Abstract

Cognitive impairment is a prevalent and disabling non-motor feature of Parkinson’s disease (PD), distinct from the pathological and clinical profiles of Alzheimer’s disease (AD), often characterized by deficits in executive function, attention, and processing speed rather than memory loss. In PD, mild cognitive impairment (MCI) may emerge early in the disease trajectory, even preceding motor symptoms, and significantly elevates the risk of progressing to dementia, which affects approximately 50–90% of patients over time. Early identification of individuals at risk for this progression is critical to empower patients, caregivers, and healthcare providers to implement proactive care planning, including symptom management, lifestyle modifications, and potential neuroprotective interventions. Recent advances in biomarker research, neuroimaging, and cognitive screening tools have enhanced the ability to predict vulnerability to dementia, offering opportunities to tailor prevention strategies. This review synthesizes current findings to highlight how targeted approaches such as cognitive training, pharmacological trials, and addressing modifiable risk factors like sleep disturbances or depression could delay or mitigate dementia onset in PD. By bridging gaps in understanding the neurobiological pathways linking PD and cognitive decline, these strategies aim to improve long-term outcomes and quality of life for those living with the disease.

Introduction

Parkinson’s disease (PD) has historically been viewed primarily as a motor disorder, but there is growing recognition of its significant impact on cognitive function [1]. Cognitive decline is a prominent non-motor symptom in PD, with dementia (PDD) being a serious long-term consequence that many patients eventually face. Cognitive changes can manifest even before a PD diagnosis, and a notable proportion of newly diagnosed individuals already exhibit cognitive deficits [2]. Furthermore, a considerable percentage of non-demented patients experience mild cognitive impairment (MCI), which is a strong predictor of progression to dementia [3]. Considering these findings, this review aims to present the current evidence base, explore potential underlying mechanisms, and discuss the implications of these findings for designing prevention strategies to mitigate the development of dementia in individuals with Parkinson’s disease.

The prevalence and progression of cognitive impairment in PD

The cognitive impact of PD is substantial and begins early in the disease course. Studies indicate that approximately 25% of individuals with PD exhibit subtle cognitive decline or mild cognitive impairment (MCI) at the time of diagnosis [4]. The long-term prognosis is even more concerning, with research suggesting that as many as 83% of patients will develop dementia after 20 years [4]. Importantly, cognitive deficits can sometimes precede motor symptoms, highlighting the potential for presymptomatic cognitive decline [5]. Individuals with PD face a three to five times greater risk of developing cognitive impairment compared to age-matched controls without PD [6].

Cross-sectional studies estimate the prevalence of Parkinson’s Disease Dementia (PDD) to be between 24% and 31% [7]. However, longitudinal studies reveal a stark increase in dementia risk with disease duration. A cohort study demonstrated a progressive rise in dementia incidence, with estimated risks ranging from 3% to 12% within the first 5 years of PD diagnosis, escalating to 9%–27% after 10 years. Beyond the 10-year mark, the prevalence of dementia dramatically increases, reaching an estimated 50% at 15 years, 74% at 20 years, and a substantial 90% after 25 years of living with Parkinson’s disease [8]. These alarming figures underscore the crucial need for long-term monitoring and the development of effective interventions to mitigate the development of dementia in individuals with PD. Meta-analyses confirm this heightened risk, demonstrating an annual risk of dementia of around 4.5% in PD patients and indicating that individuals with PD are over three times more likely to develop dementia than healthy controls [9]. (Figure 1).

The cognitive decline observed in PD and PDD is not a simple, singular process but rather a complex interplay of several interacting factors. Multiple mechanisms have been implicated, contributing to the multifaceted nature of the disease. These include dysregulation of neurotransmitter systems, neuroinflammation, abnormal protein aggregation, and structural brain changes.

Potential mechanism

The progression of cognitive decline and dementia in Parkinson’s disease (PD) is driven by a complex interplay of neurotransmitter system dysregulation, proteinopathies, genetic predispositions, and clinical risk factors. (Figure 1).

At the neurochemical level, dopaminergic and cholinergic denervation play critical roles in specific cognitive domains [10]. The relationship between executive function and dopamine is underscored by evidence that striatal dopamine denervation and D2 receptor deficiency in the insula lobe are strongly correlated with mild cognitive impairment in PD [11]. Functional magnetic resonance imaging (fMRI) studies demonstrate decreased neural activity within frontal-striatal circuits specifically involving the prefrontal cortex, striatum, and thalamus – when patients with executive dysfunction are subjected to task-switching and working memory paradigms [12]. Furthermore, postmortem evaluations reveal that PD patients exhibiting dopaminergic neuronal deficiency in the ventral tegmental area (VTA) have a heightened tendency to convert to dementia [13]. Positron emission tomography (PET) imaging corroborates these findings, showing a reduction in D2 receptor metabolism in the insula lobe of cognitively impaired PD patients, thereby confirming that expression changes of dopamine within midbrain-cortex circuits underpin cognitive decline [11].

