- The cerebral hemispheres: They account for ~ 85% of the brain's weight. The neurons in them are connected by the corpus callosum (thick bundles of nerve cell fibers). The left hemisphere appears to focus on details whereas the right hemisphere focuses on broad background. The cerebral cortex is the outer layer of these hemispheres, controlling voluntary movement, and regulating cognitive functions. The hemispheres have four lobes, each of which having different roles: the frontal lobe (for executive functions like thinking, organizing, planning, and problem solving, as well as memory, attention, and movement); the parietal lobe sitting behind the frontal lobe (for perception and integration of stimuli from the senses); the occipital lobe at the back of the brain (for vision); and the temporal lobe running along the side of the brain under the frontal and parietal lobes (for senses of smell, taste, and sound, and the formation and storage of memories).
- The cerebellum: Located beneath the occipital lobe and having also two hemispheres. It plays roles in balance and coordination, and motor learning.
- The brain stem: Located at the base of the brain, it connects the spinal cord with the rest of the brain. Its functions are crucial to survival (heart rate, blood pressure, breathing, sleep and dreaming).
- The limbic system: Lying deep inside the cerebral hemispheres, it links the brain stem with the higher reasoning elements of the cerebral cortex. It plays a key role in memory, emotion, and instinctive behaviors. It includes: the amygdala(for strong emotions such as fear), the hippocampus (for learning and short-term memories and their conversion into long-term memories for storage in other brain areas; the thalamus (for sensory and limbic information); and the hypothalamus(for monitoring activities such as body temperature, food intake, and the body’s internal clock).
|Type||Cause(s) or Mark(s)||Symptoms|
|Vascular dementia (VD)
(may overlap with AD)
|Reduced blood flow to the brain||Multiple small strokes|
(FTD) (much less common than AD)
|Changes in behavior, memory problems, difficulty speaking|
|Lewy body dementia (LBD)||Hallucinations, delusions, increased sleeping, REM behavioral disturbance, etc.|
|Alzheimer dementia (AD)||Amyloid beta plaques and neurofibrillary tangles (?)||Memory loss, severe cognitive deficits|
Subjective cognitive impairment (SCI)is a worsening condition that is noticeable to the individual but, in standard neuropsychological testing, still falls in the normal range. Brain MRI may show some shrinkage. It may last a decade or two before the impairment progresses to the next stage.
Mild cognitive impairment (MCI) typically follows SCI. Neuropsychological tests show that memory, organizing, speaking, calculating, planning, or other cognitive abilities are abnormal (even though the individual may still be able to perform daily activities). MCI does not inevitably progress to AD but, in many people, especially those in whom there is memory loss, AD will follow within a few years.
The first symptoms are often mistakenly attributed to aging or stress:
- Mild cognitive difficulties (evidenced by detailed neuropsychological testing up to eight years before the clinical diagnosis criteria), particularly short term memory loss;
- Subtle problems with executive functions (attentiveness, planning, flexibility, abstract reasoning);
- Impairments in semantic memory (memory of meanings, concept relationships);
- Apathy (a most persistent neuropsychiatric symptom throughout the course of the disease;
- Depressive symptoms, irritability and reduced awareness of subtle memory difficulties are also common.
Mild cognitive impairment (MCI) is a preclinical transitional stage of the disease between normal aging and dementia. It can present with a variety of symptoms and, when memory loss is the predominant symptom, it is termed "amnestic MCI" and is frequently seen as a prodromal stage (an early or premonitory symptom) of the disease.
This stage is characterized by the increasing impairment or difficulties of:
- Learning and memory;
- Language (shrinking vocabulary; decreased word fluency; impoverishment of oral and written language);
- Executive functions;
- Agnosia (perception);
- Apraxia (execution of movements; difficulties in writing, drawing, dressing, coordination, planning) that may be more prominent than memory problems.
- Episodic memory (older memories of the person);
- Semantic memory (facts learned);
- Implicit memory (how to do things, such as using a fork to eat or how to drink from a glass).
This stage is characterized by:
- Progressive deterioration eventually hindering independence;
- Inability to perform most common activities of daily living;
- Paraphasia (speech difficulties due to an inability to recall vocabulary, incorrect word substitutions);
- Reading and writing skills are progressively lost;
- Complex motor sequences become less coordinated (so the risk of falling increases);
- Worsened memory problems (failure to recognize close relatives);
- Impaired long term memory, which was previously intact;
- Behavioral and neuropsychiatric changes become more prevalent.
