Long before symptoms like memory loss even emerge, the underlying pathology of Alzheimer’s disease, such as an accumulation of amyloid protein plaques, is well underway in the brain.
A longtime goal of the field has been to understand where it starts so that future intervention could begin there.
A new study by MIT neuroscientists at The Picower Institute for Learning and Memory could help those efforts by pinpointing the regions with the earliest emergence of amyloid in the brain of a prominent mouse model of the disease.
Notably, the study also shows that the degree of amyloid accumulation in one of those same regions of the human brain correlates strongly with the progression of the disease.
“Alzheimer’s is a neurodegenerative disease so in the end you can see a lot of neuron loss,” said Wen-Chin “Brian” Huang, co-lead author of the study and a postdoc in the lab of co-senior author Li-Huei Tsai, Picower Professor of Neuroscience and director of the Picower Institute.
“At that point it would be hard to cure the symptoms. It’s really critical to understand what circuits and regions show neuronal dysfunction early in the disease. This will, in turn, facilitate the development of effective therapeutics.”
In addition to Huang, the study’s co-lead authors are Rebecca Canter, a former member of the Tsai lab, and Heejin Choi, a former member of the lab of co-senior author Kwanghun Chung, associate professor of chemical engineering and a member of the Picower Institute and the Institute for Medical Engineering and Science.
Many research groups have made progress in recent years by tracing amyloid’s path in the brain using technologies such as positron emission tomography and by looking at brains post-mortem, but the new study adds substantial new evidence from the 5XFAD mouse model because it presents an unbiased look at the entire brain as early as one month of age.
The study reveals that amyloid begins its terrible march in deep brain regions such as the mammillary body, the lateral septum and the subiculum before making its way along specific brain circuits that ultimately lead it to the hippocampus, a key region for memory, and the cortex, a key region for cognition.
The team measured the excitability of neurons in the mammillary body of 5XFAD mice and found they were more excitable than otherwise similar mice that did not harbor the 5XFAD set of genetic alterations. The image is adapted from the Picower Institute/MIT video.
The team used SWITCH, a technology developed by Chung, to label amyloid plaques and to clarify the whole brains of 5XFAD mice so that they could be imaged in fine detail at different ages.
The team was consistently able to see that plaques first emerged in the deep brain structures and then tracked along circuits such as the Papez memory circuit to spread throughout the brain by 6-12 months (a mouse’s lifespan is up to three years).
The findings help to cement an understanding that has been harder to obtain from human brains, Huang said, because post-mortem dissection cannot easily account for how the disease developed over time and PET scans don’t offer the kind of resolution the new study provides from the mice.
Importantly, the team directly validated a key prediction of their mouse findings in human tissue: If the mammillary body is indeed a very early place that amyloid plaques emerge, then the density of those plaques should increase in proportion with how far advanced the disease is.
Sure enough, when the team used SWITCH to examine the mammillary bodies of post-mortem human brains at different stages of the disease, they saw exactly that relationship: The later the stage, the more densely plaque-packed the mammillary body was.
Starting early in the life of an Alzheimer’s model (5XFAD) mouse using SWITCH technology, researchers were able to see amyloid plaque buildups (stained white) in deep regions of the brain early in disease. Over succeeding months, the plaques spread from there along specific circuits. At each new age the video starts anew from the mammillary body. Credit: Picower Institute/MIT.
“This suggests that human brain alterations in Alzheimer’s disease look similar to what we observe in mouse,” the authors wrote.
“Thus we propose that amyloid-beta deposits start in susceptible subcortical structures and spread to increasingly complex memory and cognitive networks with age.”
The team also performed experiments to determine whether the accumulation of plaques they observed were of real disease-related consequence for neurons in affected regions.
One of the hallmarks of Alzheimer’s disease is a vicious cycle in which amyloid makes neurons too easily excited and overexcitement causes neurons to produce more amyloid.
The team measured the excitability of neurons in the mammillary body of 5XFAD mice and found they were more excitable than otherwise similar mice that did not harbor the 5XFAD set of genetic alterations.
