Diseases and Disorders

The Progression of Alzheimer's Disease

Emma Colavita


Alzheimer’s Disease (AD) is a neurodegenerative disorder, typically affecting individuals 65 years and older. AD results in memory loss, confusion, changes in personality, and eventually, complete loss of independence. AD progresses through a series of stages: the preclinical stage, early (mild) stage, middle (moderate) stage, and late (severe) stage. The preclinical stage is defined as the phase at which pathophysiological biomarkers, such as reduced levels of cerebrospinal fluid and amyloid traces in PET, are present. Early-stage AD is the stage at which biomarkers begin to present externally in individuals. The abundance of neurofibrillary tangles (NFT) or neuritic plaque pathology in AD patients can target and inhibit specific brain regions rather than just the whole brain. Middle-stage AD shows more pronounced cognitive functional deficits that can be attributed to abnormalities in the connectivity of different brain regions. Late-stage AD is characterized by an overload of pathological biomarkers, as well as oxidative damage to lipids, proteins, RNA, and DNA. It was concluded that the levels of 8-OHG (8-hydroxyguanine) may suggest that DNA oxidation occurs early in the progression of AD.

The Preclinical Stage

Recent research has revealed that it is now possible to identify Alzheimer’s disease (AD) using biomarkers before clinical symptoms arise in individuals {1}. The concept of a preclinical Alzheimer’s stage first emerged during the late 20th century and was originally defined as “cognitively unimpaired individuals who displayed AD brain lesions on postmortem examination” {1}. However, through the development of pathologic markers, the preclinical stage was reexamined and is now defined as the point at which these markers appear in cognitively normal individuals.

According to the 2011 National Institute on Aging and Alzheimer’s Association (NIA-AA), the preclinical stage is composed of three stages, followed quickly by mild cognitive impairment or “prodromal AD”. Prodromal AD is the phase at which pathophysiological biomarkers, such as cerebrospinal fluid and amyloid traces in a positron emission tomography (PET), are present {2}. Intraparenchymal growth of plaque-like amyloid deposits has been associated with the development of AD. These plaques are formed as deposition and transformation of soluble amyloid β-protein monomers occur and these monomers become insoluble and fibrillar aggregates containing “amyloid β-protein in a β-pleated sheet conformation” {3}. This process is called “seeded polymerization,” and occurs in monomers with slow-nucleation, but fast growth. These soluble amyloid β-protein monomers are located in the extracellular space of the cerebrospinal fluid, and insoluble aggregates have been identified by examinations of brain tissue in biopsies {3}. Additionally, research has linked reduced levels of cerebrospinal fluid—which is common in AD patients—to amyloid plaques hindering the transportation of soluble amyloid β-protein monomers between the brain and the cerebrospinal fluid {4}. Due to these findings, abnormal pathophysiological processes in the brain are now reliably detected in vivo in the cerebrospinal fluid {2}.


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Figure 1. MRI scans (gray) and illustrations (color) show the difference between a brain affected by Alzheimer’s disease and a normal brain {5}.


The Early (Mild) Stage

During the early stage of Alzheimer’s disease, the affected individual may continue to function independently and perform tasks such as driving and participating in normal social activities. Common difficulties may include identifying the right word or name, remembering names when introduced to new people, having difficulty performing tasks in social or work settings, forgetting material that was just read, losing, or misplacing a valuable object, and experiencing increased trouble with planning or organizing {6}. 

Molecular imaging with positron emission tomography (PET) has proven to be a highly promising methodology for visualizing and tracking pathophysiological changes, as well as targeting biomarkers for potential disease-modifying therapeutic intervention. The application of molecular imaging of AD is specifically targeted at identifying amyloid, tau neurofibrillary tangles, and microglial activation, while also monitoring the overall progression of the disease. Neuroinflammation is also a common marker in AD patients, resulting in abnormally prolonged microglial activation which has the potential to further contribute to  neurodegeneration {7}. 

