Chemotherapy-related cognitive impairment (CRCI), colloqually referred to as "chemo brain," affects up to 80% of cancer patients undergoing treatment. It manifests in memory, attention, and executive function deficits, sometimes persisting long after treatment ends. Intriguingly, the symptomatology and biological mechanisms underlying CRCI overlap significantly with those of Alzheimer’s disease (AD).

In a recent journal pre-proof published in The American Journal of Pathology, Matthew Torre, MD; Camila A. Zanella, PhD; and Mel B. Feany, MD, PhD examined these shared pathways and offered insights into the processes that could put chemotherapy patients at an elevated risk of developing AD.

“Because of the clinical significance of AD and CRCI, the projected increase in affected patients, and the clinical overlap, it is compelling to consider chemotherapy exposure as a potential risk factor for AD. Given the epidemiologic data, which generally report an inverse correlation between history of cancer/chemotherapy and AD/dementia, it is likely that only a subset of chemotherapy patients may be at higher risk,” they wrote.

AD, the most prevalent form of dementia, affects 6.9 million Americans aged 65 and older, a figure projected to double by 2060. In parallel, cancer survivorship is rising, with an estimated 22.1 million U.S. survivors by 2030. While cancer and AD appear unrelated, AD and CRCI share risk factors such as advanced age, reduced cognitive reserve, and genetic predispositions like the apolipoprotein E (APOE) E4 allele.

The APOE4 allele, a well-established genetic risk factor for late-onset AD, also increases vulnerability to CRCI. Homozygous carriers of APOE4 face a 15-fold higher risk of developing AD, while APOE2 appears protective against both disorders, the authors noted. Additionally, a single nucleotide polymorphism (SNP) in the TOMM40 gene—implicated in mitochondrial function—has been linked to cognitive impairment in both chemotherapy patients and AD, highlighting potential genetic intersections.

Neuroinflammation is a hallmark of AD, characterized by the activation of microglia and astrocytes, increased synapse pruning, and a pro-inflammatory cytokine environment. Elevated levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in AD patients are known to exacerbate tau and amyloid-beta (Aβ) pathology.

Chemotherapy similarly induces neuroinflammation, both directly (via blood-brain barrier-permeable agents such as methotrexate) and indirectly (through elevated systemic cytokines). Rodent studies demonstrate that clearing microglia reverses chemotherapy-induced cognitive deficits, emphasizing the inflammatory contribution to CRCI. Interestingly, both AD and CRCI show microbiome alterations, further linking systemic inflammation to central nervous system effects.

Oxidative stress and mitochondrial dysfunction are early features of AD, driving neuronal damage and cognitive decline. Chemotherapy intensifies these processes by increasing reactive oxygen species, inducing mitochondrial DNA damage, and impairing mitochondrial respiration. For instance, cisplatin, a common chemotherapeutic, disrupts mitochondrial dynamics, contributing to neurotoxicity.

Emerging therapeutic interventions, including antioxidant therapy and mitochondrial-targeted treatments, show promise in preclinical models of both CRCI and AD, the authors noted.

Neuronal and synaptic loss strongly correlate with cognitive dysfunction in AD, with up to 65% neuronal loss in key hippocampal regions in severe cases. Chemotherapy-treated rodents display parallel phenomena, including reduced dendritic branches, synaptic markers, and neurogenesis in the hippocampus. Radiologic studies in humans reveal cortical and hippocampal atrophy in chemotherapy patients, suggesting similar neuropathological changes.

Cellular senescence—a state of irreversible cell-cycle arrest—is implicated in both AD and CRCI. Senescent cells secrete pro-inflammatory cytokines and disrupt brain homeostasis. Chemotherapy is a known inducer of senescence, particularly in astrocytes, microglia, and endothelial cells, mirroring patterns observed in AD. Recent studies suggest ablating senescent cells can restore cognitive function in animal models, highlighting a potential therapeutic avenue.

