INTRODUCTION:

Alzheimer's disease is a multifactorial disease with no one known cause, and various modifiable and non-modifiable risk factors are linked to its development and progression. The most significant risk factor for the development of Alzheimer's disease is age. Rare genetic mutations are linked to the development of Alzheimer's disease before the age of 65, which is known as 'early onset' or 'familial' Alzheimer's disease (B5% of all cases)¹. The two main pathological features of Alzheimer's disease are the accumulation of amyloid-beta plaques and the formation of neurofibrillary tangles within neurons².

Neurofibrillary tangles consist of abnormal, intracellular paired helical filaments made of hyperphosphorylated tau proteins, leading to synaptic and neuronal loss³. Alzheimer's disease primarily affects the association areas of the cerebral cortex and the hippocampus in the human brain⁴.

While there is currently no cure for Alzheimer's disease, certain medications can help slow its progression and manage symptoms. When initiating treatment, doctors typically classify the symptoms into two categories: "cognitive" and "behavioral and psychiatric"⁵. The vascular hypothesis for Alzheimer's disease (VHAD) has gained significant attention in the scientific community over the past two decades. VHAD suggests a connection between Dementia and heart diseases at both systemic and CVD levels. Extensive research has been conducted to elucidate this relationship due to the substantial overlap between AD and CVD in older individuals. Current evidence highlights that vascular pathology is a main risk cause for dementia and is connected to lower cognitive scores across various domains. Additionally, CVD plays a role in neuronal loss in AD and the development of AD-related amyloid-beta (A-ß) and tau pathologies⁶.

Tau, a microtubule dependent protein, acts a crucial role in Alzheimer and similar tauopathies. In healthy conditions, tau helps to maintain the physical microtubule stability. In Alzheimer’s, tau becomes abnormally hyperphosphorylated, leading to the disassembly of microtubules and the cluster of tau molecules into NFT’s. These NFTs are a indicator of AD and other tauopathies, contributing to neurodegeneration. Research has shown that tau hyperphosphorylation is linked to disruptions in cellular signaling pathways, particularly involving an imbalance in protein kinases and phosphatases. Unlike normal tau, which aids in microtubule assembly, hyperphosphorylated tau inhibits this process by sequestering normal tau in a prion-like manner. This abnormal tau behaviour plays significant role in progression of AD pathology⁷.

Understanding molecular biology in protein tau and its involvement in neurofibrillary tangle formation is crucial for developing novel therapies for Alzheimer's disease and related disorders. Targeting tau as a therapeutic strategy holds promise for addressing the underlying pathology associated with these neurodegenerative conditions⁷.

While reactive oxygen species (ROS) play an essential role in various cellular functions and signaling pathways by regulating enzyme activity, excessive ROS production can lead to damage of biomolecules, including lipids and proteins⁸.

Neurodegeneration, synapse loss, and a decrease in synaptic strength are caused by alterations in the separation of amyloid precursor-protein, the creation of the APP fragment amyloid-beta (Aβ), and the aggregation of hyperphosphorylated tau protein⁹.

The meticulous research results demonstrated that tau and Aβ proteins are critical elements of neurofibrillary tangles (NFTs) and plaques, respectively, and have a significant impact on the molecular aetiology of the disease. There is currently no recognised cure for the underlying cause, and the exact cause is still a mystery. However, certain FDA-approved medications that identify the NMDA receptor and acetylcholinesterase (AChE) merely offer symptomatic alleviation, while being important components of AD therapy⁴. Apolipoprotein E (apo-E) was discovered to bind selectively to immobilised Aβ peptide in human cerebrospinal fluid, supporting the tracking of the ε4 allele of the apo-E as a key risk cause for traditional (late development) Alzheimer’s¹⁰. In patients in their sixth or seventh decade of life who have one or two ε4 alleles, genetic epidemiology has strongly demonstrated an increased chance of developing AD. The existence of the apoE4 protein significantly progresses the quantity in fibrillar A-β deposits in comparison to effects of the apoE3 protein, as demonstrated by subsequent elegant research in apoE deletion and transgenic mice models¹¹.

Alzheimer is a multi-causal condition influenced by hereditary predisposition and environmental causes. Genetic mutations like PSEN1, PSEN2, and APP are linked to familial AD, with a 50% chance of inheritance. While age is a primary risk factor, genetic factors explain only a small portion of cases. Lifestyle factors such as heart health and diet can impact brain health and reduce AD risk. Heritability for AD is high, with genetic factors affecting both men and women equally¹².

