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The neuropathology of aging and Alzheimer’s disease in domestic cats
* Corresponding author: Warren Ladiges
Mailing address: Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA.
Email: wladiges@uw.edu
Received: 17 June 2025 / Accepted: 18 June 2025 / Published: 27 June 2025
DOI: 10.31491/APT.2025.06.171
Abstract
Current animal models for Alzheimer's disease (AD) research face significant translational challenges, with many promising preclinical findings failing to yield effective human therapies. Interestingly, aging pet cats naturally develop neuropathology-like lesions representing amyloid beta plaques and neurofibrillary tangles containing hyperphosphorylated tau, in contrast to most other AD animal models that primarily exhibit amyloid plaques. Pet cats share environmental exposures with humans, develop similar age-associated comorbidities, and exhibit behavioral changes that correspond to neuropsychiatric disorders in humans that often precede AD dementia. Clearly, domestic cats represent an underutilized but superior model for investigating AD pathogenesis and gerotherapeutic interventions, but extensive funding will be needed to develop networks of pet cat owners and referring veterinarians to take advantage of these translational characteristics.
Keywords
Alzheimer's disease, domestic cats, aging, neuropathology, translational animal model, research funding
Changes in brain structure and function continue throughout life,
and studies at multiple levels of analysis in model organisms
and humans are helping to define the normal trajectory of changes
in the brain over the adult lifespan. Human and animal studies
suggest that adaptive or resilient processes may be needed for
maintenance of brain structure and function during normal aging.
At the molecular and cellular level of analysis in animal models,
brain aging is associated with changes in gene and epigenetic expression,
mitochondrial and energy metabolism, protein homeostasis, neural plasticity,
and synaptic function. What remains unclear is when these aging changes
transition to pathological aging and disease phenotypes. Complicating
the understanding of the role of aging in AD is the fact that most animal
studies employ adult but not aged genetic models of disease. Integration
of research at various levels of analysis, from cells to neural networks,
in older adults and in appropriate animal models is needed to reach a global
understanding of brain aging and its contribution to, and promotion of,
pathological processes underlying AD.
AD is the most common neurodegenerative disease in humans, affecting millions
of people worldwide and accounting for nearly two thirds of dementia cases.
The disease is characterized by pathologic accumulations of two types of
protein aggregates in specific brain regions, which include plaques
composed of amyloid beta (Aβ) peptide, and neurofibrillary tangles (NFTs)
composed of hyperphosphorylated tau protein formed intracellularly in neurons.
These accumulations contribute to progressive neuronal loss and cognitive
dysfunction. Transgenic rodent models historically have been used to
investigate pathophysiologic mechanisms and identify candidate drugs for
early preclinical studies, however, candidate drugs validated in these
models have generally failed in human clinical trials. A better understanding
of the mechanisms and pathogenesis of AD in an animal model that naturally
develops similar pathologies of AD would be invaluable for developing new
translational therapeutic strategies targeting the disease.
Several animal species have been shown to develop one or more age-related
lesions that are comparable to AD. In general, nonhuman primates and dogs
develop spontaneous A deposition with age, but do not reliably recapitulate
tau pathology. Wild-type rodents also do not spontaneously form plaques or
NFTs, but genetically engineered mice have been developed that have single,
double or multiple mutations in genes responsible for the production of A and/or
tau proteins. It is now becoming clear that domestic cats can spontaneously
develop both Aβ deposition and NFTs, as well as associated neuronal loss, in a
pattern of distribution similar to humans, and which develop with increasing
age [1]. Concurrently with the
progression of neuropathology, cats develop behavioral and cognitive dysfunction.
Aβ deposition can be seen in the brains of adult pet cats predominantly
as plaques composed of Aβ1-42. They are most commonly found in the cerebral
cortex, with extension to the hippocampus and basal ganglia. Adult cats
also express 6 tau isoforms, including hyperphosphorylated 3R and 4R
isoforms, which can form aggregates in the presence of Aβ in the form
of pretangles, threads, dystrophic neurites, NFTs or ghost tangles.
These features of feline NFTs, accompanied by neuronal loss and occurring
with intracellular oligomers in the same brain region, distinguish the
cat from dogs and nonhuman primates.
The aging pet cat is therefore an innovative model to study AD because
of the development of naturally occurring AD-like lesions, with similar
comorbidities as older people, sharing the same environment, and with
the development of behavioral changes with increasing age. In addition,
pet cats have not been studied with the explicit intent of using a
scientifically valid translational animal model for brain aging and
AD. The concept of a cat brain infrastructure based on neuropathology
is highly innovative and will provide access to a model of brain aging
and AD that will allow in-depth investigation into causes and mechanisms
not available in other animal models.
The impact the domestic cat AD model can have on human health is highly
significant because new information gathered regarding brain aging as a
risk factor for the development of AD-like neuropathology can reveal
targets for gerotherapeutic treatment and intervention. The fact that
cats can be challenging to determine levels of cognitive impairment
does not diminish the value of the model since a number of abnormal
neuropsychiatric behaviors are seen in both cats and humans, which
in humans can be associated with increased risk for AD. This neuropsychiatric
aspect of AD is less studied because there are no well characterized animal
models. Early onset of neuropsychiatric problems in pet cats based on owner
history and veterinary clinical records can be used as predictive phenotypes
in preclinical therapeutic trials. The domestic pet cat thus has unique
advantages as a naturally occurring model of AD that can provide the
translational relevance needed to advance the successful treatment
and prevention of AD. But funding for the development of networks of pet
cat owners and referring veterinarians will be needed to take full advantage
of this model.
Declarations
Availability of data and materials
Not applicable.
Financial support and sponsorship
Referenced studies were supported in part by NIH grant R01 AG067193 (Ladiges- PI).
Conflicts of interest
Warren Ladiges is a member of the editorial board of Aging Pathobiology and Therapeutics. The authors declare that they have no conflicts and were not involved in the journal’s review or decision regarding this manuscript.
References
1. Jenna Klug, Jessica M. Snyder, Martin Darvas, C Dirk Keene, & Warren Ladiges. Aging pet cats develop neuropathology similar to human Alzheimer’s disease. Aging Pathobiology and Therapeutics, 2020, 2(3): 120-125.