- Crying, outbursts of unpremeditated aggression;
- Resistance to caregiving;
- Illusionary misidentifications;
- Anosognosia (lost insight of the disease process and limitations); and
- Urinary incontinence. Urinary incontinence can develop.
The final stages of the disease are characterized by:
- Complete dependence of the patient upon caregivers;
- Language reduction to simple phrases or even single words, eventually leading to complete loss of speech. However, despite the loss of verbal language abilities, people can often understand and return emotional signals;
- Although aggressiveness can still be present, extreme apathy and exhaustion are much more common;
- Ultimately, inability to perform even the simplest tasks independently;
- Bedridden and inability to feed oneself.
Based on twin and family studies, the genetic heritability of AD (and its memory components) is about 49-79%. It includes two varieties:
Early onset familial AD (EOFAD): Around 0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance [7-8] with an onset before age 65. Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: (1) those encoding amyloid precursor protein (APP), (2) presenilin 1 and (3) presinilin 2. Here, some of the mutations increase the production of a small protein called Aβ42 (the main component of senile plaques) while others merely alter the ratio Aβ42/ Aβ40 (the other major form) without increasing Aβ42 levels.
Late onset sporadic AD (LOSAD): This is the majority of cases of AD. Here, both environmental effects and genetic modifiers may act as risk factors. The best known genetic risk factor is the inheritance of the allele ε4 of the Apo lipoprotein E (or ApoE ε4). Between 40-80% of people with AD possess at least one ApoE ε4 allele. ApoE ε4 increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes . This is the strongest known genetic risk factor. More recent genome-wide association studies (GWAS) have found 21 areas in genes that appear to affect the risk, including: ABCA7, BIN1, CASS4, CD2AP, CELF1, CLU, CR1, DRB5, EPHA1, FERMT2, HLA, INPP5D, MEF2C, MS4A, NME8, PICALM, PTK2B, SIC24A4, SORL1, TREM2, and ZCWPW1 [10-11].
The amyloid hypothesis postulates that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease (14). There are four supports for this postulate: (1) The gene for APP is located on chromosome 21; (2) people with trisomy 21 (Down syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of AD by 40 years of age; and (3) a specific isoform of ApoE4 is a major genetic risk factor for AD. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms (such as ApoE4) are not very effective at this task, leading to excess amyloid buildup in the brain; and (4) transgenic mice that express a mutant form of the human APP gene develop fibrillary amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits. On the basis of laboratory and animal studies, various compounds were designed to test the hypothesis on humans. Unfortunately, while these compounds performed as predicted, the AD patients on whom they were tested either got not better or incredibly got worse!
This hypothesis proposes that tau protein abnormalities initiate the disease cascade  wherein hyper phosphorylated tau begins to pair with other threads of tau eventually forming neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton, which collapses the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
There is evidence that exposure to toxic elements (metals) may be a contributing factor to the development of Alzheimer's disease. The same holds but tentatively for air pollution exposure.
In his earlier publications and recent book , Professor Dale Bredesen of the University of California at Los Angeles posited that the cause of AD is three-pronged: (1) Inflammation (from infection, diet, or other causes); (2) Neurotrophy (from decline or shortage of supportive nutrients, hormones, and other brain-supporting molecules); and (3) Toxicity (from substances such as metals or biotoxins), from which the acronym derives. These would correspond to three different subtypes of AD. In this view, and excepting the genetic hypothesis, the multiple other hypotheses advanced so far would be merely risk (not causative) factors for AD. In particular, the amyloid cascade and tau hypotheses are protective responses of the brain from these three categories of metabolic threats. In a separate publication, more will be said about the INT hypothesis and its overarching seminal work.
This hypothesis states that poor functioning of the blood brain barrier (BBB) may be involved . The cellular homeostasis of bio metals (such as ionic copper; iron and zinc) is disrupted in AD, though it remains unclear whether this is produced by or causes the changes in proteins. These ions affect and are affected by tau, APP and ApoE, and their dysregulation may cause oxidative stress that may contribute to the pathology. However, this link remains controversial.
Systemic markers of the innate immune system are risk factors for late-onset AD .
This is the oldest hypothesis that proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine . It has not received widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective . Other cholinergic effects have also been proposed leading to generalized neuro inflammation.
