Aging, Beta-Amyloid, and Memory Networks

Although cognitively normal, brain aging in older adults occurs in a highly heterogeneous manner: it undergoes a wide range of abnormal neural changes that are not clinically evident. One of these abnormal neural changes is an accumulation of beta-amyloid (Aβ), a pathological hallmark of Alzheimers disease (AD). Approximately 20-35% of cognitively normal older adults were shown to harbor a high level of Aβ deposition, equivalent to the level of AD patients, and brain systems supporting memory were shown to be particularly vulnerable to the effect of Aβ deposition. Using amyloid PET, glucose metabolism PET, and functional magnetic resonance imaging (fMRI), we demonstrated that differential neural plasticity occurs in response to aging and  deposition in cognitively normal elderly in both regional activity and functional synchrony across the frontoparietal control regions and medial temporal lobes (right parahippocampal gyrus [rPHG]) implicated in episodic memory.

Hwamee Oh & William J. Jagust (2013). Frontotemporal network connectivity during memory encoding is increased with aging and disrupted by beta-amyloid. The Journal of Neuroscience, 33(47), 18425-37.

Hwamee Oh, Christian Habeck, Cindee Madison, William J. Jagust (2014). Covarying patterns of Abeta deposition, glucose metabolism, and gray matter volume in cognitively normal elderly. Human Brain Mapping, 35(1): 297-308.

*Jeremy Elman, *Hwamee Oh, Cindee M. Madison, Suzanne L. Baker, Jacob W. Vogel, Shawn M. Marks, Sam Crowley, James P. ONeil, William J. Jagust (2014). Neural compensation in older people with brain Abeta deposition. Nature Neuroscience, 2014; 17(10): 1316-8.*Co-First Authors.

Hwamee Oh, Jason Steffener, Ray Razlighi, Christian Habeck, Dan Liu, Yunglin Gazes, Sarah Janicki, Yaakov Stern (2015). Abeta-related hyperactivation in fronto-parietal control regions in cognitively normal elderly. Neurobiology of Aging 36(12), 3247-54.

Hwamee Oh, Jason Steffener, Ray Razlighi, Christian Habeck, Yaakov Stern. (2016). Beta-amyloid deposition is associated with decreased right prefrontal activation during task switching among cognitively normal elderly. The Journal of Neuroscience, 36(6), 1962-70.

Hwamee Oh, Cindee M. Madison, Suzanne L. Baker, Gil Rabinovici, William J. Jagust (2016). Dynamic relationships between age, beta-amyloid deposition, and glucose metabolism link to the regional vulnerability to Alzheimers disease. Brain, 139 (8): 2275-2289.


Neuromorphological Changes with Aging and Beta-Amyloid Deposition

Not only functional alterations described above but also neuromorphological changes occur with aging and Aβ deposition. In a set of studies, we examined changes in brain structure using gray matter volume and cortical thickness. Independent of Aβ deposition, a substantial aging-related reduction in gray matter volume and cortical thickness was found in most of brain regions, while Aβ-related gray matter atrophy was additionally found in frontal and parietal cortices and hippocampus [Figure]. Among these regions undergoing gray matter atrophy, contributions of gray matter volume to cognition in older adults were more regionally specific, but the structure-cognition relationship was different dependent upon the level of Aβ deposition: A fronto-striatal network was related to cognition in older adults without Aβ deposition, while a hippocampal network was related to cognition in older adults with Aβ deposition. These findings contribute to a growing movement within cognitive aging research to better understand aging-related neural constraints that are driven by more heterogeneous etiologies than previously thought and their differential impact on cognition.

Hwamee Oh, Elizabeth C. Mormino, Cindee Madison, Amynta Hayenga, Andre Smiljic, William J. Jagust (2011). Beta-amyloid affects frontal and posterior brain networks in normal aging. NeuroImage, 54(3), 1887-1895.

Miranka Wirth, Sylvia Villeneuve, Claudia M. Haase, Cindee Madison,Hwamee Oh, Susan Landau, Gil Rabinovici, William J. Jagust (2013). Associations between Alzheimer’s disease biomarkers, neurodegeneration, and cognition in normal older people. JAMA Neurology, 70(12):1512-9.

Hwamee Oh, Cindee Madison, Sylvia Villeneuve, Candace Markley, William J. Jagust (2014). Association of gray matter atrophy with age, beta-amyloid, and cognition in aging. Cerebral Cortex, 24(6): 1609-18.

Qolamreza Razlighi, Hwamee Oh, David Parker, Christian Habeck, Yaakov Stern. (2017). Dynamic patterns of brain structure-behavior correlation across the lifespan. Cerebral Cortex, 27(7), 3586-99.


Cognitive Changes with Aging and Beta-Amyloid Deposition

Considering that a relatively large proportion of cognitively normal elderly presents with Aβ deposition, it is not clear to what extent age and Aβ deposition contribute to cognitive changes in normal older adults. In a series of studies, we found that regardless of Aβ deposition, older adults, compared to young controls, show poorer performance in visual episodic memory and executive functions while performance in verbal episodic memory and semantic memory is preserved. Aβ-positive older adults, however, showed greater cognitive decline compared to Aβ-negative older adults, suggesting that even within a normal range of cognition, Aβ deposition is detrimentally associated with cognitive functions in normal older adults. In collaboration with researchers at Harvard/MGH, we further showed a significantly negative relationship between amyloid and cognition in a meta-analysis conducted on a large sample (7140 subjects) collapsing across 64 published studies.

Hwamee Oh, Cindee Madison, Thaddeus J. Haight, Candace Markley, William J. Jagust (2012). Effects of age and beta-amyloid on cognitive changes in normal elderly people. Neurobiology of Aging, 33(12), 2746-55.

Trey Hedden, Hwamee Oh, Alayna P. Younger, and Tanu Patel (2013). Meta-Analysis of Amyloid-Cognition Relations in Cognitively Normal Older Adults. Neurology, 80(14), 1341-8.


Individual Difference and Lifestyle Factors Moderating Brain Aging and Beta-Amyloid Deposition

A degree of the relationship between brain aging and cognition, however, seems to vary across individuals. In a set of studies, we showed that the observed relationship between Aβ deposition and cognition was moderated by a level of neural integrity such as metabolic rates and that cognitively stimulating activities across the lifetime affect the degree of AD pathology during aging.

Hwamee Oh, Qolamreza R. Razlighi, Yaakov Stern (2018). Multiple pathways of reserve simultaneously present in cognitively normal older adults. Neurology, 90(3): 197-205.

Miranka Wirth, Hwamee Oh, Beth Mormino, Candace Markley, Susan Landau, William J. Jagust (2013). The effect of beta-amyloid on cognitive decline is modulated by neural integrity in cognitively normal elderly. Alzheimers & Dementia, 9(6): 687-698.

Rik Ossenkoppele, Cindee Madison, Hwamee Oh, Miranka Wirth, Bart N.M. van Berckel, William J. Jagust (2014). Is Verbal Episodic Memory in Elderly with Amyloid Deposits Preserved Through Altered Neuronal Function? Cerebral Cortex, 24(8): 2210-8.

Susan M. Landau, Shawn M. Marks, Elizabeth C. Mormino, Gil D. Rabinovici, Hwamee Oh, Robert S. Wilson, William J. Jagust (2012). Association of lifetime cognitive engagement and low beta-amyloid deposition. JAMA Neurology, 69(5), 623-29.

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