Alzheimer’s disease is quickly becoming one of the most known diseases in the country due to its devastating effects and lack of treatment options. Within this lethal disease, there is a smaller group, those individuals that are diagnosed with early-onset Alzheimer’s disease. It is understood that these individuals see faster effects of the disease and die considerably sooner, but it is not understood why. This review compares the early-onset (EOAD) and late-onset (LOAD) types to try and determine some of the most blaring differences between the two. The genetic basis linking EOAD and LOAD has been the apolipoprotein E gene (APOE) to indicate metabolic alteration with the ε 4 allele specifically. The topographical atrophy disparities between EOAD and LOAD supported the more noticeable cognitive differences between the two Alzheimer’s disease categories. The faster and wider spread atrophy of EOAD patients correlates with the difficulty they experience with attention, language, visuo-spatial, and executive functions. Finally , brain metabolism differs between both AD subtypes as well, where EOAD indicates the wide spread damage and metabolic breakdown across more diverse regions of the brain.
Alzheimer’s disease is an age-related neurodegenerative disorder and is seen in an estimated 35 million people worldwide [
Differences clearly exist between the two groups. In late-onset Alzheimer’s disease (LOAD), adults over the age of 65 show the characteristic decline in memory function and some mood swings. This then escalates over time to the patient being unable to properly control their own body. Unfortunately, in EOAD an estimated 30% of the patients will experience aphasia, apraxia and agnosia before memory disturbances [
When the hallmarks of Alzheimer’s disease are viewed: Amyloid Beta (Aβ) plaque and tau tangles, the EOAD and LOAD patients differ still. In the EOAD patients lower cerebrospinal fluid levels of Aβ plaque and very high total tau levels were displayed. These results were found with brain imaging techniques [
It is currently believed that less than one percent of EOAD cases are caused by an autosomal dominant mutation. The genes that account for these familial cases are PSEN1, PSEN2, and APP (6). The familial cases account for a very small proportion of the early onset patients. More commonly seen is the APOE ε4 allele in sporadic AD cases. Flier stated, 50% - 60% of individuals with AD are ε4 carriers [
APOE in the brain is mostly produced by astrocytes and microglia. It functions as a ligand receptor-mediated endocytosis of lipoprotein particles [
In a study carried out by Chartier-Harlin and colleagues, the APOE ε4 allele presence was compared between early-onset and late-onset Alzheimer’s patients and controls for the same age groups [
In a study carried out by Ishii and colleagues, the local gray matter concentration between early-onset AD and late-onset AD was compared, along with controls at the same age [
In a study carried out by Frisoni and colleagues, they also compared the grey matter atrophy of EOAD and LOAD patients [
In a study by Bird, postmortem levels of choline acetyltransferase activity in the brains of EOAD, LOAD, and age-matched controls were viewed [
frozen brain from the frontal cortex, superior temporal gyrus, Ammon’s horn, putamen, and lateral cerebellar hemisphere [
In a rat model study of AD, the metabolism in the rat brain was followed to determine the neurochemical outcome through the course of the disease. This study found that impaired neuronal mitochondria metabolism in the hippocampus, frontal cortex, frontal cingulate cortex, and retrosplenial cingulate cortex where a deceased amount of glutamate, GABA, and aspartate production occurred [
Studies that previously compared cerebrospinal fluid (CSF) levels of β-amyloid have been inconsistent in the past, they may either find no significant change, a slight decrease, or increase [
It should be noted that in Chiaravalloti and colleague’s study, they found some different results in the cerebrospinal fluid samples [
Cerebrospinal fluid is an important part of the brain, but blood flow is another measurable factor that needs to be considered. Within the brain, blood flow is what provides the needed oxygen and glucose used by the neurons to survive [
In another study that followed vascular dysregulation, Iturria-Medina and colleagues, tested for over 230 biomarkers seen in LOAD patients and sorted them according to their abnormality [
Some research has shown that cognitive dysfunction can be linked to high-sugar/fat diet and a sedentary lifestyle [
A study done on patients with Type 1 or 2 diabetes mellitus displayed significant memory impairment and attention deficits on cognitive testing compared to their controls [
Baker and colleagues carried out a similar study on 23 adults with no previous diagnosis of prediabetes or diabetes [
A positron emission tomography (PET) study on EOAD and LOAD patients viewed regional cerebral metabolic patterns [
In a study carried out by Kim and colleagues, a PET scan on participants compared the hypometabolic brain patterns in patients [
These findings demonstrate differences associated with glucose metabolism. Taken together with the previous data, the results here point to early-onset Alzheimer’s disease as being an overall more wide-spread and faster paced disease than the late-onset version. This was demonstrated in the results obtained from previous studies that viewed the grey matter atrophy, the neurochemical changes, metabolic dysfunction, and glucose metabolism changes due to the metabolic dysfunction.
Alzheimer’s is believed to have many causes, a genetic basis, Amyloid Plaque and tau Tangles formation, or hypometabolism in the brain. All are thought to play a part in the more uncommon Early-Onset Alzheimer’s Disease. This review compared these parameters, and a few others to outline the differences between LOAD and EOAD, or see if there really is much of a difference.
The APOE ε4 allele is indicative that an individual is more likely to develop
Alzheimer’s disease. This specific allele has been linked to conformational changes of the Aβ proteins, and causes them to clump together and diminish its role in neural growth and repair. The ε4 allele has been linked to metabolic alterations in the brain via increased low density lipoproteins (LDLs). This increase has been previously known to cause atherosclerosis, which affects blood flow, in this case to the brain. This same allele is not super indicative of when an individual will develop the hallmark signs of AD, but it is more common for individuals with this allele to have AD.
Differences in the atrophy and chemicals that occur in EOAD and LOAD brains supports the view that EOAD is a faster paced form of Alzheimer’s disease. Since EOAD patients have a difficult time with attention, language (including aphasia and apraxia), visuo-spatial, and executive functions, the locations of their greatest brain atrophy makes sense. It was shown that the greatest amount of atrophy for EOAD was in the bilateral inferior parietal lobes, occipital lobe, and basal forebrain. These same areas also demonstrated low levels of acetyl-transferase and GABA.
Some of the most trademark signs for the Late-Onset patients are their disappearing memory and mood swings. Their greatest location of atrophy and neurochemical dysfunctions was found in the hippocampus. This makes sense due to the hippocampus’s main role in emotion regulation, recalling long-term memories, and spatial navigation.
One of the newest theories is that AD may be linked to a decrease in sleep. Studies done in rodents support this idea since wakefulness resulted in the accumulation of Aβ. Likewise, NREM sleep supported glymphatic clearance of Aβ [
This review has demonstrated that Early-Onset Alzheimer’s, although a more uncommon form, is a more wide spread disease. When compared to the Late-Onset variant, EOAD demonstrates a broader array of complications that is more wide spread throughout the brain. This includes more damages due to atrophy across the entire brain, not just specific regions. The metabolic dysfunction and metabolism differences also demonstrated more wide spread metabolic dysfunction. Thus, this causes these patients to die much sooner after diagnosis than their Late-Onset counterparts. All of these patients demonstrate similar problems, just in different locations throughout the brain. More research needs to be done in the area of metabolic dysfunction for EOAD, and for all Alzheimer patients in general.
Griffith, J.A. and Kelly-Worden, M. (2018) Early-Onset Alzheimer’s Disease and Metabolic Dysfunction, a Comparative Review. Advances in Alzheimer’s Disease, 7, 1-11. https://doi.org/10.4236/aad.2018.71001