In a preview of a potential future therapeutic strategy, when the researchers used a genetic approach to silence the neurons in the mammillary body of some 5XFAD mice but left neurons in others unaffected, the mice with silenced neurons produced less amyloid.
After observing in mice that the mammillary body is a key early locus for the emergence of amyloid plaques in Alzheimer’s disease, researchers confirmed that the density of amyloid plaques increases with increasing disease stage in the human mammillary body. Credit: Picower Institute/MIT.
While the study findings help explain much about how amyloid spreads in the brain over space and time, they also raise new questions, Huang said. How might the mammillary body affect memory and what types of cells are most affected there?
“This study sets a stage for further investigation of how dysfunction in these brain regions and circuits contributes to the symptoms of Alzheimer’s disease,” he said.
In addition to Huang, Canter, Choi, Tsai and Chung, the paper’s other authors are Jun Wang, Lauren Ashley Watson, Christine Yao, Fatema Abdurrob, Stephanie Bousleiman, Jennie Young, David Bennett and Ivana Dellalle.
Funding: The National Institutes of Health, the JPB Foundation, Norman B. Leventhal and Barbara Weedon fellowships, The Burroughs Wellcome Fund, the Searle Scholars Program, a Packard Award, a NARSAD Young Investigator Award and the NCSOFT Cultural Foundation funded the research.
Dementia is a general term that refers to a decline in cognitive ability severe enough to interfere with activities of daily living. Alzheimer disease (AD) is the most common type of dementia, accounting for at least two-thirds of cases of dementia in people age 65 and older. A
lzheimer disease is a neurodegenerative disease that causes progressive and disabling impairment of cognitive functions including memory, comprehension, language, attention, reasoning, and judgment. It is the sixth leading cause of death in the United States.
Alzheimer disease is typically a disease of old age. Onset before 65 years of age (early onset) is unusual and seen in less than 10% of Alzheimer disease patients. The most common presenting symptom is selective short-term memory loss. The disease is invariably progressive, eventually leading to severe cognitive decline. There is no cure for Alzheimer disease, although there are treatments available that may improve some symptoms.
Symptoms of Alzheimer disease depend on the stage of the disease. Alzheimer disease is classified into preclinical, mild, moderate, and late-stage depending on the degree of cognitive impairment.
The initial presenting symptom is usually recent memory loss with relative sparing of long-term memory and can be elicited in most patients even when not the presenting symptom. Short-term memory impairment is followed by impairment in problem-solving, judgment, executive functioning, lack of motivation and disorganization, leading to problems with multitasking and abstract thinking.
In the early stages, impairment in executive functioning may be subtle. This is followed by language disorder and impairment of visuospatial skills.
Neuropsychiatric symptoms like apathy, social withdrawal, disinhibition, agitation, psychosis, and wandering are also common in the mid to late stages.
Difficulty performing learned motor tasks (dyspraxia), olfactory dysfunction, sleep disturbances, extrapyramidal motor signs like dystonia, akathisia, and parkinsonian symptoms occur late in the disease. This is followed by primitive reflexes, incontinence, and total dependence on caregivers.,,
Alzheimer disease is a gradual and progressive neurodegenerative disease caused by neuronal cell death. It typically starts in the entorhinal cortex in the hippocampus. There is a genetic role identified for both early and late-onset Alzheimer disease. Several risk factors have been associated with Alzheimer disease.
Increasing age is the most important risk factor for Alzheimer disease. Traumatic head injury, depression, cardiovascular and cerebrovascular disease, higher parental age, smoking, family history of dementia, and presence of APOE e4 allele are known to increase the risk of Alzheimer disease. Higher education, use of estrogen by women, use of anti-inflammatory agents, and regular aerobic exercise is known to decrease the risk of Alzheimer disease.
