg, AADvac; Axon Neuroscience SE).64 Given the promising results from clinical trials, these agents warrant investigation for CCD treatment. However, it is important to note that NFTs are not typically observed in CCD, which may limit the efficacy of anti-τ treatments in this context.
Conclusions
Canine cognitive dysfunction is a prevalent and increasingly recognized neurodegenerative disorder that affects aging dogs, and it shares several clinical, pathological, and molecular characteristics with AD in humans. Despite its pervasiveness, current diagnostic and treatment options remain limited. Diagnosis primarily relies on behavioral questionnaires, which can be error-prone due to owner subjectivity, environmental factors, and the presence of other conditions that may mask or exacerbate symptoms. Advances in diagnostic imaging, biomarker identification, and cognitive assessment tools have significantly improved early detection, but further refinements are needed to enhance accuracy and reliability.
Given the strong parallels between CCD and AD, numerous treatment approaches developed for AD have been explored for CCD. These interventions target Aβ accumulation, mitigate oxidative stress, or reduce neuroinflammation. In addition to pharmacological treatments, holistic strategies, such as environmental enrichment, tailored nutrition, and dietary supplements, offer promising complementary and preventive benefits.
Future research should further focus on the understanding of CCD’s molecular mechanisms, the development of targeted therapies, and preventive strategies. Comparative studies between CCD and AD present a unique opportunity to uncover shared pathological mechanisms, which potentially advance both CCD and human AD. Ultimately, a collaborative approach involving veterinarians, researchers, and pet owners is essential for improving early intervention, advancing treatment strategies, and enhancing the overall well-being of aging canine companions.
Acknowledgments
None reported.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the composition of this manuscript.
Funding
The authors have nothing to disclose.
ORCID
Jijun Hao https://orcid.org/0000-0002-6769-9069
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