Brain-derived neurotrophic factor (BDNF) signaling is pivotal for synaptic transmission, plasticity, and neuronal survival, playing a crucial role in learning and memory. Reduced BDNF levels are consistently linked to both AD and CRCI, with BDNF mRNA reductions in the hippocampus of AD patients and significant decreases in proBDNF in the parietal cortex during advanced AD. These changes are exacerbated by systemic inflammation, tau hyperphosphorylation, and Aβ overexpression, contributing to early neurodegeneration.

In animal models, BDNF administration has demonstrated significant potential in reversing cognitive deficits and supporting neuronal resilience. Similar therapeutic effects have been observed in CRCI models, where BDNF upregulation through treatments such as riluzole or TrkB receptor agonists improved cognition, neurogenesis, and myelination. These findings present BDNF signaling as a shared therapeutic target for CRCI and AD, warranting further exploration in clinical trials.

White matter damage is a prominent feature in both AD and CRCI. The loss of myelin integrity, gliosis, and reduced oligodendrocyte precursor cells (OPCs) compromise cognitive functions such as memory and processing speed. In AD, these disruptions are linked to early Aβ deposition and neuroinflammation. Chemotherapeutic agents such as methotrexate further exacerbate these effects, inducing demyelination and impairing OPC survival.

Research highlights that pharmacological stimulation of BDNF signaling in OPCs can mitigate these damages, emphasizing its role in enhancing myelination and cognitive outcomes. Additionally, understanding how chemotherapeutics influence myelin-related pathologies in AD models may yield insights into mitigating cognitive decline.

The blood-brain barrier (BBB) and cerebral vascular health are critical to neuroprotection. In AD, increased BBB permeability and vascular dysfunction contribute to reduced clearance of Aβ, microglial activation, and synapse loss. APOE4 carriers exhibit exacerbated BBB disruption, linking genetic predisposition to vascular pathophysiology.

Chemotherapy similarly compromises BBB integrity, with proinflammatory cytokines elevating its permeability. Paclitaxel, for instance, induces cerebral endothelial cell senescence and microvascular damage. Understanding how chemotherapy-induced vascular changes interact with AD pathogenesis—such as impaired Aβ clearance—is essential to developing interventions that preserve cognitive function, the authors wrote.

Tau aggregates are central to AD pathogenesis, with their distribution correlating strongly with cognitive deficits. Chemotherapy-induced tau abnormalities, including hyperphosphorylation and aggregation, have been observed in both clinical and preclinical CRCI studies. The potential neuroprotective effects of taxanes—a chemotherapy class stabilizing microtubules—add complexity to understanding tau’s role in CRCI.

Emerging evidence links transposable elements (TEs) to neurodegeneration, particularly in AD. Aberrant TE activation contributes to neuronal death and neuroinflammation. Chemotherapy-induced changes in chromatin structure and TE expression suggest a novel pathway through which CRCI may accelerate cognitive decline. Investigating TE reactivation in the human brain post-chemotherapy could illuminate its role in CRCI and AD.

The overlapping biology of CRCI and AD opens the door to innovative strategies for prevention and treatment, the authors noted. Genetic screening for APOE4 or TOMM40 variants could identify patients at higher risk of CRCI and AD, enabling early interventions. The authors also noted that treatment approaches that show promise for either AD or CRCI could be beneficial for treatment of the other condition.

Further research is needed to confirm whether chemotherapy accelerates AD pathology in preclinical models and to identify potential synergies between these conditions. Clinical trials evaluating shared interventions could not only improve survivorship for cancer patients but also offer broader insights into neurodegenerative diseases.

“Once there is a better understanding of the shared biological pathways underlying CRCI and AD, the ultimate goal is to enable clinicians to identify chemotherapy patients who are at increased risk of future cognitive decline and prophylactically treat these patients with disease-modifying therapies,” they wrote, citing the need for further research in this area.