Although cardiovascular risk factors, such as hypercholosterolemia, hypertension, diabetes, and smoking are associated with a higher risk of onset and course of AD, the corresponding treatment drugs have had no effect on AD.
Smoking is a significant AD risk factor but it is unclear whether smoking alone could cause AD.
An infection with Spirochetes (a bacterium) may cause dementia and may be involved in the pathogenesis of Alzheimer's disease.
Dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which then causes amyloid production and tau hyper-phosphorylation as a side effect.
AD is usually diagnosed based on three factors :
- The person's medical history;
- The history from relatives; and
- The behavioral observations.
- The presence of characteristic neurological and neuropsychological features; and
- The absence of alternative conditions.
Advanced medical imaging with computed tomography, MRI, PET and single photon emission computed tomography (SPECT) can be used to help exclude other cerebral pathologies or subtypes of dementia. Moreover, they may predict conversion from prodromal stages (mild cognitive impairment) to AD. Assessment of intellectual functioning, including memory testing can further characterize the state of the disease. Diagnostic criteria exist to ease and standardize the diagnostic process for practicing physicians. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.
The (U.S.) National Institute of Neurological and Communicable Disorders and Stroke (NINCDS) and the Alzheimer's disease and Related Disorders Association (ADRDA, now known simply as the Alzheimer' Association, AA) issued diagnostic criteria (24) that are the most currently used. Extensively updated in 2007, these criteria require that the presence of cognitive impairment and a suspected dementia syndrome be confirmed by neuropsychological testing before a clinical diagnosis of possible or probable AD be made. A histopathologic confirmation including a microscpic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation.
- Perceptual skills;
- Constructive abilities;
- Problem solving; and
- Functional abilities.
There are four tests that are administered for the diagnosis of AD:
These tests including the mini-mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis. However, more comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease.
In early AD, this examination will usually provide normal results, except for obvious cognitive impairment, which may not differ from that resulting from other diseases processes, including other causes of dementia. Further neurological examinations are crucial in the differential diagnosis of AD and other diseases (26). Interviews with family members are also utilized in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease, over time, of the person's mental function.
It provides extra information on some features of the disease or is used to rule out other diagnoses. Thus: Blood tests can identify other causes for dementia than AD; thyroid function tests; B12 assessment; ruling out syphilis; ruling out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes); assessing levels of heavy metals (e.g. lead, mercury) and anemia; ruling out delirium.
These tests are employed for depression, since depression can either be concurrent with AD (an early sign of cognitive impairment) or even be the cause.
- C-PIB-PET scan: It is not recommended to be used as an early diagnostic tool or for predicting the development of AD when patients show signs of mild cognitive impairment (MCI).
- 18F-FDG PET scans: It is not supported by evidence as a single test for identifying patients who may develop AD.
Epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether these factors can help to prevent AD (30-33).
Engaging in intellectual activities (reading, playing board games, completing crossword puzzles, playing musical instruments, regular social interactions) show a reduced risk for AD. This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning, providing the individual a cognitive reserve that delays the onset of dementia manifestations (34).
Education delays the onset of AD's syndrome without changing the duration of the disease.
Even later in life, it seems to delay getting AD.
This is also associated with a reduced risk of AD. Physical exercise is associated with a decreased rate of dementia and is also effective in reducing symptom severity in those who are already afflicted by the disease.
Conclusions on dietary components have at times been difficult to ascertain as results have differed between population-based studies and randomised controlled trials. Nonetheless, a healthy diet lowers the risk of AD and improves outcomes in those with AD. A diet high in saturated fats and simple carbohydrates (mono- and di-saccharide) increases the risk. The Mediterranean diet's beneficial cardiovascular effect has been proposed as the mechanism of action (30-33).
May decrease the risk of AD.
There is limited evidence that it is associated with a lower risk of AD.
There is tentative evidence for a protective effect.
No consistent evidence of any benefit, including for vitamin A,B12 and E, the alpha-tocopherol form of vitamin E, selenium, zinc, and folic acid with or without vitamin B12.
Omega-3 fatty acid supplements from plants and fish, and dietary docosahexaenoic acid (DHA), do not appear to benefit people with mild to moderate AD.
No benefit shown in humans despite a tentative evidence of benefit in animals. Likewise, there is no convincing evidence that ginkgo has any positive effect on cognitive impairment and dementia.
