How is AD diagnosed?
A full diagnosis of AD requires a post-mortem pathological examination of the brain. However, pre-mortem diagnosis can now be made with 95% accuracy using a combination of methods, including a detailed history and neuropsychological testing of cognitive function. Other causes of dementia need to be ruled out, such as hypothyroidism, vitamin deficiencies, infections, tumors, and depression. Differentiation between AD and other neurodegenerative dementias, including frontotemporal dementia, Lewy body dementia, and Creutzfeldt-Jakob disease, is also required.
Brain imaging and cerebrospinal fluid examination can help in the differential diagnosis. MRI in AD patients often shows atrophy of brain areas associated with learning and memory, as well as decreased glucose metabolism, and PET for abnormal protein deposition (Aβ) reveals increased uptake of isotopically labeled ligands. CNS abnormalities include decreased Aβ peptides and increased tau protein levels.
How serious are the problems associated with AD?
Very serious! This is because people are living longer and aging is a major risk factor for AD. The AD Society estimates that without effective preventive measures, the number of people with AD in the United States will increase from the current 5 million to 11-16 million by 2050, and the number of people with AD worldwide will increase from the current 26 million to over 100 million. This will place a serious burden on the health care system because of the long duration of AD, the disruption of patient function, and the enormous cost.
What are the causes of AD?
There are many causes of AD. Much evidence suggests that neurodegenerative diseases, including AD, are associated with abnormal aggregation of harmful proteins in the nervous system. ad-related ones include Aβ, apolipoprotein E (apoE), the microscopically related protein tau, and the presynaptic protein synuclein, which has also been linked to Parkinson’s disease. In the normal human brain and other organs, amyloid precursor protein (APP) is sheared by β-secretase and γ-secretase to produce Aβ, but it is quickly cleared from the brain.
If excessive production or impaired clearance pathways result in increased concentrations, Aβ aggregates to form oligomers, protofibrils, fibers, and amyloid plaques. tau and synuclein also aggregate to form inclusion bodies within neurons, called neurogenic fiber tangles and Lewy vesicles, respectively. Amyloid plaques and neurogenic tangles are the hallmark lesions of AD, and some patients also have Lewy vesicles in their brains.
How do these lesions contribute to cognitive impairment?
This is a hot topic of current research. It is commonly believed that Aβ and tau cause abnormal neural network activity and impair the synapses that maintain learning, memory and other cognitive functions. Eventually, sensitive neurons atrophy and die in response to excitotoxicity (overstimulation of transmitter receptors on neurons), calcium disorders, inflammation, and energy and growth factor deficiencies. apoE4 is associated with abnormal aggregation of Aβ and tau and may also damage mitochondria and other cytoskeletons.
Aβ, tau, apoE and synuclein interact with other molecules to affect multiple signaling pathways for neural activity and survival. Transgenic mice and other experimental models have been used to study this complex relationship and to identify the most important biochemical cascades of signaling associated with the development of AD.
Is AD inherited?
Yes, the etiology of a minority of patients with early onset AD (probably <1%) is associated with mutations in a number of autosomal dominant genes that encode proteins involved in Aβ production, such as APP, progerin 1 and 2 (PS1, 2). Progerin is the enzymatic center of the γ-secretase complex. The genetic risk factor most associated with most AD is APOEε4, which encodes apoE4. The higher amount of apoE3 and the lower amount of apoE2 in apoE are protective factors for AD. More than 60% of Caucasian AD patients carry at least one APOEε4 gene. Other genetic variants that have been clearly associated with AD include, other apolipoprotein genes, clusterin (apoJ), the intracellular transporter protein PICALM and the complement component (3b/4b) receptor 1, which can affect Aβ levels, synaptic function and inflammation.
What are the non-genetic factors?
AD risk factors may also include low educational attainment, severe head trauma, cerebrovascular disease, diabetes and obesity. However, it is not clear whether avoiding these factors will reduce the occurrence of AD, especially in those with risk genes, which are thought to interact with other disease genes and environmental factors. A healthy person can develop AD early because of a PS1 mutation, or because they carry two APOEε4 genes, or because they carry one or more less risky genes but have overweight or diabetes.
What is the relationship between aging and AD?
Aging is the most important risk factor for AD. Even the most risky autosomal dominant mutations for AD do not usually lead to significant lesions until the age of 40 or 50. There are several mechanisms that protect the young brain from AD, including high levels of growth factors, good energy metabolism and effective protein misfolding clearance mechanisms and cellular repair. The loss of these protective mechanisms contributes to the development of AD. Aging also increases obesity, diabetes and atherosclerosis, which may contribute to the development of AD through metabolic and vascular mechanisms.
Inflammation may be a common pathway for these factors, as immune cells, particularly macrophages and microglia and astrocytes, have increased inflammatory activity with aging. Some of this increased activity is beneficial, while others may contribute to age-related diseases such as AD.
Is there an appropriate treatment?
There are currently three main classes of AD medications: acetylcholinesterase inhibitors; glutamate receptor antagonists; and drugs for depression and behavioral abnormalities.AD decreases acetylcholine levels in the brain and inhibition of its degrading enzyme acetylcholinesterase improves cholinergic neurotransmission. Excitotoxicity due to overstimulation of glutamate receptors is associated with AD, so blocking these receptors may be a therapeutic measure. Several clinical trials have shown some improvement in AD with inhibition of acetylcholinesterase or NMDA receptors, although these effects are small and do not cure or reverse AD.