As AD progresses and functions such as memory and language become impaired, it is incredibly likely that specific cognitive systems or brain regions are being targeted. To test this theory, Dr. Johnson and her team observed clinically diagnosed AD patients in the mild stage who presented severe frontal lobe impairments to see if they “would exhibit a greater-than-expected degree of either neurofibrillary tangles (NFTs) or neuritic plaque pathology in the frontal lobes” {8}. In this experimental design, the team examined the neuropsychological profiles and identified senile plaque and NFT accumulation in the frontal, entorhinal, temporal, and parietal cortices in three AD patients who demonstrated disproportionate frontal impairments in the mild stage of the disease. These patients showed significant difficulty in completing tests such as the Trail Making Test A and FAS fluency test. An additional group of 3 patients with “typical” AD were also selected for the purpose of comparison. The two groups had no significant differences in “educational level, sex, age of onset, disease duration, interval between clinical evaluation and death” {8}. 

Neuropsychological profile scores showed that, compared to the typical AD patients, the frontal AD patients performed significantly worse on frontal lobe function tests, including Trail Making Test A and FAS fluency. The Trail Making Test (TMT), “provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions” {9}. TMT scores from the typical AD group ranged from 47 to 69 seconds and did not overlap with the frontal AD patients, whose scores ranged from 100 to 167 seconds. Also, FAS fluency scores in the frontal AD group were consistently below-average, whereas the typical AD group performed within the normal range {8}. After analyzing brain tissue samples from these patients in the neuropathological studies, it was revealed that, “despite comparable entorhinal NFT loads, the frontal AD group showed a significantly higher NFT load (t4=14.3; P<.001) in the frontal cortex than the typical AD group” {8}. It was also shown that there was no significant difference between the two test groups in the degree of NFT pathology in other brain regions. This proves that AD pathology can target and inhibit specific brain regions, rather than just the brain as a whole {8}.

The Middle (Moderate) Stage

Typically, the middle stage of Alzheimer’s disease is the longest, lasting about 4 years on average and resulting in more pronounced symptoms, which require a greater level of care. People in this stage may begin to confuse words, become angry or frustrated, and exhibit uncharacteristic behaviors. Additional symptoms include experiencing changes in sleep patterns, such as sleeping during the day and becoming restless at night, showing an increased tendency to wander and become lost, demonstrating personality and behavioral changes, including suspiciousness and delusions or compulsive, repetitive behavior like handwriting or tissue shredding, being forgetful of events or personal history, and feeling moody or withdrawn, especially in socially or mentally challenging situations {6}.

Brain networking studies of AD patients have demonstrated that cognitive functional deficits may be attributed to abnormalities in the connectivity of different brain regions, although, as Zhao writes, “there is no consensus as to what the alteration pattern is.” Previous studies identifying altered brain network patterns in AD patients have not produced consistent results due to vastly different subject groups representing a variety of different measurements. Different stages of the disease manifest different neural mechanisms that directly correlate to specific behavioral symptoms, thus it is virtually impossible to produce results that will apply to all aspects of AD. Zhao and their team identified this issue and focused their study on moderate AD patients to eliminate extraneous measurement. The team hypothesized that “the brain network of AD is characterized by the disruption of efficient small-world topological properties based on resting-state fMRI data” {10}. 

The subjects included in the study were AD patients in the moderate stage of the disease, as well as a group of normal controls (NCs) who matched the AD group in age and education. All AD patients underwent the Mini-Mental State Examination (MMSE), and the normal control patients underwent the Mattis Dementia Rating Scale (DRS) equivalent to their age matched cognitive level {10}. The MMSE is an examination to measure cognitive impairments in “undeveloped, uneducated, diseased, or very old populations' ' {11}. All AD participants met the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer Disease and Related Disorders Association (NINCDA-ADRDA) criteria for dementia, and all NCs were categorized as non-demented. Additionally, all patients completed a full physical and neurological examination using a variety of neuropsychological assessments and standard laboratory tests. AD patients completed a brain MRI scan and displayed no abnormalities other than brain atrophy {10}.

