Evidence from brain imaging, genetic, and pharmacological studies supports that ADHD involves dopaminergic dysregulation within mesocortical and mesostriatal circuits, including the prefrontal cortex and striatum, which are critical for executive control, attention, and reward processing (Volkow et al., 2009; Véronneau-Veilleux et al., 2022; MacDonald et al., 2024). However, functional imaging and computational modeling studies indicate that ADHD does not reflect a uniform dopaminergic hypofunction but rather a tonic–phasic imbalance, characterized by reduced tonic dopamine levels and increased phasic fluctuations in cortico-striatal loops during reinforcement learning (Tripp and Wickens, 2009; Véronneau-Veilleux et al., 2022).

This concept aligns with PET and fMRI evidence showing lower D2/D3 receptor and dopamine transporter (DAT) availability in mesoaccumbens and midbrain regions, correlating with deficits in attentional control and reward sensitivity (Volkow et al., 2009; Kollins and Adcock, 2014). In contrast, Lewy body dementia and Parkinsonian dementias are characterized by progressive degeneration of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta, leading to striatal dopamine loss and manifesting in motor and cognitive impairment (Lee et al., 2023; Prasad et al., 2023). This neurodegenerative pathology fundamentally differs from the functional dysregulation observed in ADHD, which is primarily neurotransmission-based rather than neurodegenerative in nature (Prasad et al., 2023).

Although ADHD is primarily functional rather than degenerative, chronic dopaminergic imbalance may lead to compensatory stress on synapses, promoting vulnerability to later neurodegenerative changes (Volkow et al., 2009).

It is noteworthy that dopaminergic abnormalities are not unique to Lewy body disorders. Increasing evidence implicates dopamine dysfunction in AD as well, where altered dopamine synthesis, receptor expression, and terminal integrity contribute to executive dysfunction, apathy, and accelerated cognitive decline. These convergent findings imply that ADHD-related dopaminergic vulnerability could interact with Alzheimer’s-relevant pathophysiology (e.g., synaptic failure, network disconnection), providing a plausible mechanistic route by which developmental dopaminergic dysregulation increases later-life risk across multiple dementia syndromes rather than only LBD (Martorana and Koch, 2014; Pan et al., 2019; Grünblatt et al., 2023).

Interestingly, previous reports have explored potential links between ADHD and Parkinson’s disease (PD), yet the evidence remains limited and inconclusive, with most studies failing to demonstrate a robust association (Becker et al., 2023). Genetic findings align with this view: Geissler et al. (2017) analyzed nine ADHD-related candidate single-nucleotide polymorphisms (SNPs) across seven genes and found no significant association with PD after correction for multiple testing. In contrast, longitudinal data now consistently indicate a stronger association between adult ADHD and dementia, particularly Lewy body dementia (Golimstok et al., 2024). Furthermore, it is important to note the high comorbidity between Lewy body dementia and AD, with many patients exhibiting overlapping neuropathological features (Galvin, 2024). This convergence supports the notion that ADHD may act as a neurodevelopmental vulnerability factor for late-life dementia, particularly in individuals at risk for mixed or overlapping Lewy body dementia –AD pathology, rather than for isolated Parkinsonian syndromes.

Grünblatt et al. (2023) proposed the Wnt/mTOR hypothesis, suggesting that ADHD-related neurodevelopmental dysregulation intersects with mechanisms implicated in AD. Disruption in Wnt signaling impairs neurogenesis, synaptic plasticity, and mitochondrial function, while aberrant mTOR activation contributes to oxidative stress and protein aggregation, potentially bridging early ADHD phenotypes with late-life cognitive decline (Grünblatt et al., 2023). While most mechanistic attention has focused on the Wnt/mTOR axis in AD, emerging evidence suggests that this pathway may also contribute to the pathophysiology of other dementias. The mTOR signalling cascade (mTORC1/2) is implicated in neurodegenerative mechanisms across multiple disorders, including frontotemporal dementia (FTD) and PD, where it modulates autophagy, protein aggregation, and synaptic plasticity (Zhu et al., 2019; Querfurth and Lee, 2021). In cellular and animal models of progranulin-deficient frontotemporal lobar degeneration (FTLD-TDP), both canonical and non-canonical Wnt cascades are overactivated, implicating aberrant Wnt/β-catenin signalling in FTD pathology (de la Encarnación et al., 2016; Rodríguez-Periñán et al., 2023). Although direct evidence in Lewy body dementia remains limited, the convergence of Wnt dysregulation and mTOR hyperactivation across the Alzheimer’s and other neurodegenerative spectra provides a mechanistic basis for the hypothesis that this pathway plays a wider role in neurodegenerative risk.