Having a first-degree relative with Alzheimer disease increases the risk of developing Alzheimer disease by 10% to 30%. Individuals with 2 or more siblings with late-onset Alzheimer disease increases their risk of getting Alzheimer disease by 3-fold as compared to the general population.,,
Alzheimer disease is typically a disease of old age. The global prevalence of dementia is reported to be as high as 24 million and is predicted to increase 4 times by the year 2050. Estimated health care cost of Alzheimer disease is $172 billion per year in the United States alone. In 2011, the United States had an estimated 4.5 million people age sixty-five and above, living with clinical Alzheimer disease.
The incidence of dementia is predicted to double every 10 years after 60 years of age. Age-specific incidence increases significantly from less than 1% per year before 65 years of age to 6% per year after 85 years of age. Incidence rates of Alzheimer disease are slightly higher for women, especially after 85 years of age.
Alzheimer disease is characterized by an accumulation of abnormal neuritic plaques and neurofibrillary tangles.
Plaques are spherical microscopic lesions that have a core of extracellular amyloid beta peptide surrounded by enlarged axonal endings. Beta-amyloid peptide is derived from a transmembrane protein known as an amyloid precursor protein (APP). The beta-amyloid peptide is cleaved from APP by the action of proteases named alpha, beta, and gamma-secretase. Usually, APP is cleaved by either alpha or beta-secretase and the tiny fragments formed by them are not toxic to neurons.
However, sequential cleavage by beta and then gamma-secretase results in 40 and 42 amino acid peptides (beta-amyloid 40 and beta-amyloid 42). Elevation in levels of beta-amyloid 42 leads to aggregation of amyloid that causes neuronal toxicity. Beta-amyloid 42 favors formation of aggregated fibrillary amyloid protein over normal APP degradation. APP gene is located on chromosome 21, one of the regions linked to the familial Alzheimer disease. Amyloid deposition occurs around meningeal and cerebral vessels and gray matter in Alzheimer disease. Gray matter deposits are multifocal and coalesce to form milliary structures called plaques.
Neurofibrillary tangles are fibrillary intracytoplasmic structures in neurons formed by a protein called tau. The primary function of tau protein is to stabilize axonal microtubules. Microtubules run along neuronal axons and are essential for intracellular transport. Microtubule assembly is held together by tau protein.
In Alzheimer disease, due to aggregation of extracellular beta-amyloid, there is hyper-phosphorylation of tau which then causes the formation of tau aggregates. Tau aggregates form twisted paired helical filaments known as neurofibrillary tangles.
They occur first in the hippocampus and then may be seen throughout the cerebral cortex. There is a staging system developed by Braak and Braak based on topographical staging of neurofibrillary tangles into 6 stages, and this Braak staging is an integral part of the National Institute on Aging and Reagan Institute neuropathological criteria for the diagnosis of Alzheimer disease.
Another feature of Alzheimer disease is granulovacuolar degeneration of hippocampal pyramidal cells by amyloid angiopathy. Some reports indicate that cognitive decline correlates more with a decrease in density of presynaptic boutons from pyramidal neurons in laminae III and IV, rather than an increase in the number of plaques.
Vascular contribution to the neurodegenerative process of Alzheimer disease is not fully determined. Risk of dementia is increased fourfold with subcortical infarcts. Cerebrovascular disease also exaggerates the degree of dementia and its rate of progression.,,
Genetic Basis of Alzheimer Disease
Alzheimer disease can be inherited as an autosomal dominant disorder with nearly complete penetrance. The autosomal dominant form of the disease is linked to mutations in 3 genes: AAP gene on chromosome 21, Presenilin1 (PSEN1) on chromosome 14, and Presenilin 2 (PSEN2) on chromosome 1. APP mutations may lead to increased generation and aggregation of beta-amyloid peptide. PSEN1 and PSEN2 mutations lead to aggregation of beta-amyloid by interfering with the processing of gamma-secretase. Mutations in these 3 genes account for about half of the familial forms of early-onset Alzheimer disease.