No concrete evidence in improving the symptoms of AD or dementia;
Statins (which are cholesterol-lowering drugs) have not been effective in preventing or improving the course of the disease. Non-steroidal anti-inflammatory drugs (NSAIDs) can reduce the likelihood of developing AD and reduce inflammation-related amyloid plaques. Hormone replacement therapy may, however, increase the risk of dementia.
Six medications are currently used to treat the cognitive problems of AD of which five are Acetylcholinesterase (ACE) inhibitors (tacrine, rivastigmine, galantamine, donepezil, and Huperzine A) and the fifth one is an NMDA receptor agonist (memantine). However, no medication has been clearly shown to delay or halt the progression of the disease and the benefit from their use is small.
- ACE inhibitors: Reduction in the activity of the cholinergic neurons is a well-known feature of AD. ACE inhibitors are employed to reduce the rate at which acetylcholine (Ach) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons. There is evidence for the efficacy of these medications in mild to moderate Alzheimer's disease and in the advanced stage. Their use in MCI has not shown any effect in a delay of the onset of AD.
- NMDA receptor agonist:Memantine was first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate. Glutamate is an excitatory neurotransmitter of the nervous system; excessive amounts in the brain can lead to cell death through a process called excitotoxicity, which consists of the overstimulation of glutamate receptors. (Note: Excitotoxicity occurs not only in AD but also in other neurological diseases such as Parkinson's and multiple sclerosis.) Memantine has a small benefit in the treatment of AD. Reported adverse events with this drug are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue. The combination of memantine and donepezil is of clinically marginal effectiveness.
- In other words, memantine inhibits the transmission of brain signals between neurons via the neurotransmitter glutamate. Inhibiting that transmission reduces glutamate's excitotoxic effect (meaning the toxic effects associated with neuronal activation) and so may initially impair cognitive function. Like for ACE inhibitors, memantine does not get at the underlying cause of AD or stop the progress of AD and even less cure it.
- Atypical antipsychotics: Antipsychotics are modestly useful in reducing aggression and psychosis in people with AD, but their advantages are offset by serious adverse effects such as stroke, movement difficulties, cognitive decline and, when used for a long term, increased mortality. While promising, Huzerpine A requires further evidence before its use can be recommended.
Adjuncts to pharmaceutical treatments, psychosocial interventions are classified as oriented within behavior, emotion, cognition, and stimulation approaches.
- Behavioral interventions: They have not improved overall functioning, but they can help reduce some derivative behavioral problems such as incontinence.
- Emotion-oriented interventions: These include several therapies: reminiscence, validation, supportive, sensory integration, and simulated presence. A Cochrane review has found no evidence to support the usefulness of these therapies.
- Cognition-oriented treatments: These include reality orientation and cognitive retraining (that is the reduction of cognitive deficits). Both have shown some efficacy improving cognitive capacities, although in some studies these effects were transient and negative effects such as frustration have also been reported.
- Stimulation-oriented treatments: They include art, music, pet therapies, exercise, and any other kind of recreational activities. They have shown modest support for improving behavior, mood and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the change in the person's routine.
Given that AD has presently no cure and renders people incapable of tending to their own needs, caregiving is essentially “the” treatment and must therefore be carefully managed over the course of the disease.
An example of such a vaccine under investigation was ACC-001, although the trials were suspended in 2008. Another similar agent is Bapineuzumab, an antibody designed as identical to the naturally induced anti-amyloid antibody .
Unlike preventative vaccination, putative immunological therapies would be used to treat people already diagnosed. They are based on the concept of training the immune system to recognize, attack, and reverse the deposition of amyloid, thereby altering the course of the disease. However, immunotherapeutic agents have been found to cause some concerning adverse drug reactions, such as amyloid-related imaging abnormalities [36, 37].
Other approaches are Neuroprotective agents, such as AL-108, and metal-protein interaction attenuation agents, such as PBT2. A TNFα receptor-blocking fusion protein etarnacept has shown encouraging results.
As of 2014, the safety and efficacy of more than 400 pharmaceutical treatments had been or were being investigated in over 1,500 clinical trials worldwide, and approximately a quarter of these compounds are in Phase III trials, the last step prior to review by regulatory agencies. On the other hand, in the decade 2002–2012, 244 compounds were assessed in Phase I, Phase II, or Phase III trials, and only one of these (memantine) received FDA approval (though others were still in the pipeline).
- Antiviral medication: The herpes simplex virus HSV-1 has been found in the same areas as amyloid plaques. This suggested the possibility that AD could be treated or prevented with antiviral medication. Studies of antivirals in cell cultures have shown promising results.