Moreover, mutations in LRRK2, a major genetic cause of familial and sporadic PD, directly interact with the Wnt/β-catenin pathway, modulating synaptic and neurogenic processes and linking Wnt dysregulation to Lewy body and Parkinson-related dementias (Berwick and Harvey, 2012; Harvey and Outeiro, 2019). Although direct experimental evidence in Lewy body dementia remains limited, the convergence of Wnt signalling abnormalities and mTOR hyperactivation across AD, FTD, and PD supports a shared vulnerability mechanism in neurodegeneration. However, no definitive mechanistic study to date has evaluated Wnt/mTOR interplay in dementia with Lewy Bodies or α-synucleinopathies, signalling an important gap for future research.

Chronic low-grade inflammation and oxidative stress, characterized by elevated IL-6 and TNF-α, have been observed in ADHD and are recognized contributors to neurodegeneration (Holmes et al., 2009; Corominas-Roso et al., 2017). Impaired antioxidant defenses in ADHD may further exacerbate vulnerability to neuronal injury, synergizing with age-related processes.

Recent peer-reviewed research deepens understanding of the biological connection between ADHD and late-life dementias, including AD. A 2025 study from Switzerland proposed the first neuropathological mechanism linking ADHD to neurodegeneration (Berberat et al., 2025). This study employed quantitative susceptibility mapping (QSM) MRI and blood biomarkers (neurofilament light chain, NfL) in 61 adults (25–45 years old), showed greater iron buildup in the right precentral cortex and higher blood levels of neurofilament light chain compared to controls. Both biomarkers are recognized indicators of neuronal damage and early cognitive decline in Alzheimer’s and other dementias. The authors interpret these results as potential evidence of accelerated neurobiological aging in ADHD, mediated by iron dysregulation and oxidative stress.

Complementary findings were reported recently, where a large genetic study demonstrated that individuals with a high polygenic risk for ADHD exhibit increased risk of AD and age-related cognitive decline, mediated by dopaminergic and synaptic regulatory genes shared between both disorders (Leffa et al., 2025). However, this genetic convergence may not extend to all neurodegenerative syndromes, particularly PD. A prior genetic study analyzing nine ADHD candidate SNPs in a large European cohort found no significant association with PD after correction for multiple testing (Geissler et al., 2017).

Comorbid depression, anxiety, sleep disturbances, and substance use are prevalent in adult ADHD and independently increase dementia risk (Becker et al., 2023; Levine et al., 2023). Lifestyle factors such as sedentary behavior, poor diet, and cardiovascular risk further amplify neurodegenerative susceptibility, emphasizing the need for comprehensive management strategies (Li et al., 2022; Bernacer et al., 2025).

ADHD has been associated with an increased risk of developing dementias beyond Parkinsonian and Lewy body-related disorders, notably AD and other age-related neurodegenerative conditions. Emerging evidence suggests that ADHD may constitute a lifelong vulnerability that reduces the brain’s capacity to tolerate neuropathology, a concept formalized as cognitive reserve (CR) (Stern, 2009; Díaz-Orueta et al., 2010).

CR refers to the brain’s ability to maintain cognitive function despite neuropathological burden. It arises from both innate capacity and life experiences, including education, occupational complexity, intellectual engagement, and lifestyle factors, which enhance neural efficiency, flexibility, and compensatory network recruitment (Stern, 2009; Díaz-Orueta et al., 2010). Structural and functional neuroimaging studies show that higher CR is associated with greater brain volume, cortical thickness, and adaptive network activation during cognitive tasks, which together confer resilience against dementia (Bartrés-Faz and Arenaza-Urquijo, 2011; Conti et al., 2021; Wei et al., 2024).

In adults with ADHD, chronic executive dysfunction, attentional inefficiency, and altered prefrontal-striatal dopaminergic signaling may reduce CR, limiting the brain’s compensatory capacity and lowering the threshold at which neuropathology manifests clinically. As noted earlier in this manuscript, neuroimaging and biomarker studies have reported features suggestive of accelerated neurobiological aging, such as iron accumulation and elevated neurofilament light chain, which may further compromise CR and contribute to heightened vulnerability to age-related cognitive decline (Berberat et al., 2025; Leffa et al., 2025).

Future research should explore whether interventions targeting CR, such as educational enrichment, cognitive training, and lifestyle modification, could mitigate the long-term dementia risk in adults with ADHD, complementing pharmacological strategies.