Alzheimer's disease (AD) is a neurological condition that worsens over time and causes memory loss, cognitive decline, behavioral abnormalities, and ultimately death Dementia is caused by several things. The most prevalent type of dementia is Alzheimer's disease (AD) Neuropathologically, the disease is characterized by the accumulation of aberrant proteins that lead to the development of intracellular neurofibrillary tangles (NFTs) and extracellular senile plaques. Amyloid-? (A?), which is neurotoxic, is the main component of senile plaques ^(1). AD is the sixth most common cause of death for older adults (2). Alois Alzheimer, a German psychiatrist, identified a rare type of mental illness in 1906 that affected Augustine Deter and was typified by "progressive cognitive impairment, focal symptoms, hallucinations, delusions, and psychosocial incompetence" ^(2). Neuropathologically, the disease is characterized by the accumulation of aberrant proteins that lead to the development of intracellular neurofibrillary tangles (NFTs) and extracellular senile plaques. Amyloid-? (A?), which is neurotoxic, is the main component of senile plaques ^(3). Despite decades of encouraging research on Alzheimer's disease, there are currently no effective disease-modifying medications available. This could be partly caused by the intricate interactions between tau and amyloid abnormalities, neuroinflammation, and cerebrovascular impairment, as well as the considerable difficulties in diagnosing and staging Alzheimer's disease ^(4). However, AD can manifest in two ways: the frequent late-onset AD (LOAD), sometimes referred to as senile dementia, which develops after age 65 as a result of ageing, and the uncommon early-onset dementia leading to AD (EOAD), which occurs before age 65 ^(5). As life expectancy rises globally, Alzheimer's disease is the only illness predicted to increase in incidence at an alarming rate, in contrast to other conditions like cancer and heart disease that significantly affect healthcare today ^(6).

The frequency of dementia is expected to increase by 2050, with two-thirds of those affected residing in low- and middle-income nations, according to an estimate made by Alzheimer's Disease International in 2018.By 2050, the prevalence of dementia is expected to increase across Europe, according to the latest recent research. While there is less compelling evidence for ftfg in frequency, there is growing evidence that dementia incidence is declining in high- income nations ^(7). Dementia is the most common cause of mortality in England and Wales, making up 11.6% of all recorded deaths in 2015.According to recent research, dementia may be becoming less common in western nations, especially among men and in Low and middle-income nations, which exhibit trends of rising rates of diabetes, hypertension, and cardiovascular illness, are predicted to see the most increases in dementia incidence in the upcoming years ^(8). People 65 and older have a yearly incidence rate of 1% for AD, while those 85 and older have an incidence rate of about 8%. Cholinesterase inhibitor treatment, caregiver stress reduction, community support, delaying institutionalization, lifestyle planning, and legal concerns all depend on early detection of AD

(9). the social, environmental, and genetic elements that contribute to this neurological degeneration's development. The main risk factor for Alzheimer's disease development is thought to be aging; only 1-6 percent of cases are early-onset AD (EOAD), which is defined by onset between the ages of 30 and 65. However, the ?4 allele of the Apolipoprotein E (ApoE) gene, present in about 40% of AD patients, is the most significant genetic risk factor. The fact that DNA from HSV-1, an infection that is known to be a risk factor for AD, has been found in the brains of people with the ApoE-?4 allele shows how risk factors can influence one another

(10).

Pathophysiology:

The pathophysiology of Alzheimer's disease has been thoroughly investigated since it was discovered and classified, which has confirmed the two main neuropathological motifs— plaques and neurofibrillary tangles—that were initially discovered in the early 1900s by Alois Alzheimer and Oskar Fischer. The first kind, known as senile plaques, are extracellular clumps of beta-amyloid protein (A?), which is created when amyloid precursor protein (APP), a crucial membrane glycoprotein, is cleaved by proteases. While ?-secretase and ?-secretase can differently cleave APP to yield A? peptides of varying lengths ^(11). It is still unknown what exactly causes Alzheimer's disease. Scientists' amyloid cascade theory is now the main theory explaining the pathophysiology of AD. The primary cause of Alzheimer's disease, according to the theory, is the build up of toxic amyloid beta-protein (A?) in the central nervous system (CNS). A? may build up and form a structure rich in ?-Sheet if there are extracellular abnormalities in A? levels in the brain ^(12). Amyloid plaques are extracellular deposits mostly made up of two by products of APP metabolism, improperly folded A? with 40 or 42 amino acids (A?40 and A?42). Because A?42 is more insoluble and fibrillizes more quickly than A?40, it is more prevalent in plaques. In general, amyloid deposition develops in the Iso cortex and only later affects subcortical areas; it does not always progress in a stereotyped manner. Amyloid plaques affect the entorhinal cortex and hippocampus forms less than NFTs do^(13). The brain recognizes these plaques as foreign material and triggers an immunological and inflammatory response by triggering the production of cytokines and activating microglia, which ultimately results in cell death and neurodegeneration. The ?, ?, and ? secretases enzymatically cleave the amyloid precursor protein (APP) to produce the A? peptides that make up the A? plaque ^(14).

Hypothesis Of Pathophysiology of Alzheimer’s Disease

The chance of developing AD is increased by several acquired factors. These include the most frequently reported risk factor, cerebrovascular diseases, diabetes, hypertension, obesity, and dyslipidemia^(15).