Results showed significant frequencies of node alteration in 19 brain regions in the AD patients. These regions showed tremendous alterations in clustering coefficients (Cp), and local efficiency (Elocal) are widely distributed in default mode networks. These networks are composed of the: right posterior cingulate gyrus (PCC_R), the anterior cingulate and paracingulate gyrus (ACC), the opercular part of the inferior frontal gyrus (IFGoper), the superior frontal gyrus (SFG), regions in the temporal lobe such as the superior temporal gyrus (STG), and regions in the subcortical structure such as the right thalamus (THA_R), left lenticular nucleus pallidum (PAL_L) and right lenticular nucleus putamen (PUT_R) {10}. Other brain regions showed significant alteration in global efficiency (Eglobal), and path length (Lp) and was primarily distributed in regions of the temporal lobe, including “the middle temporal gyrus temporal pole (MTGp) and right middle temporal gyrus (MTG_R), and sensory motor regions, such as the right supplementary motor area (SMA_R) and right precentral gyrus (PreCG_R)” {10}. 

The team further explored areas of the brain where topological parameters showed significant differences between the AD and NC patients. Their findings demonstrated that most networks of topological properties, including Cp, Lp and Elocal, were increased in AD patients as opposed to the control groups across these widely distributed regions. These altered regions were grouped into three clusters: the default mode network, structures of the subcortical region, and regions of the temporal lobe. Nearly all regions in a typical default mode network were identified to have alteration in their results, including, “the ACC, PCC, middle prefrontal cortex (MPFC), hippocampus (HIP) and inferior parietal cortex (IPL)” {10}. The second cluster includes areas of the subcortical structures, such as, “the thalamus (THA), lenticular nucleus putamen (PUT), and INS” {10}. Lastly, the third cluster was composed of regions of the temporal lobe, including, “the superior/middle temporal gyrus temporal pole (STGp/MTGp) and the bilateral middle temporal gyrus (MTG)” {10}. This temporal region demonstrated a significant decrease in Eglobal in AD patients. It was also discovered that Eglobal was decreased in the motor areas of AD patients, such as the SMA_R and PreCG_R regions.

MMSE scores from the control group of subjects averaged 27.8±1.3, which fits within the age-matched standard. However, the AD group averaged 15.3±2.9, demonstrating a significant cognitive impairment {10}. Additionally, the results of this study reveal that patients with moderate AD showed severe disruption in the topological properties of brain networks compared to patients in the normal control group. These alterations were mainly noted in the default mode network, the structures of the subcortical region, and regions of the temporal lobe {10}.



Figure 2. Surface rendering of the distribution of altered nodes. Orange indicates altered nodes at P<0.05. Blue indicates altered nodes at a connection density of 22% {9}.


The Late (Severe) Stage

By the late stage of Alzheimer’s disease, dementia symptoms are so severe that individuals completely lose the ability to respond to their environment, communicate effectively with others, and eventually, the control of movement, as well as experience significant personality changes and require extensive care. Symptoms in the late stage of the disease include difficulty eating and swallowing, difficulty walking and eventually, inability to walk, loss of awareness of recent experiences as well as of their surroundings, severe difficulty with communication, and becoming vulnerable to infections, especially pneumonia {6}. 

Late-stage AD (LAD) is typically characterized by an abundance of, “neurofibrillary tangles (NFT), senile plaques (SP) or beta-amyloid (Aβ) plaques, neuropil thread formation, neuron and synapse loss, and proliferation of reactive astrocytes in the entorhinal cortex, hippocampus, amygdala and association areas of frontal, temporal, parietal and occipital cortex” {12}. These pathological biomarkers are heavily relied on in the diagnostic process of AD using the National Institute on Aging-Reagan Institute (NIA-RI) criteria. Neuritic plaque (NP) density—taken from the frontal, temporal, and parietal lobes—also provide low, intermediate, and high classifications for the progression of AD. Patients exhibiting Mild Cognitive Impairments (MCI) demonstrate an increase in NP in non-cortical areas, as well as an increase in NFT in the entorhinal cortex, hippocampus, and amygdala {12}.