Despite the significant role of tau in AD, there has been limited focus on targeting tau therapeutically compared to amyloid-beta (Aß). However, recent advancements have highlighted the potential of tau as a therapeutic target for AD treatment¹. Studies have identified agents capable of blocking tau phosphorylation effectively, suggesting a polypharmacy approach involving multiple drugs targeting different aspects of AD pathology may be most effective⁷. AD clinical syndromes, Cognitive-Behavioural Syndromes (CBS) suspected to be linked to AD, exhibit a range of variations, especially in individuals under the age of 65. Accurate diagnosis of MCI and AD-related dementia relies on a thorough assessment that integrates pathologic AD biomarkers like CSF and amyloid PET. Nevertheless, the routine clinical application of AD CSF and PET biomarkers is not recommended for the majority of symptomatic individuals to confirm or rule out AD pathology. These tests are typically reserved for unique, rapidly evolving, or early-onset syndromes, or when the comprehensive evaluation yields inconclusive results¹³.

To improve the diagnosis performance from MRI by leveraging the more sensitive but less available PET, traditional methods such as interpolation for the missing modality in radiomics analysis have been employed. However, these methods typically perform not well due to inaccurate interpolation¹⁴. Anti-amyloid monoclonal antibodies (mAbs) are a class of drugs authorized for the Alzheimer treatment. Currently, two approved agents are aducanumab (Aduhelm®) and lecanemab (Leqembi®). These drugs received accelerated approval based on their ability to lower Beta-amyloid plaques as observed upon amyloid PET i.e, positron emission tomography. Donanemab is another mAb currently under review for standard approval, based on data from Phase II and Phase III trials. These monoclonal antibodies (mAbs) target large fibrillar Aβ aggregates, reduce Aβ levels as shown by amyloid PET scans, and are linked to amyloid-related imaging abnormalities (ARIA). They vary in the specific amyloid species they target, pharmacokinetic factors such as half-life and infusion frequency, and the trial populations involved. The efficacy and safety of these drugs can only be directly compared if they are evaluated in equivalent arms of the same clinical trial, given the variations in trial design and patient selection criteria. Approval of these mAbs marks a significant advancement in AD therapeutics with disease-modifying properties, although additional research is required to improve efficacy, safety, convenience, and to deepen the understanding of the observed effects¹⁵.

We investigated the relationship between BBB i.e, blood-brain barrier permeability, reflected via Cerebro-spinal fluid/plasma albumin quotient (Qalb), also CSF inflammation, as measured by levels of inflammatory cytokines, in a cohort of biologically defined AD patients. Our findings suggest that increased BBB permeability, as indicated by higher Qalb values, is linked to increased levels of inflammatory cytokines in the cerebrospinal fluid (CSF). This relationship highlights the potential role of BBB dysfunction in the pathogenesis of AD, as it may contribute to the entry of peripheral immune cells and the subsequent activation of inflammatory processes in the central nervous system (CNS). Our results also indicate that BBB permeability may serve as a potential biomarker for CSF inflammation in AD, which could have implications for the development of novel therapeutic strategies targeting BBB dysfunction and inflammation in this neurodegenerative disorder¹⁶.

Quantitative analysis of Aβ biomarkers in biofluids is crucial for non-invasive early detection of Alzheimer's disease (AD). Various methods like ELISA and biosensors have been developed, but they face challenges like sensitivity issues. Lateral flow immunoassays (LFIAs) are cost-effective and rapid but lack sensitivity. Combining LFIAs with surface-enhanced Raman scattering (SERS) enhances sensitivity. A new self-calibrating SERS-LFIA biosensor improves quantification accuracy by embedding internal standard SERS nanoparticles in the test line. This innovation enhances the detection performance for Aβ biomarkers in biofluid samples, offering a promising strategy for improved quantitative analysis of clinically significant protein biomarkers¹⁷.

Alzheimer's disease remains a clinical diagnosis, though cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers can improve diagnostic accuracy. Present therapies, such as cholinesterase inhibitors and memantine, increase its life’s quality but don’t alter/decelerate the progression of the disease. Ongoing studies focus on addressing the fundamental pathology of active AD and determining and categorizing interventions for individuals with preclinical, or asymptomatic, AD¹⁸.

Incidence:

Studies have shown that the occurrence rates of Alzheimer's Disease (AD) are lower in Asian nations compared to developed regions. While there is existing research on the prevalence of dementia in countries like India, there is a notable lack of comprehensive data on the occurrence, particularly from long-term prospective studies. Previously, it was revealed that the adjusted age In a study on older adults in Trivandrum (COAT), the prevalence of dementia, including Alzheimer's disease (AD), was 4.86% (with AD accounting for 1.91%) in an elderly community in the southern Indian state of Kerala¹⁹. The complexity of evaluating dementia prevalence in the Asian-Pacific region is highlighted in various studies. The region's rapidly growing population of individuals with dementia is expected to pose significant societal and economic burdens. Research emphasizes the importance of understanding population trends, risk factors, and the impact of dementia on diverse Asian populations. Additionally, the lack of knowledge and misconceptions about Alzheimer's within Asian communities, coupled with the challenges in identifying early signs of the disease, contribute to delayed treatment and potentially worse outcomes¹⁹.