- Reduction of beta-amyloid levels: This is a common target of compounds (such as apomorphine) under investigation. Immunotherapy or vaccination for the amyloid protein is one treatment modality under study.
- Inhibiting tau aggregation: In 2008, two separate clinical trials showed positive results in modifying the course of disease in mild to moderate AD with methylthioninium chloride and dimebon (an antihistamine). Unfortunately, work with methylthioninium chloride showed that bioavailability of methylthioninium from the gut was affected by feeding and by stomach acidity, leading to unexpectedly variable dosing. Further, the consecutive phase-III trial of dimebon failed to show positive effects in the primary and secondary endpoints. A new stabilized formulation, as the prodrug LMTX was in phase-III trials (in 2014).
Preliminary research on the effects of meditation on retrieving memory and cognitive functions have been encouraging. A 2015 review suggests that mindfulness = based interventions may prevent or delay the onset of MCI and AD.
Rare cases of possible transmission between people are being studied, e.g., to growth hormone patients.
Fungal infection of AD brains has also been described (see above the corresponding hypothesis discussed above).
- Magnetic resonance imaging (MRI) with volumetric: Combined with certain numerical programs (Neuroreader and NeuroQuant), MRI with volumetric provides percentile scores comparing the patient with other patients of a similar age with regard to shrinkage of the brain and brain regions.
- Single photon emission computed tomography (SPECT): Of the many medical imaging techniques available, SPECT appears to be superior in differentiating AD Alzheimer's disease from other types of dementia, giving a greater level of accuracy compared with mental testing and medical history analysis. Advances have led to the proposal of new diagnostic criteria [38,39].
- Positron emission tomography: PET scanning can be used in five different instances:
- With the radiopharmaceutical called florbetapir (containing the longer-lasting radionuclide fluorine-18) to diagnose AD. It was given FDA approval for this use [38, 39];
- To reliably determine the levels of Aβ deposition by the measurement of Aβ levels in the CNS. Using immunosuppression and mass spectrometry, Nakamura., et al. (2018)  have used as plasma biomarkers the ratios [APP699/Aβ1-42, Aβ1-40 /Aβ1-42] and a composite score to reliably predict individual deposition levels of Aβ in the brain. These results highlight the potential use of plasma biomarkers to predict Aβ burden;
- When the diagnosis is difficult or uncertain such as, for example, distinguishing between fronto-temporal dementia and AD. In the latter case, FDG-PET shows a characteristic pattern of reduced glucose metabolism in the temporal and parietal regions, often including the posterior cingulate an d precuneus, which are often impaired in AD;
- Amyloid-PET scans to show amyloid accumulation in the brain, which may occur without AD and conversely. Ongoing studies aim to determine whether a positive amyloid PET scan in the absence of symptoms will be helpful in AD diagnosis. However, the pattern of amyloid accumulation does not correlate well with the brain regions displaying symptoms. Note that this scan can detect relatively large collections of amyloid, but it does not reveal whether the amyloid is present in the blood vessels, and cannot look at relatively rapid changes in single amyloid plaques. Amyloid in blood vessels can, in rare case, lead to hemorrhages.
- Tau-PET scans tend to show abnormalities that correspond more closely with symptoms.
- PiB-PET: This amyloid-imaging modality remains investigational. It is likely to be used in conjunction with other markers rather than as an alternative. Volumetric MRI can detect changes in the size of brain regions. Measuring those regions that atrophy during AD's progress is showing promise as a diagnostic indicator. It may prove less expensive than other imaging methods currently under study. The imaging agent Florbetapil can help to detect Alzheimer's brain plaques, but will require additional clinical research before it can be made available commercially [41,42].
- CSF testing: This may be helpful in the diagnosis of AD. Here, Aβ-42 shows a characteristic reduction in the CSF and an increase in the total tau and phospho-tau.
- Electroencephalography (EEG): Can be helpful in evidencing non convulsive seizure activity, which occurs in ~ 5% of AD patients.