Is there a role for diet and lifestyle changes?
It is often thought that adopting a healthy diet and lifestyle to avoid high cholesterol and high blood pressure may help prevent AD because of the association between vascular disease and AD. Regular physical activity increases growth factors in the memory brain areas of the brain. Epidemiological studies have shown that social engagement and active thinking also reduce the risk of AD. In mouse models, increased activity and an enriched environment prevented or delayed the onset of AD-like symptoms. However, the relatively poor condition of the control group in these studies may exaggerate the benefits of an “enriched environment”.
Are there other treatment options?
My view is that the most important thing right now is to enroll AD patients and their relatives in carefully designed, well-controlled, prospective clinical trials. It is important to increase the proportion of AD patients and healthy older adults in clinical trials. Conversely, OTC drugs and herbal remedies with unproven efficacy are not recommended as so-called “dietary therapies”.
The claims to fame for these compounds are notoriously transient. They’ve also added a troublesome burden of confounding variables (‘noise’) among They’ve also added a troublesome burden of confounding variables (‘noise’) among trial subjects and complicate the task of designing informative clinical trials.
Why do most drug clinical trials fail?
There are multiple reasons. In some cases, trials have shown that the drug target did not target a key pathogenic mechanism. In other cases, the drug may block one pathogenic pathway, but the overall benefit may be small because other pathogenic mechanisms are still at play in this multifactorial disease. For example, in a recent trial of an anti-Aβ agent, APOEε4 gene carriers had more side effects and less therapeutic effect than non-carriers.
It is also difficult to assess whether drugs affect the most relevant indicators. A large body of evidence suggests that Aβ oligomers impair synaptic and cognitive function more than amyloid plaques. Plaque counts can be measured by radiographic methods, but Aβ oligomer levels cannot be measured on patients, so it is uncertain whether anti-Aβ therapy reduces harmful Aβ oligomer levels. Treatment failure may also be due to “too little, too late”, and AD can progress unnoticed for years. Some of my colleagues believe that even the so-called early clinical stages of AD have actually reached a stage of progression where brain function is irreversible.
Is it possible to reverse AD?
This relies in part on the plasticity of the brain, which is still far more plastic than other organs, although AD-related factors such as Aβ and apoE4 impair the brain’s recovery mechanisms. On the other hand, removing these factors may restore its powerful repair mechanisms, thus repairing or helping to bypass the disrupted neural circuits and making it possible to achieve functional recovery. Many people have shown good neurological recovery after nerve damage from various causes. Experiments are therefore needed to investigate whether AD-injured brains show similar recovery of function after removing inhibitors of regeneration.
Is stem cell therapy available?
The idea of stem cell therapy is based on the possibility of stem cells replacing damaged neurons. However, challenges remain for AD because the disease affects multiple neurons in different brain regions. It is unclear whether stem cells can be induced to differentiate into these types of cells and whether these cells can effectively integrate into the damaged neural circuits, especially in the adverse environment of AD, which is full of harmful proteins and inflammatory mediators. Elimination of deleterious factors contributes to regeneration and repair.
The current effect of stem cells is to serve as a model for the study of multiple etiologies of AD. It is now possible to isolate pluripotent stem cells from patient skin cells and differentiate them into neurons or other brain cells. Comparing these cell models may help to identify causative factors and regulatory genes in different patients.
Is prevention feasible?
Prophylactic treatment should begin years before the first symptoms of AD appear. Administering treatment for such a long period of time requires drugs with minimal adverse effects, as well as the ability to identify populations with significant risk factors. Although there have been some research advances, we do not currently have reliable early biomarkers. An AD neuroimaging study is now underway to determine if measuring brain volume changes, intracerebral glucose metabolism and amyloid deposition, and cerebrospinal fluid Aβ and tau levels will help identify people at risk. Plasma proteomics studies have revealed a number of protein “fingerprints” that may be used in the early diagnosis of AD. Although whole genome sequencing is not yet available as a routine screening tool, screening for known dominant genetic mutations such as APP, PS1, PS2 and APOEε4 is of great interest.
Should everyone be genetically tested?
A number of considerations need to be taken into account, including family history, expectations for life and expectations for disease prevention. If there has been a case of early onset AD in the family and you are planning to have children, then screening for autosomal dominant mutations associated with AD is appropriate. In summary, AD genetic testing should only be performed with the advice of an experienced physician and genetic counselor. Many clinicians do not recommend screening for APOEε4 and other susceptibility genes because, although these genes are risk factors, some carriers do not develop AD.
The lack of effective preventive measures also makes determining someone’s risk of developing the disease not very meaningful, although it can be helpful in beating the disease.
Is there any hope for us?
Of course there is. As our understanding of the mechanisms of AD improves, drugs will be developed that target the cause rather than the symptoms, and some such drugs are already in clinical trials, with many more in development. The application of genomic and proteomic characterization of risk factors on a large scale allows us to identify which drugs respond best to different types of patients. Selecting the most representative patients improves the efficiency of clinical trials and helps provide guidance for long-term protective treatment strategies.