A possible decrease in dementia rates in wealthy countries is associated with lifestyle choices and cardiovascular risk elements. Education, high blood pressure, tobacco use, and diabetes are pivotal factors. Lowering these risks has the potential to result in a substantial decrease in dementia cases by 2050. Patterns indicate enhanced education and well-being in affluent nations but deteriorating cardiovascular health in certain lower to middle-income countries. These elements could influence the occurrence of dementia on a worldwide scale²⁰. Factors such as old age, diabetes, family history, lifestyle choices, brain injuries, and heart-related issues are identified as common risk factors for Alzheimer's among Asian individuals. The stigma surrounding Alzheimer's in many Asian communities, where there is limited awareness and terminology to describe the condition, further complicates early detection and care. As the Asian population ages and grows, the projected increase in Alzheimer's cases among Asian Americans by 2030 underscores the pressing need for targeted research, perception, support systems to approach the evolving landscape of dementia in the region¹⁹.

In India, Chandra and colleagues identified an occurrence of 1.74 per 1,000 for individuals aged 55 and above, and 4.7 per 1,000 for those over 65. In regions like India and Africa, characterized by high birth rates and a growing proportion of young individuals, dementia rates remain relatively low. A negative correlation exists between aging and birth rates, impacting the incidence of the disease. As birth rates decline, there’s potential for a surge in AD cases in these regions²¹.

The combined incidence rate of Alzheimer's disease (AD) with individuals aged 65 and older in Europe was 19.4 per 1000 person-years. Studies from the US Seattle and Baltimore areas showed an incidence rate of 15.0 per 1000 person-years for AD in individuals aged 65 and older, with a higher rate in females than males. The incidence of AD typically increases with age until around 85 years, after which it may plateau or decline, indicating potential factors influencing vulnerability to the disease at advanced ages. Gender differences in AD incidence have been observed, with higher rates among women in some European studies but no significant gender disparity in North America. Geographic variations exist, with higher AD incidence rates in north-western European countries compared to southern countries. Developing countries generally exhibit lower AD incidence rates than North America and Europe, such as 7.7 per 1000 person-years in Brazil and 3.2 per 1000 person-years in India²².

Alzheimer's disease and Related Disorders Association criteria, as outlined by the Institute of Neurological and Communicative Disorders and Stroke, include classifications for Alzheimer's disease (AD) that are certain, likely, and plausible. Furthermore, a secondary classification was utilized for those who met the clinical parameters for likely AD but did not participate in neuroimaging investigations. These people were categorized as AD²³ compliant. Vascular or mixed vascular/AD dementia was the diagnosis made for subjects exhibiting significant cognitive impairment and cerebrovascular illness based on examination, imaging, or history. Every single person in this category had modified Hachinski ischemia scores greater than²⁴.

The year of diagnosis was determined based on when the individual met the DSM-III-R criteria for dementia. At that time, there were no widely accepted criteria for vascular dementia. In 1992, we retrospectively applied the criteria established by the State of California Alzheimer's Disease Diagnostic and Treatment Centers. Every individual diagnosed with vascular dementia met the criteria for either probable or possible vascular dementia²⁵. Using a person-years technique, statistical analysis was used to calculate AD incidence rates within 5-year age ranges. Individuals identified as at risk were assigned person-years from the beginning of the study until they were diagnosed with Alzheimer's disease (AD) or another form of dementia, their last date of contact, or their death. Using a Poisson distribution to model the number of new cases in each age group, a 95% confidence interval for the incidence rate was computed for each 5-year age category²⁶.

Using logistic regression analysis, researchers smoothed an age-specific incidence curve for Alzheimer's disease (AD). For each year of age, they calculated the number of individuals who remained disease-free and reached that age, as well as the number who developed AD during that year. The expected age-specific probability of AD incidence was then modeled by estimating the log odds of developing AD as a function of age. Furthermore, the impact of gender and education on incidence was evaluated by incorporating these demographic factors into additional logistic regression models alongside age. The median duration between the onset of cognitive decline and AD diagnosis was also estimated, with disease onset defined as the year when a family member, friend, or doctor first observed symptoms, typically memory loss²⁷.

