Over the course of life, memory fades to varying degrees, robbing older adults of the ability to recall personal experiences. It has long been believed that this progressive, almost inevitable process is a consequence of nature’s removal of dendritic spines, a key component of synapses, from brain neurons as they age.
A study published in Scientific progress led by researchers from the University of Alabama at Birmingham and Rush University Medical Center, Chicago, Illinois, now provides evidence that the retention of past life experiences is maintained by the quality -; not the quantity -; of synapses in old age.
This is a paradigm breaker. For 35 years, the prevailing dogma was that memory decline is primarily mediated by the loss of the dendritic spine, which is a surrogate for synapses. As we age between 40 and 85 years, there is a natural loss of dendritic spines and synapses, which is completely normal. This natural loss can contribute to the lack of cognitive acuity we all feel as we age. However, we show that even if there is synapse loss, the remaining synapses can compensate for that loss.”
Jeremy Herskowitz, Ph.D., associate professor in the UAB Department of Neurology and corresponding author of the study
Herskowitz says this has a huge implication. “Even in older people, people aged 80, 90 or 95, there is still enough plasticity in the formation of synapses to retain memory. This means that a therapy to remodel dendritic spines and synapses can dramatically facilitate memory as you get older or if you experience memory disturbances due to Alzheimer’s disease.”
The research was made possible by the Religious Orders Study and Rush Memory and Aging Project, or ROSMAP, at Rush University. ROSMAP enrolls Catholic nuns, priests and brothers aged 65 or over who do not have known dementia at the time of registration. Participants receive medical and psychological evaluations each year and agree to donate their brains after death.
Herskowitz and colleagues studied postmortem brain samples from 128 ROSMAP participants. Participants had a mean age of 90.5 years at the time of death, with variable cognitive performance scores and Alzheimer’s disease-related neuropathology. All had undergone annual cognitive testing for episodic memory, visuospatial ability/perceptual orientation, perceptual speed, semantic memory, and working memory. The study included two samples from each brain, one from the temporal cortex, which has structures essential for long-term memory, and one from the frontal premotor cortex.
After staining the brain samples, photographing thin slices and building three-dimensional digital reconstructions of 55,521 individual dendritic spines on 2,157 neurons, researchers used two statistical methods, one of which used innovative machine learning, to see if any of the 16 different measures of spinal morphology correlated with any of 17 different measures of brain function, age and neuropathology of Alzheimer’s disease. One of the measures of brain function was episodic memory; the ability to remember everyday events and personal experiences from the past.
For neurons from the temporal cortex, researchers found that the diameter of the dendritic spine head, but not the amount of spines, improved the prediction of episodic memory in models that included β-amyloid plaque scores, neurofibrillary tangle pathology, and sex. Larger head diameters were associated with better episodic memory performance, supporting the emerging hypothesis that in the temporal cortex, synaptic strength is more important than quantity for memory in old age.
“Targeting pathways that maintain spine diameter or synaptic strength, rather than pathways that maintain or generate new spines or synapses, could potentially provide greater therapeutic benefits for older adults in preclinical stages of Alzheimer’s disease,” said Herskowitz.
A dendrite is a branched extension of a neuron body that receives impulses from other neurons. Each dendrite can have thousands of tiny projections called spines. The head of each spine can form a point of contact, called a synapse, to receive an impulse sent by the axon of another neuron. Dendritic spines can quickly change shape or volume as they form new synapses, part of the process called brain plasticity. Creating or eliminating synapses is a fundamental mechanism of brain function.
Collecting the tens of thousands of spine measurements took two and a half years. This painstaking work began in 2019 and continued throughout the COVID-19 pandemic, as UAB researchers worked under COVID restrictions, Herskowitz says.
Co-first authors of the study, “Dendritic Spinal Head Diameter Predicts Episodic Memory Performance in Older Adults,” are Courtney K. Walker and Evan Liu, UAB Department of Neurology.
Other authors include Kelsey M. Greathouse, Ashley B. Adamson, Julia P. Wilson, Emily H. Poovey, Kendall A. Curtis, Hamad M. Muhammad, and Audrey J. Weber, UAB Department of Neurology; David A. Bennett, Rush University Medical Center; Nicholas T. Seyfried, Emory University School of Medicine; and Christopher Gaiteri, SUNY Upstate Medical University, Syracuse, New York.
Support came from National Institutes of Health grants NS061788, AG067635, AG061800, AG054719, AG063755, AG068024, AG10161, AG72975, AG15819, AG17917, AG46152, and AG61356.
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Magazine reference:
Walker, C.K., et al. (2024) Dendritic spine diameter predicts episodic memory performance in older adults. Scientific progress. doi.org/10.1126/sciadv.adn5181.