Dementia profoundly disrupts the brain’s ability to store and retrieve memories, primarily by interfering with the complex biological processes that underlie memory formation, consolidation, and recall. Memory storage in the brain is not a simple on/off mechanism but involves a cascade of molecular and cellular events across multiple brain regions, including the hippocampus, thalamus, and cortex. Dementia, especially Alzheimer’s disease (AD), impairs these processes at various levels, leading to progressive memory loss.
Memory formation begins in the hippocampus, a critical brain area for encoding new experiences into short-term memory. From there, memories undergo a gradual transformation into long-term storage through a series of molecular “timers” that regulate gene expression and structural changes in neurons across different brain regions. These timers involve transcriptional regulators such as Camta1 and Tcf4 in the thalamus and Ash1l in the anterior cingulate cortex, which are essential for maintaining memories over time. Disruption of these regulators impairs the functional connections between brain regions, causing memory loss[1].
In dementia, particularly Alzheimer’s disease, the problem is not always with the initial encoding of memories but often with their retrieval. Research using chemogenetic techniques in mouse models of AD shows that neurons involved in learning are still capable of encoding memories, but the natural cues that normally reactivate these neurons and allow memory recall fail. Artificial stimulation of these learning-tagged neurons in the lateral entorhinal cortex (LEC) and dentate gyrus (DG) can restore memory retrieval, indicating that the memory traces exist but are inaccessible due to impaired neuronal reactivation[2].
Another critical factor in dementia-related memory loss is the degradation of perineuronal nets (PNNs), which are mesh-like structures surrounding neurons. These nets protect neurons and support proper communication necessary for memory formation, especially social memory. In Alzheimer’s disease, enzymes called matrix metalloproteinases (MMPs) become overactive, breaking down PNNs and leading to the loss of social memory, such as the ability to recognize loved ones. Preventing PNN degradation in animal models preserves social memory despite other Alzheimer’s pathology, suggesting a novel therapeutic target independent of amyloid plaques[3][7][9].
At the molecular level, dementia also affects gene regulation related to memory. For example, boosting levels of nicotinamide adenine dinucleotide (NAD+), a molecule involved in cellular metabolism, can correct abnormal gene splicing events seen in dementia. One gene affected is EVA1C, which is necessary for memory improvements. In mouse models, increasing EVA1C activity in the hippocampus prevents memory impairments caused by dementia-related tau pathology. Human studies show elevated EVA1C mRNA in Alzheimer’s brains, indicating that dysregulation of this gene contributes to memory loss[4].
Vascular health also plays a significant role in dementia and memory impairment. Cells lining the brain’s blood vessels, including endothelial cells and pericytes, are crucial for maintaining the blood-brain barrier and cerebral blood flow. Genetic vulnerabilities in these vascular cells contribute to dementia risk by promoting small vessel disease and cerebral blood flow reduction, which in turn impair brain function and memory. This vascular contribution to dementia highlights the multifactorial nature of memory loss in these conditions[5].
In addition to molecular and vascular factors, the brain has some intrinsic mechanisms to clear pathological features of dementia, such as amyloid plaques. Activation of certain proteins like Sox9 can enhance the brain’s natural ability to remove these plaques, potentially slowing memory decline[6].
In summary, dementia affects memory storage in the brain through a combination of disrupted molecular timers that maintain long-term memories, impaired neuronal reactivation preventing memory retrieval, degradation of protective neuronal nets critical for social memory, altered gene regulation affecting neuronal health, and compromised vascular function reducing brain support. These interconnected mechanisms explain why dementia leads to the progressive and multifaceted memory loss characteristic of the disease.
Sources:
[1] Medical Xpress, 2025
[2] NIH PMC, Chemogenetic Reactivation Study
[3] Neuroscience News, Perineuronal Nets and Social Memory
[4] NAD+ and Gene Splicing in Dementia, NAD.com
[5] Imperial College London, Vascular Cells and Dementia Risk
[6] SciTechDaily, Brain Clearance of Alzheimer’s Plaques
[7] McKnight’s, Perineuronal Nets and Social Cognition
[9] News Medical, Perineuronal Nets and Alzheimer’s Memory Loss