There are three such novel tests under study:
- Neural exosomes: Professor Edward J. Goetzl and his colleagues at the University of California at San Francisco have come up with a blood test that evidences AD in neural exosomes (tiny fragments of cells and materials expelled from cells that circulate in the blood). These exosomes include increases in Aβ-42 (the main one associated with AD), phosphorylated tau, cathepin D (a protease that is increased in exosomes), RESY (indicating levels of trophic support), and phosphorylation ratio of IRS-1 (indicating insuline resistance). The test can also reveal insulin resistance and many other critical parameters of brain biochemistry. Not only will this test assess cognitive decline, but also the type of AD (1, 2 or 3) and, most importantly, whether the treatment program is effective or needs adjustments. This approach also has the potential “to assess neurotransmitter pathways, hormonal signaling, trophic factor signaling, vitamin effects on neural function, trauma effects, vascular compromise, therapeutic responses, and many more biochemical signatures in the brain” .
- Retinal imaging: Retinal imaging can overcome the limitations of the PET-amyloid imaging approach. It has the following advantages: (a) It provides an early evaluation and assessment of risk for cognitive decline. Although, as described earlier, Aβ in the brain can be imaged with a PET scan, only relatively large accumulations of amyloid can be imaged. In particular, whether the amyloid is in the blood vessels cannot be revealed; (b) it can identify many (often hundreds of small plaques; (c) it can map the location of each plaque; (d) it can potentially reveal whether the amyloid affects the retinal blood vessels (and, by extension, the brain's vessels as well) in addition to neurons and synapses themselves; (e) it can accurately assess the effectiveness of treatment; and (f) it is much less expensive than a PETscan (44).
- Eye movement tracking:Damage to the mesial temporal lobe deep in the brain occurs early in AD. It impairs the ability to remember and recognize novelties in one's environment. An object recognition imaging test has been developed that takes advantage of this feature but tracking eye movements, thus detecting impairment of the hippocampus and nearby structures .
- Alzheimer A. “Über eine eigenartige Erkrankung der Hirnrinde [About a peculiar disease of the cerebral cortex]”. Allgemeine Zeitschrift für Psychiatrie und Psychisch- Gerichtlich Medizin 64.1–2 (1907): 146–148.
- Alzheimer A. “About a Peculiar Disease of the Cerebral Cortex”. Alzheimer Disease and Associated Disorders 1.1 (1987): 3–8.
- Berrios G. “Alzheimer's disease: A conceptual history”. International Journal of Geriatric Psychiatry 5.6 (1990): 355–365.
- Ballard C., et al. “Alzheimer's disease”. Lancet 377.9770 (2011): 1019–1031.
- Kraepelin E. “Clinical Psychiatry: A Textbook for Students and Physicians (Reprint). (Translated by Diefendorf A. Ross. Kessinger Publishing. (2007): 568.
- Bredesen D. “The end of Alzheimer's: The first program to prevent and reverse the cognitive decline of dementia”. Vermillion publishers (U.K.) and Avery publishers (U.S.) (2017): 307.
- Margaret Gatz., et al. “Role of genes and environments for explaining Alzheimer disease”. Archives of General Psychiatry 63.2 (2006): 168–174.
- Stephen C. Waring and Roger N. Rosenberg. “Genome-wide association studies in Alzheimer disease”. Archives of Neurology 65.3 (2008): 329–334.
- Kaj Blennow., et al. “Alzheimer's disease”. The Lancet 368.9533 (2006): 387–403.
- Lambert JC., et al. “Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease”. Nature Genetics 45.12 (2013):1452–1458.
- Robert W. Mahley., et al. “Apolipoprotein E4: A causative factor and therapeutic target in neuropathology including Alzheimer.s disease” Proceedings of the U.S. National Academy of Sciences 103.15 (2006): 5644–5651.
- Rita Guerreiro., et al. “TREM2 variants in Alzheimer's disease” The New England Journal of Medicine 368.2 (2012): 117–127.
- Eikelenboom P., et al. “Neuroinflammation: An early event in both the history and pathogenesis of Alzheimer's disease”. Neuro-Degenerative Diseases 7.1–3 (2010): 38–41.
- John Hardy and David Allsop. “Amyloid deposition as the central event in the etiology of Alzheimer's disease”. Trends in Pharmacological Sciences 12.10 (1991): 383–388.
- “Long-term effects of Aβ42 immunization in Alzheimer's disease: Follow-up of a randomized, placebo-controlled Phase I trial”. Lancet 372.9634 (2008): 216–223.
- Pascale N. Lacor., et al.“Aß oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease”. The Journal of Neuroscience 27.4 (2007): 796–807.
- Juha Laurén., et al. “Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers”. Nature 457.7233 (2009):1128–1132.
- Amritpal Mudher and Simon Lovestone. “Alzheimer's disease: Do tauists and baptists finally shake hands?” Trends in Neurosciences 25.1(2002): 22–26.
