Transcriptomic Changes Highly Similar to Alzheimer’s Disease Are Observed in a Subpopulation of Individuals During Normal Brain Aging

Aging is a major risk factor for late-onset Alzheimer’s disease (LOAD). How aging contributes to the development of LOAD remains elusive. In this study, we examined multiple large-scale transcriptomic datasets from both normal aging and LOAD brains to understand the molecular interconnection between aging and LOAD. We found that shared gene expression changes between aging and LOAD are mostly seen in the hippocampal and several cortical regions. In the hippocampus, the expression of phosphoprotein, alternative splicing and cytoskeleton genes are commonly changed in both aging and AD, while synapse, ion transport, and synaptic vesicle genes are commonly down-regulated. Aging-specific changes are associated with acetylation and methylation, while LOAD-specific changes are more related to glycoprotein (both up- and down-regulations), inflammatory response (up-regulation), myelin sheath and lipoprotein (down-regulation). We also found that normal aging brain transcriptomes from relatively young donors (45–70 years old) clustered into several subgroups and some subgroups showed gene expression changes highly similar to those seen in LOAD brains. Using brain transcriptomic datasets from another cohort of older individuals (>70 years), we found that samples from cognitively normal older individuals clustered with the “healthy aging” subgroup while AD samples mainly clustered with the “AD similar” subgroups. This may imply that individuals in the healthy aging subgroup will likely remain cognitively normal when they become older and vice versa. In summary, our results suggest that on the transcriptome level, aging and LOAD have strong interconnections in some brain regions in a subpopulation of cognitively normal aging individuals. This supports the theory that the initiation of LOAD occurs decades earlier than the manifestation of clinical phenotype and it may be essential to closely study the “normal brain aging” to identify the very early molecular events that may lead to LOAD development.

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Transcriptomic changes highly similar to Alzheimer's disease are observed in a subpopulation of individuals during normal brain aging

10.1101/2021.06.01.446628 ◽

2021 ◽

Author(s):

Shouneng Peng ◽

Lu Zeng ◽

Jean-vianney Haure-mirande ◽

Minghui Wang ◽

Derek M. Huffman ◽

...

Keyword(s):

Gene Expression ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Large Scale ◽

Healthy Aging ◽

Brain Aging ◽

Late Onset ◽

Normal Aging ◽

Normal Brain ◽

Older Individuals

Aging is a major risk factor for late-onset Alzheimer's disease (LOAD). How aging contributes to the development of LOAD remains elusive. In this study, we examine multiple large-scale human brain transcriptomic data from both normal aging and LOAD to understand the molecular interconnection between aging and LOAD. We find that shared gene expression changes between aging and LOAD are mostly seen in the hippocampus and several cortical regions. In the hippocampus, phosphoprotein, alternative splicing and cytoskeleton are the commonly dysregulated biological pathways in both aging and AD, while synapse, ion transport, and synaptic vesicle genes are commonly down-regulated. Aging-specific changes are associated with acetylation and methylation, while LOAD-specific changes are related to glycoprotein (both up- and down-regulations), inflammatory response (up-regulation), myelin sheath and lipoprotein (down-regulation). We also find that normal aging brains from relatively young donors (45-70 years old) cluster into subgroups and some subgroups show gene expression changes highly similar to those seen in LOAD brains. Using brain transcriptome data from older individuals (>70 years), we find that samples from cognitive normal older individuals cluster with the "healthy aging" subgroup while AD samples mainly cluster with the AD similar subgroups. This implies that individuals in the healthy aging subgroup will likely remain cognitive normal when they become older and vice versa. In summary, our results suggest that on the transcriptome level, aging and LOAD have strong interconnections in some brain regions in a subpopulation of cognitive normal aging individuals. This supports the theory that the initiation of LOAD occurs decades earlier than the manifestation of clinical phenotype and it may be essential to closely study the "normal brain aging" in a subgroup of individuals in their 40s-60s to identify the very early events in LOAD development.

