Dementia profoundly affects the brain’s ability to encode long-term memories, disrupting the processes that allow new experiences to be stored and later retrieved. Long-term memory encoding is a complex neurobiological function primarily involving the hippocampus and related brain structures. Dementia, particularly Alzheimer’s disease (AD), impairs these regions and the molecular pathways critical for memory formation, leading to progressive memory loss.
At the core of long-term memory encoding is the hippocampus, a medial temporal lobe structure essential for converting short-term memories into stable, long-lasting ones. In dementia, the hippocampus undergoes atrophy, meaning it shrinks in size, which correlates strongly with deficits in episodic memory—the ability to remember specific events and experiences. This shrinkage results from neuronal loss, synaptic dysfunction, and the accumulation of pathological proteins such as beta-amyloid and tau, hallmark features of AD and related dementias [2][5].
Synaptic plasticity, the brain’s ability to strengthen or weaken synapses based on activity, is fundamental to memory encoding. Dementia disrupts synaptic plasticity by impairing mechanisms like long-term potentiation (LTP), which normally enhances synaptic strength during learning. This impairment is linked to dysfunction in NMDA receptors and a reduction in dendritic spine density, which diminishes the brain’s capacity to form and maintain new neural connections necessary for encoding memories [2].
Neurotransmitter systems also play a critical role in memory encoding and are significantly affected in dementia. For example, acetylcholine, a neurotransmitter vital for attention and encoding new information, is markedly reduced in AD due to degeneration of cholinergic neurons in the basal forebrain. This reduction impairs the brain’s ability to process and store new memories. Dopamine, noradrenaline, and serotonin systems are also disrupted, affecting cognitive flexibility, mood, and executive functions, which indirectly influence memory encoding [2].
At the molecular level, dementia involves altered gene expression and cellular dysfunction that further impair memory encoding. Research shows that in cognitively resilient individuals with AD pathology, certain transcriptional changes help preserve synaptic stability and reduce neuroinflammation, which are protective against memory decline. Conversely, in typical dementia progression, decreased activity of protective factors such as NRF2, a regulator of antioxidant responses, exacerbates neuronal damage and cognitive decline [1].
The protein CREB (cAMP response element-binding protein) is a key positive regulator of long-term memory consolidation in the hippocampus. In dementia, CREB signaling is often disrupted, leading to weaker and less stable memory formation. Experimental models demonstrate that enhancing CREB activity improves memory and synaptic plasticity, highlighting its importance in memory encoding processes affected by dementia [1].
White matter integrity, which facilitates communication between brain regions, also deteriorates in dementia. Demyelination and reduced white matter coherence slow neural signaling, impairing the integration of information necessary for encoding complex memories. This loss of connectivity contributes to the overall decline in cognitive processing speed and memory function [2].
Neuroinflammation and oxidative stress are additional pathological features of dementia that damage neurons and synapses involved in memory encoding. Chronic activation of microglia, the brain’s immune cells, leads to the release of inflammatory molecules and reactive oxygen species, which harm neuronal membranes, mitochondria, and DNA. This environment further disrupts the cellular machinery required for encoding and consolidating memories [2].
Sleep disturbances common in dementia also negatively impact memory encoding. Slow-wave sleep, important for memory consolidation and clearance of neurotoxic metabolites like beta-amyloid, is often fragmented or reduced. This impairs the brain’s ability to process and store new information effectively [2].
Non-pharmacological interventions such as cognitive stimulation have shown promise in protecting memory function in dementia. Studies in animal models of vascular cognitive impairment, a form of dementia, reveal that cognitive exercises improve hippocampal-dependent memory and vascular health, suggesting that lifestyle factors can modulate the brain’s capacity for memory encoding despite disease [4][7].
Pharmacological treatments like acetylcholinesterase inhibitors (e.g., donepezil) aim to enhance cholinergic signaling and have been shown to improve memory encoding and retrieval in some dementia patients. However, these treatments do not halt disease progression and are most effective when combined with cognitive and lifestyle interventions [4].
In summary, dementia disrupts long-term memory encoding through a combination of hippocampal atrophy, synaptic dysfunction, neurotransmitter deficits, molecular and genetic alterations, white matter degradation, neuroinflammation, oxidative stress, and sleep disturbances. These changes impair the brain’s ability to form, stabilize, and retrieve new memories, leading to the characteristic memory loss seen in dementia. Research continues to explore protective mechanisms and interventions that may preserve or enhance memory encoding in affected individuals.
Sources:
[1] PMC12640947
[2] naturalremedieshumanhealth.com
[4] nature.com/articles/s41514-025-00304-2
[5] PMC12591994
[7] nature.com/articles/s41514-025-00304-2_reference.pdf