Apolipoprotein E is a regulator of lipid metabolism that has an affinity for beta-amyloid protein and is another genetic marker that increases the risk of Alzheimer disease. Isoform e4 of APOE gene (located on chromosome 19) has been associated with more sporadic and familial forms of Alzheimer disease that present after age 65. Presence of APOEe4 allele does not always lead to Alzheimer disease, but one APOE- e4 allele increase the risk by 2- to 3-fold and 2 copies by 5-fold. Each APOE e4 allele also lowers the age of disease onset. Presence of APOE e4 allele is an important risk factor for Alzheimer disease.
Variants in the gene for the sortilin receptor, SORT1, which is essential for transporting APP from cell surface to Golgi-endoplasmic reticulum complex, have been found in familial and sporadic forms of Alzheimer disease.
History and Physical
A good history and physical examination are the keys to diagnosis. It is also essential to take a history from the family and caregivers as some patients may lack insight into their disease. It is vital to characterize onset and early symptoms to differentiate from other types of dementia. It is important to obtain a good assessment of functional abilities like basic and individual activities of daily living.
A complete physical examination with a detailed neurological exam and mental status examination is needed to evaluate disease stage and rule out other conditions. Comprehensive clinical assessment can provide reasonable diagnostic accuracy in most patients.
A detailed neurological examination is essential to rule out other conditions. In Alzheimer disease, the neurological exam is usually normal. A mental status examination should assess concentration, attention, recent and remote memory, language, visuospatial functioning, praxis, and executive functioning.
Brief standard examinations like the mini-mental status examination are less sensitive and specific, although they can be used for screening.
All follow-up visits should include a full mental status examination to evaluate disease progression and development of neuropsychiatric symptoms.
Routine laboratory tests show no specific abnormality. Complete blood count (CBC), complete metabolic panel (CMP), thyroid-stimulating hormone (TSH), B12 are usually checked to rule out other causes.,,
Brain imaging may help in the diagnosis and monitor the clinical course of the disease. MRI or CT brain can help exclude other causes of dementia like stroke or tumors. Dilated lateral ventricles and widened cortical sulci, especially in the temporal area are typical for Alzheimer disease.
Cerebrospinal fluid (CSF) is usually normal, but total protein may be mildly elevated. Measurements of total-tau, beta-amyloid, and phosphorylated tau protein are sometimes helpful for differential diagnosis. Alzheimer disease is strongly predicted if CSF has decreased beta-amyloid 42 and increased tau protein.
EEG typically shows a generalized slowing with no focal features.
The most reliable method to detect mild cognitive impairment in early disease is neuropsychological testing.
More recently, volumetric MRI is being used to precisely measure volumetric changes in the brain. In Alzheimer disease, volumetric MRI shows shrinkage in the medial temporal lobe. However, hippocampal atrophy is also linked to normal age-related memory decline, so the use of volumetric MRI for early detection of Alzheimer disease is questionable. A definite role for volumetric MRI to aid diagnosis of Alzheimer disease is not fully established yet.
Functional brain imaging techniques like PET, fMRI, and SPECT are being used to map patterns of dysfunction in smaller brain areas of the medial temporal and parietal lobe. These studies may be helpful in early detection and monitoring clinical course; however, their role in the diagnosis of Alzheimer disease is not fully established yet.
Most recently, there have been developments in brain imaging techniques to detect core histological features of Alzheimer disease, that is amyloid plaques and neurofibrillary tangles. The utility of these techniques is still being investigated.
Genetic testing is usually not recommended for Alzheimer disease. It may sometimes be used in families with rare early-onset forms of Alzheimer disease.
It is important to understand that diagnosing the type of dementia with all certainty may not be entirely possible despite excellent clinical history, physical examination and relevant testing. Some patients will complain of cognitive impairment that can be verified objectively, but is not severe enough to impair activities of daily life and thus does not meet criteria for dementia, and is usually just classified as mild cognitive impairment. However, a significant proportion of people with mild cognitive impairment will develop dementia of some type in 5 to 7 years.
Treatment / Management
Two categories of drugs are approved for the treatment of Alzheimer disease: cholinesterase inhibitors and partial N-methyl D-aspartate (NMDA) antagonists.