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Longitudinal Changes in Individual BrainAGE in Healthy Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

GeroPsych ◽

10.1024/1662-9647/a000074 ◽

2012 ◽

Vol 25 (4) ◽

pp. 235-245 ◽

Cited By ~ 64

Author(s):

Katja Franke ◽

Christian Gaser

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Healthy Aging ◽

Brain Aging ◽

Elderly Subjects ◽

Additional Increase ◽

Longitudinal Changes ◽

Novel Method ◽

The Brain

We recently proposed a novel method that aggregates the multidimensional aging pattern across the brain to a single value. This method proved to provide stable and reliable estimates of brain aging – even across different scanners. While investigating longitudinal changes in BrainAGE in about 400 elderly subjects, we discovered that patients with Alzheimer’s disease and subjects who had converted to AD within 3 years showed accelerated brain atrophy by +6 years at baseline. An additional increase in BrainAGE accumulated to a score of about +9 years during follow-up. Accelerated brain aging was related to prospective cognitive decline and disease severity. In conclusion, the BrainAGE framework indicates discrepancies in brain aging and could thus serve as an indicator for cognitive functioning in the future.

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Impacts of Iron Metabolism Dysregulation on Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201250 ◽

2021 ◽

Vol 80 (4) ◽

pp. 1439-1450

Author(s):

Najla Jouini ◽

Zakaria Saied ◽

Samia Ben Sassi ◽

Fatma Nebli ◽

Taieb Messaoud ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Antioxidant System ◽

Plasma Concentrations ◽

Normal Brain ◽

Cognitively Normal ◽

Iron Trafficking ◽

Major Species ◽

Normal Brain Function ◽

Calcium Magnesium

Background: Iron plays an important role in maintaining cell survival, with normal iron trafficking known to be regulated by the ceruloplasmin-transferrin (Cp-Tf) antioxidant system. Disruption to this system is thought to be detrimental to normal brain function. Objective: To determine whether an imbalance of iron and the proteins involved in its metabolism (ceruloplasmin and transferrin) are linked to Alzheimer’s disease (AD) and to the expression of amyloid-beta (Aβ) peptide 1–42 (Aβ1–42), which is a major species of Aβ, and the most toxic. Methods: We evaluated the concentrations of iron, calcium, magnesium, and Aβ1–42 in the cerebrospinal fluid (CSF) of patients with AD and cognitively normal controls. Correlations between the components of the Cp-Tf antioxidant system in plasma were studied to determine the role of peripheral blood in the onset and/or development of AD. We used commercial ELISA immunoassays to measure Aβ1–42, immunoturbidimetry to quantify ceruloplasmin and transferrin, and colorimetry to quantify iron, calcium, and magnesium. Results: We found that the AD group had lower CSF concentrations of Aβ1–42 (p < 0.001) and calcium (p < 0.001), but a higher CSF concentration of iron (p < 0.001). Significantly lower plasma concentrations of ceruloplasmin (p = 0.003), transferrin (mean, p < 0.001), and iron (p < 0.001) were observed in the AD group than in cognitively normal adults. Moreover, we found a strong interdependence between most of these components. Conclusion: Iron dyshomeostasis has a crucial role in the onset of AD and/or its development. Correcting metal misdistribution is an appealing therapeutic strategy for AD.

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Cross-Species Imaging Applied to the Aging Brain: Dissociating Alzheimer’s Disease from Normal Aging

Imaging the Aging Brain ◽

10.1093/acprof:oso/9780195328875.003.0008 ◽

2009 ◽

pp. 115-122

Author(s):

Sidonie T. Jones ◽

Scott A. Small

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Normal Aging ◽

Aging Brain

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Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1009485107 ◽

2010 ◽

Vol 107 (32) ◽

pp. 14164-14169 ◽

Cited By ~ 357

Author(s):

M. M. Lipinski ◽

B. Zheng ◽

T. Lu ◽

Z. Yan ◽

B. F. Py ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Aging ◽

Normal Brain ◽

Genome Wide Analysis ◽

Genome Wide

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Exploring the Pattern Associated With Longitudinal Changes of β-Amyloid Deposition During Cognitively Normal Healthy Aging

Frontiers in Medicine ◽

10.3389/fmed.2020.617173 ◽

2021 ◽

Vol 7 ◽

Author(s):