Complementing dopaminergic deficits, the disruption of the ascending cholinergic pathway is fundamental to the progression toward Parkinson’s disease dementia (PDD) [14]. Neuroimaging findings confirm that both PD and PDD patients suffer from cholinergic neuron deficits, marked by reductions in vesicular acetylcholine transporter (VAChT) and acetylcholinesterase (AChE) [14]. Insufficiencies of acetylcholine receptors in the thalamus, midbrain, temporal cortex, hippocampus, and cerebellum correlate tightly with the severity of cognitive deficits. Moreover, cholinergic deficits in the basal forebrain and prefrontal areas, alongside decreased choline acetyltransferase activity in the frontal and temporal lobes, are directly responsible for impairments in attention, learning, and memory [15].

Beyond neurotransmitter loss, postmortem studies establish that limbic and cortical Lewy body pathology serves as the primary neuropathological correlate of dementia in PD [16].  α-synuclein pathology typically spreads in a predictable staging pattern: initiating in the lower brainstem, olfactory bulb, or extracranially via the vagus nerve (from the gut or other innervated areas), subsequently advancing to the midbrain, forebrain, and limbic structures, and finally culminating in widespread neocortical involvement [16,17]. In addition to pure α–synucleinopathy, Amyloid-β plaques pathology significantly contributes to dementia in up to one-third of PD patients [18]. The co-occurrence of Amyloid-β deposition synergises with α-synuclein to accelerate synaptic failure, glial activation, and neuronal loss [19]. Similarly, alterations linked to the MAPT gene drive tau hyperphosphorylation and neurofibrillary tangle formation, bridging the pathological spectrum between primary synucleinopathies and tauopathies [20].

These pathological trajectories are heavily influenced by genetic determinants. Variants in genes such as SNCA, APOE, MAPT, TMEM175, and GBA are associated with cognitive impairment in PD [21-24]. Notably, the APOE ϵ4 allele – a well-established risk factor for sporadic Alzheimer’s disease (AD) – also plays a role in Parkinson’s-related neurodegeneration by influencing α-synuclein pathology and its associated toxicity [25,26]. Consequently, a subset of patients with Parkinson’s disease with dementia (PwPDD) exhibits classic AD-type pathology, including amyloid-β-plaques and tau neurofibrillary tangles [27,28]. Overall, dementia and PD share overlapping genetic and molecular risk factors, involving mutations that alter protein homeostasis, lysosomal function, and lipid metabolism, alongside oxidative stress and mitochondrial dysfunction. Collectively, these mechanisms accelerate the breakdown of neural networks essential for executive function, memory, and visuospatial processing.

Finally, clinical and environmental risk factors modulate the trajectory of cognitive decline. Older PD patients, particularly those with a longer disease duration, are significantly more prone to developing dementia. Sex differences also exist; compared to men, women generally require a more extended period of disease progression to develop dementia. Additionally, modifiable and comorbid factors – such as smoking, alcohol consumption, cardiovascular disease, and cerebrovascular disease – act synergistically to exacerbate cognitive impairment in this patient population [10].

Implications and Prevention Strategies

  1. Diagnostic considerations: The early identification of cognitive impairment in PD is crucial for timely intervention and management. When a patient with parkinsonism exhibits cognitive decline, a thorough evaluation is warranted. This should include:
  • Neuropsychological assessment: A comprehensive neuropsychological assessment, utilising age – and education-adjusted normative data, is essential to objectively quantify the cognitive deficits. This assessment should evaluate various cognitive domains, including attention, executive function, memory, language, and visuospatial abilities [29].
  • Neuroimaging: Detailed neuroimaging, such as MRI or CT scans, is warranted to rule out structural causes of cognitive decline, such as stroke or subdural haematoma, particularly if the cognitive changes are sudden or accompanied by new neurological signs [30].

Furthermore, it is vital to identify and address reversible factors that can exacerbate cognitive impairment, including:

  • Polypharmacy: Carefully review medications for potential cognitive side effects and minimise psychoactive medications where possible, favouring those with the fewest cognitive side-effects when treatment is necessary [29].
  • Anticholinergic burden: Vigilantly screen for medications with anticholinergic properties, both direct and indirect, and avoid problematic drugs like oxybutynin when alternatives exist. Over-the-counter medications, like those containing diphenhydramine, should also be reviewed and discontinued in favour of non-pharmacological sleep hygiene or targeted pharmacological approaches [29,31,32].
  • Comorbid conditions: Actively manage comorbid conditions such as vascular disease, neuropsychiatric symptoms, sleep apnoea, and orthostatic hypotension to mitigate their impact on cognition [29].
  • Antipsychotic regimens and untreated psychiatric disorders in Parkinson’s disease progression: Neuropsychiatric features in Parkinson’s disease (PD) including depression, apathy, sleep disorders, and anxiety frequently precede or accompany mild cognitive impairment (MCI), serving as critical warning signs for a higher risk of further cognitive decline [33]. Because these clinical manifestations vary significantly among individuals and across different stages of the disease, carefully assessing the presence of these symptoms and the precise timing of their onset is clinically appropriate, providing physicians with vital insights into the potential trajectory and management of the condition. Ultimately, accurately differentiating MCI from other organic and psychiatric symptoms in PD is essential, as it paves the way for novel therapeutic strategies tailored to alter the disease’s course and improve patient outcomes [33].

Within this comprehensive management framework, addressing untreated psychiatric disorders is paramount; clinicians must actively screen for and treat conditions such as depression and anxiety, as these can significantly contribute to cognitive impairment. Concurrently, addressing sleep disturbances is critical, given that poor sleep can negatively impact cognitive function and accelerate clinical deterioration [34].

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Furthermore, optimising antipsychotic regimens to minimise cognitive side effects remains an essential component of care. Therefore, prioritising antipsychotics with a lower risk of cognitive impairment is strongly recommended, while exploring newer antipsychotics with potential neuroprotective effects should be actively considered to balance psychiatric symptom control with the preservation of cognitive reserve in patients with Parkinson’s disease [35].

2. Management strategies: The management of cognitive impairment in PD requires a multi-faceted approach involving pharmacological and non-pharmacological interventions.

  • Pharmacological interventions: Despite mixed results in various clinical trials, evidence from a meta-analysis suggests that acetylcholinesterase inhibitors (AChEIs) can effectively improve both global impressions of efficacy and objective cognitive function in patients with Parkinson’s disease dementia (PDD) [36]. Consequently, while rivastigmine remains a primary option, it is also clinically reasonable to consider alternative AChEIs such as donepezil and galantamine when formulating a comprehensive management strategy for cognitive impairment in PDD [37]. While incorporating these agents into a preventive dementia approach appears conceptually feasible, further rigorous studies regarding this specific application are still needed to establish definitive guidelines [38].
  • Non-pharmacological interventions: Lifestyle interventions play a crucial role in maintaining cognitive function [39]. These include:
    • Regular exercise: Encouraging regular physical activity can improve cognitive function and overall well-being.
    • Social engagement: Promoting social interaction and participation in meaningful activities can help maintain cognitive stimulation and reduce feelings of isolation.
    • Cognitive training: Engaging in cognitive training programs can help improve specific cognitive functions, such as memory and attention.
    • Healthy diet: Adopting a healthy diet rich in fruits, vegetables, and healthy fats can support brain health.
  • Supportive care: Providing supportive care for patients and their caregivers is essential. This includes:
    • Encouraging communication: Encouraging patients to communicate their challenges and seek support for mood disorders.
    • Caregiver support: Providing education and support to caregivers to help them manage the challenges of caring for a person with cognitive impairment.

3. The Importance of proactive care planning: Given the high likelihood of cognitive decline in PD, it is crucial to initiate advance care planning early in the disease course. This involves discussing the patient’s values, preferences, and goals for future care. Advance care planning allows patients to make informed decisions about their medical treatment, financial affairs, and living arrangements. This process empowers individuals to maintain control over their lives and ensures that their wishes are respected as their disease progresses.

4. Implications for healthcare professionals: For healthcare professionals, a proactive approach is essential in addressing the cognitive aspects of PD. This involves:

  • Providing comprehensive information: Providing comprehensive information about the cognitive aspects of Parkinson’s disease at diagnosis.
  • Regular cognitive assessments: Ensuring regular cognitive assessments to detect early signs of cognitive impairment.
  • Early referrals: Arranging early referrals to occupational therapy, physical therapy, speech-language therapy, social work, and nutrition services.
  • Addressing psychiatric symptoms: Addressing depression and anxiety, which can significantly impact cognition.
  • Advance care planning discussions: Broaching the topic of advance care planning early in the disease course to allow patients and caregivers to proactively prepare for potential future cognitive challenges.

Conclusion

The escalating risk of dementia in Parkinson’s disease presents a significant challenge for individuals with PD, their families, and healthcare professionals. Early diagnosis, comprehensive management, and proactive care planning are essential to mitigate the impact of cognitive decline and optimise quality of life. By adopting a proactive and patient-centred approach, we can better support individuals with PD and their families as they navigate the complexities of this challenging disease. Further research is needed to develop more effective interventions to prevent or delay the onset of dementia in PD.

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