Oxidative phosphorylation refers to the reduction of molecular oxygen to water, which results in a group called the reactive oxygen species (ROS). In healthy tissues, there is a constant balance between ROS generation and antioxidant protection mediated by antioxidant enzymes, including, “copper/zinc superoxide dismutase, manganese superoxide dismutase, glutathione peroxidase, and catalase among others and small antioxidant molecules such as glutathione, vitamin E, and vitamin C” {12}. When this balance is disrupted and antioxidant capacities shift toward free radical generation, oxidative stress will occur and cause oxidative damage to lipids, proteins, RNA, and DNA. Damage to these biomolecules will contribute to loss of function and lead to exacerbated damage. Oxidative damage is particularly prevalent in the brain due to its high oxygen consumption rate, its high energy demands, rich abundance of polyunsaturated fatty acids and lipids, and relatively limited antioxidant capacity relative to other organs {12}. Typically, ∼2% of oxygen consumed by cells during the oxidative phosphorylation process is converted to ROS. However, this may very well be higher in AD patients, who have impaired oxidative phosphorylation. Oxidative damage studies in LAD demonstrated that lipid peroxidation, protein oxidation, and RNA oxidation are significantly increased in numerous neocortical brain regions. Additional studies also suggest that oxidative damage to biomolecules and vulnerable brain regions may be an early event in the pathogenesis of AD. Mitochondrial DNA (mtDNA) seems to be the primary target for free radical damage that leads to cellular degeneration and aging—which further suggests that oxidative damage is associated with a variety of neurodegenerative diseases {12}.

Oxidative attacks by ROS, especially hydroxyl radicals, on DNA can lead to strand breaks, DNA protein cross-linking, and the replication of sister cell chromatid exchanges and translocations in nuclear DNA (nDNA). These attacks contribute to the generation of over 20 oxidized base adducts, the most prominent of which being 8-hydroxyguanine (8-OHG) due to its low oxidation potential in comparison to the other 3 DNA bases. DNA damage and its connection to neurodegeneration in AD were first explored in 1990, where Mullaart et al. demonstrated a 2-fold increase in DNA strand breaks in the brain of an AD patient {13}. This breakage is hypothesized to cause the activation of poly (ADP-ribose) polymerase (PARP), defined as, “a zinc finger DNA-binding protein that could cause depletion of intracellular NAD+ and depletion of energy stores resulting in cell death” {12}. A separate study conducted by Lyras et al showed, “increased 8-OHG, 8-hydroxyadenine (8-OHA) and 5-hydroxycytosine (5-OHC) in total DNA from AD parietal lobe compared to age and gender-matched control subjects. This study also showed increased thymine glycol, 4,6-diamino-5-formamido-pyrimidine (FapyAde), FapyGua, and 5-hydroxyuracil (5-OHU), a degradation product of cytosine in various brain regions in AD” {14}. In the study conducted by Lovell and Markesbery, they sought to record the abundance of 8-OHG, FapyGua, 8-OHA, FapyAde, and 5-OHC in nDNA isolated from frontal, temporal and, parietal lobes and cerebellum of LAD {12}.

Specimens used in this study were all from short postmortem intervals (roughly 2-4 hours) and were comprised of LAD and age-matched normal controls. Analysis results demonstrate drastic elevations of 8-OHG, 8-OHA, and 5-OHU in temporal and parietal lobes in AD compared to age-matched control subjects; however, no significance in FapyGua or FapyAde was observed in this initial study. In a more recent study, comparing the levels of nDNA oxidation to mtDNA oxidation, Lovell and Markesbery found significant elevations of 8-OHG, 8-OHA, 5-OHC and FapyAde in mtDNA from parietal and temporal lobes of LAD patients, as well as increased 5-OHC in mtDNA from LAD frontal lobe. “Analysis of nDNA showed significantly increased 8-OHG in DNA from temporal and parietal lobes, 8-OHA in all three neocortical areas, 5-OHC in frontal and temporal lobes, 5-OHU in the temporal lobe and FapyAde in temporal lobe and cerebellum in LAD'' {12}. The levels of oxidation in mtDNA showed a 10-fold increase—particularly 8-OHG—compared to nDNA. These findings allowed Lovell and Maekesbery to conclude that the levels of 8-OHG suggest DNA oxidation occurs early in the progression of AD {12}.



Alzheimer’s disease is an unpredictable neurodegenerative disorder that does not have one specific cause or course of progression. Multiple studies have demonstrated that alterations in pathophysiological biomarkers, including cerebrospinal fluid levels and amyloid traces in a positron emission tomography, are reliable methods of identifying the preclinical stage of AD. The early stage of AD follows closely with more significant alterations in these biomarkers, as well as the development of amyloid, tau neurofibrillary tangles, microglial activation, and neuroinflammation. These additional variations have the capability to target specific brain regions and may result in varied symptoms. Middle-stage AD patients present more pronounced cognitive functional deficits and experience severe disruptions in the topological properties of brain networks. Lastly, late-stage AD patients show abnormally increased oxidation of mtDNA and nDNA, and it is suggested that DNA oxidation occurs early on in the progression of the disease.