- Deane R and Zlokovic BV. "Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease". Current Alzheimer research 4.2 (2007): 191–197.
- Kluger A., et al. “Retrogenesis: Clinical, physiologic, and pathologic mechanisms in brain aging, Alzheimer's disease and other dementing processes”. European Archives of Psychiatry and Clinical Neuroscience 249.3 (1999): 28–36.
- Paul T Francisa., et al. “The cholinergic hypothesis of Alzheimer's disease: A review of progress”. Journal of Neurology, Neurosurgery, and Psychiatry 66.2 (1999):137–147.
- Martorana A., et al. “Beyond the cholinergic hypothesis: Do current drugs work in Alzheimer's disease?” CNS Neuroscience & Therapeutics 16.4 (2010): 235–245.
- (U.S.) National Institute on Aging. “About Alzheimer's Disease's Symptoms”. (2012).
- National Institute of Neurological and Communicative Disorders and Stroke – Alzheimer's Disease (NINCDS) - Alzheimer's Disease and Related Disorders Association (ADRDA) Work Group Report under the Auspices of Department of Health and Human Services Task Force on Alzheimer's Disease (1984), Neurology 34.7: 939–944.
- American Psychiatric Association. “Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR (4th Edition Text Revision ed.). Washington, DC: American Psychiatric Association. (2000)
- G.Waldemar., et al. “Recommendations for the Diagnosis and Management of Alzheimer's Disease and Other Disorders Associated with Dementia: EFNS Guideline”. European Journal of Neurology 14.1 (2007): e1–26.
- World Health Organization (WHO). Dementia Fact Sheet No. 362. (2015).
- (U.S.) National Institute for Health and Care Excellence (NICE). “Dementia Diagnosis and Assessment”. (2014):
- Daviglus ML., et al. “NIH state-of-the-science conference: Preventing Alzheimer's disease and cognitive decline”. (2010)
- Kawas CH. “Medications and diet: Protective factors for AD?” Alzheimer Disease and Associated Disorders 20(3 Suppl 2) (2006): S89–96.
- Luchsinger JA and Mayeux R. “Dietary factors and Alzheimer's disease”. Lancet Neurology3.10 (2004): 579–587.
- José A. Luchsinger., et al. “Diet and Alzheimer's disease”. Current Neurology and Neuroscience Reports 7.5 (2007): 366–372.
- Solfrizzi Vincenzo., et al. “Lifestyle-related factors in predementia and dementia syndromes”. Expert Review of Neurotherapeutics 8.1 (2008): 133–58.
- Hawkes Cheryl A and McLaurin JoAnne. “Immunotherapy as treatment for Alzheimer's disease”. Expert Review of Neurotherapeutics 7.11 (2007):1535–1548.
- Wischik CM., et al. “Tau-aggregation inhibitor therapy for Alzheimer's disease”. Biochemical Pharmacology 88.4 (2014): 529-539.
- Szekely C A., et al. “Prevention of Alzheimer's Disease”. International Review of Psychiatry 19.6 (2007): 693-706.
- Solomon B. “Clinical immunologic approaches for the treatment of Alzheimer's disease”.Expert Opinion on Investigational Drugs 16.6 (2007): 819–828.
- Desikan., et al. “Automated MRI measures identify individuals with mild cognitive impairment and Alzheimer's disease”. Brain 132 (2009): 2048-2057.
- Rebekah Moan. “MRI software accurately IDs preclinical Alzheimer.s disease”. Diagnostic Imaging (2009).
- Nakamura., et al. “High performance plasma amyloid-β biomarkers for Alzheimer's disease”. Nature 554 .7690 (2018): 33.
- Zhang S., et al. “(11) C-PIB-PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI)”. The Cochrane Database of Systematic Reviews 7 (2014): CD010386.
- Smailagic N., et al. “18F-FDG PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI)”. The Cochrane Database of Systematic Reviews 1 (2015): CD010632.
- Goetzl EJ (2013-15). “Biomarkers and diagnostic methods for Alzheimer's disease an d other neurodegenerative disorders”. U.S. Patent 20150119278 A1.
- Verdooner SR. “Apparatus and method for identifying one or more amyloid beta plaques in a plurality of discrete OCT retinal layers”. U.S. Patent 9854963 (2018).
- Neurotrack. “A new brain health app warns users of memory decline”. (2016)