Yunyan Xie ◽

Qin Yang ◽

Chunhua Liu ◽

Qi Zhang ◽

Jiehui Jiang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Healthy Aging ◽

Inferior Frontal Gyrus ◽

Quadratic Model ◽

Precentral Gyrus ◽

Cognitively Normal ◽

Longitudinal Changes ◽

Β Amyloid ◽

The Right

The aim of this study was to determine a pattern associated with longitudinal changes of β-amyloid (Aβ) deposition during cognitively normal(CN) healthy aging. We used 18F-florbetapir (AV-45) PET images of the brains of 207 cognitively normal subjects (CN1), obtained through the Alzheimer's Disease Neuroimaging Initiative (ADNI), to identify the healthy aging pattern and 76 cognitively normal healthy subjects (CN2), obtained through the Xuanwu Hospital of Capital Medical University, Beijing, China, to verify it. A voxel-based correlation analysis of standardized uptake value ratio (SUVR) map image and age was conducted using the DPABI (Data Processing & Analysis of Brain Imaging) software to identify the pattern. The sum of squares due to errors (SSE), R-square (R2) and the root-mean-square error (RMSE) were calculated to assess the quality of curve fitting. Among them, R2 was proposed as the coherence coefficient, which was as an index to assess the correlation between SUVR value of the pattern and subjects' age. The pattern characterized by age-associated longitudinal changes of Aβ deposition was mainly distributed in the right middle and inferior temporal gyrus, the right temporal pole: middle temporal gyrus, the right inferior occipital gyrus, the right inferior frontal gyrus (triangular portion), and the right precentral gyrus. There were a significant positive correlation between the SUVR value of the pattern and age for each CN group (CN1: R2 = 0.120, p < 0.001 for quadratic model; CN2: R2 = 0.152, p = 0.002 for quadratic model). These findings suggest a pattern of changes in Aβ deposition that can be used to distinguish physiological changes from pathophysiological changes, constituting a new method for elucidating the neuropathological mechanism of Alzheimer's disease.

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Dendritic spine remodeling accompanies Alzheimer's disease pathology and genetic susceptibility in cognitively normal aging

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2018.09.003 ◽

2019 ◽

Vol 73 ◽

pp. 92-103 ◽

Cited By ~ 13

Author(s):

Benjamin D. Boros ◽

Kelsey M. Greathouse ◽

Marla Gearing ◽

Jeremy H. Herskowitz

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Susceptibility ◽

Dendritic Spine ◽

Normal Aging ◽

Cognitively Normal

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Evidence for Reduced Autobiographical Memory Episodic Specificity in Cognitively Normal Middle-Aged and Older Individuals at Increased Risk for Alzheimer’s Disease Dementia

Journal of the International Neuropsychological Society ◽

10.1017/s1355617718000577 ◽

2018 ◽

Vol 24 (10) ◽

pp. 1073-1083 ◽

Cited By ~ 14

Author(s):

Matthew D. Grilli ◽

Aubrey A. Wank ◽

John J. Bercel ◽

Lee Ryan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Older Individuals ◽

Autobiographical Memories ◽

Middle Aged ◽

Cognitively Normal ◽

Preclinical Ad ◽

Increased Risk ◽

And Gender

AbstractObjectives: Alzheimer’s disease (AD) typically eludes clinical detection for years, if not decades. The identification of subtle cognitive decline associated with preclinical AD would not only advance understanding of the disease, but also provide clinical targets to assess preventative and early intervention treatments. Disrupted retrieval of detailed episodic autobiographical memories may be a sensitive indicator of subtle cognitive decline, because this type of memory taxes a core neural network affected by preclinical AD neuropathology. Methods: To begin to address this idea, we assessed the episodic specificity of autobiographical memories retrieved by cognitively normal middle-aged and older individuals who are carriers of the apolipoprotein E ε4 allele – a population at increased risk for subtle cognitive decline related to neuropathological risk factors for AD. We compared the ε4 carriers to non-carriers of ε4 similar in age, education, and gender. Results: The ε4 carriers did not perform worse than the non-carriers on a comprehensive battery of neuropsychological tests. In contrast, as a group, the ε4 carriers generated autobiographical memories that were reduced in “internal” or episodic details relative to non-carriers. Conclusions: These findings support the notion that reduced autobiographical episodic detail generation may be a marker of subtle cognitive decline associated with AD. (JINS, 2018, 24, 1073–1183)

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