  1. Dubois, Bruno et al. (01/03/2016). Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Alzheimer's & dementia: the journal of the Alzheimer's Association. 292–323. https://doi.org/10.1016/j.jalz.2016.02.002. Retrieved: 03/11/2021

  2. Parnetti, Lucilla et al. (15/01/2019). Prevalence and risk of progression of preclinical Alzheimer's disease stages: A systematic review and meta-analysis. Alzheimer’s research & therapy. 7, 10.1186/s13195-018-0459-7. Retrieved: 03/11/2021

  3. Pitschke, M et al. (01/07/1998). Detection of single amyloid β-protein aggregates in the cerebrospinal fluid of Alzheimer's patients by fluorescence correlation spectroscopy. Nature Medicine. 832-834. https://doi.org/10.1038/nm0798-832. Retrieved: 03/11/2021.

  4. Fagan, Anne et al. (17/02/2006). Inverse relation between in Vivo Amyloid IMAGING load and cerebrospinal fluid AΒ42 in humans. Wiley Online Library. 512-519. https://doi.org/10.1002/ana.20730. Retrieved: 03/11/2021

  5. Normal vs. Alzheimer’s Brain (n.d.). Keep Memory Alive. https://www.keepmemoryalive.org/cc-nevada/alzheimers-brain. Retrieved: (03/11/2021).

  6. Stages of Alzheimer's (n.d.). Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/stages. Retrieved: 03/11/2021.

  7. Chandra, Avinash et al. (14/09/2019). Applications of amyloid, tau, and neuroinflammation pet imaging to Alzheimer's disease and mild cognitive impairment. Human brain mapping. 5424-5442. https://doi.org/10.1002/hbm.24782. Retrieved: 03/11/2021

  8. Johnson, Julene and Elizabeth Head. (1999). Clinical and pathological evidence for a frontal variant of Alzheimer disease. Arch Neurol. 1233-1239. https://doi.org/10.1001/archneur.56.10.1233. Retrieved: 03/11/2021

  9. Tombaugh, Torm. (01/03/2004). Trail making test a and b: Normative data stratified by age and education. Archives of Clinical Neuropsychology. 203-214. https://doi.org/10.1016/S0887-6177(03)00039-8. Retrieved: 03/11/2021

  10. Zhao, Xiaohu et al. (23/03/2012). Disrupted small-world brain networks in moderate Alzheimer's disease: A resting-state fmri study. Plos One. https://doi.org/10.1371/journal.pone.0033540. Retrieved: 03/11/2021

  11. Cockrell, Joseph and Marshal Folstein. (2002). Mini-Mental State Examination. Principles and Practice of Geriatric Psychiatry. 140-141. http://citeseerx.ist.psu.edu/viewdoc/download?doi= Retrieved: 03/11/2021

  12. Lovell, Mark and William Markesbery. (18/10/2007). Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease. Nucleic Acids Research. 7497-7504. https://doi.org/10.1093/nar/gkm821. Retrieved: 03/11/2021

  13. Mullaart, Erik et al.  (1990). Increased levels of DNA breaks in cerebral cortex of Alzheimer's disease patients. Netherlands Institute for Brain Research. 169-173. https://doi.org/10.1016/0197-4580(90)90542-8. Retrieved: 03/11/2021

  14. Lyras, Leonidas et al. (18/11/2002). An Assessment of Oxidative Damage to Proteins, Lipids, and DNA in brain from Patients with Alzheimer's Disease. Journal of Neurochemistry. 2061-2069. https://doi.org/10.1046/j.1471-4159.1997.68052061.x. Retrieved: 03/11/2021

Emma Colavita

Emma Colavita

Hi! My name is Emma Colavita and I am a Senior at New Century Technology Hight School. I am co-President of the NCTHS Neuroscience Club, and I'm currently participating in an internship with HudsonAlpha Institute for Biotechnology. I hope to pursue a career in research, specializing in neurodegenerative disorders such as Alzheimer's Disease. In my free time I like to read, write, and watch movies.