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Alzheimer's disease is characterized by loss of neurons and synapses in the cerebral cortex and certain sub-cortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulated gyrus. [1] Studies using MRI and PET have documented reductions in the size of specific brain regions in patients as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults. [2]

It is a widely accepted notion that the formation of amyloid plaques and neurofilbrillary tangles underlie the dementia associated with AD.[3],[4] The former, the so-called β-amyloid (Aβ) plaques, arise from a protein known as the amyloid precursor protein (APP).[5],[6] Amyloid precursor protein is a cell surface receptor that plays a central role in AD pathogenesis. Cleavage of APP by a b-secretase is the dominant pathway in the formation of the critical Aβ peptide. Cleavage of APP by b-secretase generates a soluble fragment, termed APPsb, and a membrane-tethered peptide fragment consisting of Ab still attached to the carboxyl terminus of APP. Subsequent cleavage of this membrane-tethered APP C-terminal fragment (APPCTFb) by a g–secretase generates Aβ. Cleavage by g-secretase can generate multiple isoforms of Aβ, the most common of which are Abβ0 and Aβ42. The Ab42 fragment tends to clump rather easily, forming insoluble Aβ aggregates. Progression of these aggregates into large senile plaques and deposition of these plaques around cerebral neurons is believed to the major cause of neuronal cell death and dementia associated with AD. [7] Amyloid precursor protein can also be cleaved by an a-secretase at a site within the sequence corresponding to Aβ, resulting in the formation of a p3 peptide that appears to be neuroprotective.

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. [8] Plaques are dense, mostly insoluble deposits of amyloid-beta peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of AD patients have a greater number of them in specific brain regions such as the temporal lobe. [9] Lewy bodies are not rare in AD patient's brains. [10]



Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain.[11] AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system. [12]

Neurofibrillary tangles (NFTs) are another hallmark of AD. These tangles arise from a protein known as the tau protein. Tau proteins are integral components of microtubules, which maintain the structural integrity of neurons as well as participate in essential neuron functions, such as axonal transport. Hyperphosphorylation of tau results in release of tau from microtubules, causing a collapse of neuronal structure. [3], [7], [13] Hyperphosphorylated tau proteins that are released from microtubules begin to aggregate into the dense NFTs that are observed in patients with AD. Microtubule defects coupled with the accumulation of NFTs are believed to ultimately contribute to the failure of cerebral neurons that is characteristic of AD. [3], [5], [13]


Tau is a protein whose function is to stabilize neuronal microtubules. [14] As mentioned previously, the APOE E3 allele may protect tau from hyperphosphorylation. It has been speculated that destabilization of the microtubular system may disrupt the Golgi apparatus, in turn inducing abnormal protein processing and increasing production of Aβ. [15] In addition, this destabilization may decrease axoplasmic flow, generating dystrophic neuritis and contributing to synaptic loss.



3.Disease Mechanism

In recent years, AD has attracted the attention of a wide range of biological disciplines, and substantial progress has been made in understanding the mechanisms of neuro-degeneration in AD. Four different genes have now been associated with AD and are providing insights into the pathogenesis of the disease. The roles of beta-amyloid, tau, hormonal changes, inflammation, and oxidative stress in the neuro-degeneration of AD are also being delineated. Based on these discoveries; rational therapeutic strategies are developing rapidly. [31]




The vast majority of cases of Alzheimer's disease are sporadic, meaning that they are not genetically inherited although some genes may act as risk factors. On the other hand, around 0.1% of the cases are familial forms of autosomal-dominant inheritance, which usually have an onset before age 65.[16] Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: amyloid precursor protein (APP) and presenilins 1 and 2.[17] Most mutations in the APP and presenilin genes increase the production of a small protein called Aβ42, which is the main component of senile plaques.[18] Most cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD. Nevertheless genetic differences may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE). [19],[20] The APOE4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes.[16] Geneticists agree that numerous other genes also act as risk factors or have protective effects that influence the development of late onset Alzheimer's disease.[17]

It is now understood that genetic factors play a crucial role in the risk of developing Alzheimer’s disease (AD). Rare mutations in at least 3 genes are responsible for early-onset familial AD. A common polymorphism in the apolipoprotein E gene is the major determinant of risk in families with late-onset AD, as well as in the general population.



Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.[21],[22] Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia.[23] Assessment of intellectual functioning including memory testing can further characterize the state of the disease. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be histologically examined. [24]


The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984,[24] extensively updated in 2007.[25] These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Eight cognitive domains are most commonly impaired in AD—memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities.


2.Techniques and Imaging

Currently, diagnosis of Alzheimer’s disease depends on recognition of the characteristic clinical features. The current approach to diagnosing Alzheimer’s disease is time-intensive, labor-intensive, and costly. Its sensitivity and specificity are largely dependent on the expertise of the examiner.


Assessment of cognitive function, a neuropsychological assessment, and neuroimaging are all used to establish a diagnosis of AD. The prevailing diagnostic criteria for AD are presence of clinically significant cognitive impairment with gradual onset and without secondary cause of dementia. The severity of cognitive impairment is determined by cognitive tests such as the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog), and other tools that assess the functional status of patients with AD. [3], [5] Improved diagnosis at early stages of AD is critical for the development of effective disease-modifying therapies. The need for more accurate diagnostic modalities motivates research in the areas of neuroimaging and disease biomarkers. [5], [26] Neuroimaging can detect areas of neurodamage due to atrophy in specific brain structures, such as the hippocampus. Imaging tools such as magnetic resonance imaging (MRI) and electroencephalography (EEG) can also capture disease-related changes in the brain. [27] In clinical studies, structuralMRI has been shown to be an effective biomarker for assessing prodromal and early AD-related changes.[28] Continued improvements in technology for high power imaging of the brain have the potential to improve our ability to capture and monitor Ab plaque progression.[26]

Single photon emission computerized tomography (SPECT) and positron emission tomography (PET) are relatively new imaging tools that can detect changes associated with progression of AD over time. These diagnostic imaging tools have shown promise in the early reliable diagnosis of AD. [27]


At present, a diagnosis of AD cannot be determined until the disease progresses to the symptomatic stage, at which point cognitive damage is severe enough to interfere with work and normal life activities. The use of biomarkers for early diagnosis has been limited primarily to research settings.[6] For example, biomarkers based on pathological markers such as levels of tau phosphorylation and Aβ in cerebral spinal fluid (CSF) could potentially serve as an early indicator or AD

Some of the limitations involved in the development CSF biomarkers as a diagnostic tool are cost and potential risks associated with lumbar puncture.[29],[30] As an alternative, urine and blood biomarkers may be of more value for early detection of AD, as they are less invasive and potentially less expensive than CSF biomarkers.[30]


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Article By: Guy-Armel BOUNDA, Cosette NGARAMBE

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