Cholinesterase inhibitors act by increasing the level of acetylcholine; a chemical used by nerve cells to communicate with each other and is important for learning, memory and cognitive functions. Of this category, 3 drugs: donepezil, rivastigmine, and galantamine are FDA-approved for the treatment of Alzheimer disease.
Donepezil can be used in all stages of Alzheimer disease. Galantamine and rivastigmine are approved for treatment in mild to moderate Alzheimer disease only. Donepezil and galantamine are rapid, reversible inhibitors of acetylcholinesterase. Rivastigmine is a slow, reversible inhibitor of acetylcholinesterase and butyrylcholinesterase. Donepezil is usually preferred of all because of once-daily dosing. Galantamine is available as a twice daily tablet or as a once-daily extended-release capsule. It cannot be used in end-stage renal disease or severe liver dysfunction. Rivastigmine is available in an oral and transdermal formulation. Most common side effects of cholinesterase inhibitors are gastrointestinal-like nausea, vomiting, and diarrhea. Sleep disturbances are more common with donepezil. Due to increased vagal tone, bradycardia, cardiac conduction defects, and syncope can occur, and these medications are contraindicated in patients with severe cardiac conduction abnormalities.
Partial N-Methyl D-Aspartate (NMDA) Memantine
Partial N-Methyl D-aspartate (NMDA) antagonist memantine blocks NMDA receptors and slows intracellular calcium accumulation. It is approved by the FDA for treating moderate to severe Alzheimer disease. Dizziness, body aches, headache, and constipation are common side effects. It can be taken in combination with cholinesterase inhibitors.
It is also important to treat anxiety, depression, and psychosis, which is often found in the mid to late stages of Alzheimer disease.
Environmental and behavioral approaches are beneficial especially in managing behavioral problems. Simple approaches such as maintaining a familiar environment, monitoring personal comfort, providing security object, redirecting attention, and avoiding confrontation can be very helpful in managing behavioral issues.
The expected benefits of the treatment are modest. Treatment should be stopped or modified if no significant benefits or if intolerable side effects.
Regular aerobic exercise has been shown to slow the progression of Alzheimer disease.
Differential diagnosis of Alzheimer dementia includes- Mild cognitive decline, Pseudodementia, Depression, Lewy body dementia, Vascular dementia, Mixed dementia, and frontotemporal lobar degeneration. Other disorders to consider and rule out when evaluating for Alzheimer disease include age-associated memory impairment, alcohol or drug abuse, depression, vitamin-B12 deficiency, hearing or visual impairment, electrolyte imbalance, thyroid problems, normal pressure hydrocephalus, Parkinson disease with dementia, polypharmacy, Wernicke-Korsakoff syndrome.
Some atypical presentations of Alzheimer disease include:
- The multidomain amnestic syndrome affects multiple areas of cognition especially language and spatial orientation with relative sparing of memory in early stages.
- Posterior cortical atrophy manifests as progressive cortical visual impairment with features such as simultagnosia, object, and space perception deficits, acalculia, alexia, and oculomotor apraxia, with relative sparing of anterograde memory, non-visual language function, behavior, and personality. Neuroimaging shows occipitoparietal or occipitotemporal atrophy.
- Primary progressive aphasia is characterized by progressive language difficulty with relative sparing of memory and other cognitive functions in early disease.
- Dysexecutive or frontal variant patients have impairment in executive functions relative to memory loss.
David Orenstein – MITImage Source:
The image is adapted from the Picower Institute/MIT video.
Original Research: Open access
“3D mapping reveals network-specific amyloid progression and subcortical susceptibility in mice”. Rebecca Gail Canter, Wen-Chin Huang, Heejin Choi, Jun Wang, Lauren Ashley Watson, Christine G. Yao, Fatema Abdurrob, Stephanie M. Bousleiman, Jennie Z. Young, David A. Bennett, Ivana Delalle, Kwanghun Chung & Li-Huei Tsai.
Communications Biology doi:10.1038/s42003-019-0599-8.