The most significant risk factor is age. According to a recent study that examined 1246

participants between the ages of 30 and 95, the risk rose with age, especially in APOE ?4 carriers and after the age of 70. Consequently, it may influence the risk of AD as people age. In cognitively normal people, age dramatically raises the probability of ligand retention in amyloid PET. In addition to APOE, several genes have recently been shown to substantially alter the risk for AD on a genome-wide level. Through genome-wide association investigations, variations in genes related to endocytosis, inflammatory response, and lipid metabolism have been found. ABCA7, CLU, CR1, CD33, CD2AP, EPHA1, BIN1, PICALM, MS4A, CASS4, CELF1, DSG2, FERMT2, HLA-DRB5-DBR1, INPP5D, MEF2C, NME8, PTK2B, SLC24H4-RIN3, SORL1, and ZCWPW1 are among the genes that have polymorphisms in or close to them that are linked to AD risk ^(16). Carrying at least one APOE ?4 allele and being older than 65, albeit this is not a set age, are the highest risk factors for Alzheimer's disease.27 Furthermore, especially after the age of 80, women are more prone than males to get Alzheimer's disease.20 Despite sharing a similar amyloid ? burden, women are considerably more likely to have a larger tau load ^(17). Furthermore, the foods that influence the general risk factors for AD, such as insulin resistance (IR) and inflammation, can be determined once they are understood. Every method can advance our knowledge of how nutrition and dietary factors impact AD risk ^(18).

Cardiometabolic factors have been identified as critical among the several other potentially modifiable risk factors for AD that have been shown in numerous studies, in addition to the hereditary factors. High blood pressure, diabetes, obesity, high levels of low-density lipoprotein (LDL) and low levels of high-density lipoprotein (HDL) cholesterol, and the development of AD have all been associated with cardiometabolic risk factors ^(19).

Diagnosis:

Late-onset the symptoms of AD usually appear after the age of 60 and progress gradually from modest memory impairment to severe cognitive decline, ultimately leading to total disability and death. Even though biomarkers like plasma A?, CSF A? and tau, amyloid imaging for AD, and cognitive decline prediction have advanced significantly in recent years [3–5], studies of plasma A? in particular have yielded conflicting results, and there are currently no conclusive diagnostic tests or biological markers of the disease. A clinical examination serves as the basis for the diagnosis during life ^(20).

A diagnostic evaluation that includes the following components is recommended by the Expert Panel for patients who are suitable for aducanumab treatment:

1. a thorough history that is adequate to determine the type and duration of cognitive symptoms, functional changes, and behavioral status;
2. objective confirmation of cognitive decline through standardized testing.
3. a thorough neurological and physical examination
4. a review of all current medications and supplements
5. adequate laboratory testing, such as a complete blood count, electrolyte panel, thyroid stimulating hormone, lipids and triglycerides, liver function tests, and serum vitamin B12 level ,to rule out other concurrent conditions that may contribute to cognitive deterioration^(21).

MRS is an imaging method that develops and quantitatively analyzes certain nuclei and related compounds using the magnetic resonance principle and chemical shift events. High resolution, no bone aberrations, no ionizing radiation damage, multidirectional and multiparameter imaging, and the capacity to visualize brain regions without the need for contrast agents are some of the benefits of this technology (Chen et al., 2019). Chemical compounds can be distinguished based on their variations on the MRS spectral peak line due to variations in chemical shifts. Because the area of the formant in MRS is proportional to the number of resonance nuclei, the compound's concentration can be observed. Acquired using head MRI are not very useful for diagnosing AD, and they don't show many signs of the physiological and metabolic alterations linked to AD ^(22).

Biomarkers:

Alzheimer's disease medication development, biomarkers can also be very helpful in choosing the best therapeutic candidates for costly and time-consuming phase 3 clinical trials. Together with a positive impact on the clinical course, biomarkers will be crucial in demonstrating In that a medication has an impact on the disease's underlying pathophysiology, which is necessary to classify the medication as having a disease-modifying effect ^(23). In the recently developed diagnostic criteria for AD, biomarkers play a crucial role in determining the pathophysiological mechanisms behind cognitive impairment or in assisting in the prediction of the time it will take for dementia to develop. In 1998, an international consensus committee on genetic and biochemical indicators of AD proposed criteria for a meaningful biomarker (The National Institute on Aging Working committee, 1998; Ronald and Nancy Reagan Research Institute of the Alzheimer's Association, 1998) ^(24). There are two types of AD biomarkers: topographic biomarkers and pathophysiologic biomarkers. These two categories of biomarkers can help doctors recognize, distinguish, and diagnose AD symptoms. Pathophysiologic markers linked to AD lesions include amyloid positron emission tomography (PET), amyloid and tau protein concentrations in cerebrospinal fluid (CSF), and plasma levels of amyloid, tau, and other protein biomarkers. Topographic biomarkers are associated with the regional consequences of AD pathology, including tau PET, regional hypometabolism on fluorodeoxyglucose (FDG)-PET, and regional/local atrophy on structural magnetic resonance imaging (MRI)^(25). The density of the pathological lesions is addressed in relation to the subject's age in another study about age and how it affects the severity of AD Furthermore, a number of studies have found the age marker to be a primate factor . Alongside the aforementioned, AD can also be classified as early onset familial AD, in which the illness primarily manifests before the age of 60. In this instance, AD is inherited autosomally dominantly and manifests as a genetic disease. At the same time, if neuronal damage and amyloid-? (A?) biomarkers were also tested affirmatively, biomarkers that indicate a high chance of AD owing to MCI could be more accurate. We can only obtain an intermediate chance of AD due to MCI based only on the A? protein evaluation. Patients will be presumed to have a lesser risk of developing AD if there is just one biomarker of neurologic impairment and A? cannot be measured ^(26).