Assessment	Cases number (%)
Alzheimer’s Disease
Absolute	1(0.6)
Likely	71(45.8)
Feasible	28(18.1)
History reflective of Alzheimer’s Disease	14(9.0)
Multi-Infarct cognitive impairment	16(10.3)
Parkinson’s disease dementia (PDD)	11(7.1)
Dementia and related disorder	4(2.5)
Atypical dementia	10(6.5)
whole	155(100)

(Incidence rates of AD according to age and gender in the Baltimore Longitudinal Study of Ageing)²⁷

Prevalence:

Certain CSF biomarkers also positron emission tomography (PET) scans can identify cerebral amyloid aggregation, a typical histopathological event in Alzheimer dementia (AD). Estimates of the prevalence of amyloid pathology are crucial for designing clinical trials and organising medical care. Estimating the incidence of amyloid anomaly in people across the AD clinical spectrum is crucial to lowering screening failure rates and increasing recruiting efficiency in light of newly developed disease-modifying anti-amyloid treatments²⁸. Numerous studies have linked AD to ageing [10–13], perhaps because AD typically affects people starting in 65^th age and doubles in frequency every 5 years, leading to a time-dependent exponential growth. This is the case in 90% of cases. The two types of prevalence linked with AD—familiar and sporadic—present the same nosologic and clinical signs. The familiar type can manifest earlier, but the sporadic kind is more common and typically begins at age 65. It's interesting to note that AD can start around age 30 in situations of trisomy of chromosome 21. The gradual nature of the neurological deficit results in neurophysiological changes that accompany mental impairment. These changes have the potential to serve as a preclinical test for the differentiation of AD from normal ageing²⁹.

Using univariate meta-regressions, the impact of significant possible factors of heterogeneity (e.g., span, sex, diagnostic criteria, place, time) the incidence and prevalence rates among individuals aged 60 and older were assessed.

Estimates of point prevalence, period prevalence, incidence rate, and incidence proportion were calculated. all increased with age (p <0.001). According to the subjects' sex, females had greater estimated rates of incidence and prevalence than males. The estimations of point, period, incidence rate, and incidence proportion were unaffected by the start, midpoint, or end of the trial. Neither Begg's nor Egger's tests revealed a significant funnel plot asymmetry for Determine the period prevalence, point prevalence, incidence rate, or incidence proportion of Alzheimer's disease (AD) dementia. (p > 0.05). After a visual assessment³⁰.

The neurofibrillary changes associated with Alzheimer's disease progress at an indeterminate rate. One reason for this uncertainty is the challenge of conducting histopathological follow-ups on the same individual over several decades. The current study examines a staged sample of 887 brains obtained from routine autopsies and utilizes a newly developed classification system that categorizes neurofibrillary alterations related to Alzheimer's into six distinct stages, as outlined by Braak and Braak (1991). The objective is to assess the speed of transition between these stages by interpreting cross-sectional data through a dynamic longitudinal lens. For 5% of a cumulative sample, the time taken to progress through the various stages of the disease is estimated. Statistics indicate that it takes at least 16 years for 5% of individuals to advance from stage I to stage II, approximately 14 years from stage II to III, around 13 years from stage III to IV, and about 5 years from stage IV to V (which represents Alzheimer's disease). Consequently, these neurofibrillary changes linked to Alzheimer's have origins that may extend back approximately 50 years, potentially beginning during puberty. The analysis reveals the duration required for transitions between selected stages, providing a valuable resource for epidemiological studies. Conversely, favorable factors might delay progression, even if individuals in the studied cohort die "prematurely" before fully developing Alzheimer's disease. In contrast, a possible risk factor could shorten this interval³¹.

Few research have looked at the relationship between physical sickness and cognition, or the frequency of coexisting medical disorders in AD patients. AD-related neuronal disorder may result in incomplete or delayed treatment, noncompliance, and erroneous symptom reporting. On the other hand, physical ailments and drugs may have an effect on brain degeneration or cognition. In this research, we explore the prevalence of medical comorbidity and its impact on cognition and function using data from a multi-setting survey of people with Alzheimer's disease³².

Given that the primary risk factor for dementia is ageing, any epidemiological method taken in Portugal in this context requires an understanding of the country's demographic makeup. A persistent rise in the average life expectancy at birth, a fall in child mortality, a rise in emigration, a sharp decline in fertility, and the resulting ageing of the population characterise Portugal's recent demographic tendencies.24 One of the most important causes of population ageing is the rise in the average life expectancy at birth. According to data from 2011 to 2013, the average life expectancy at birth in Portugal was 80.0 years (82.79 years for women and 76.91 years for men). This represents an increase of around three years over the previous ten years (3.36 years for males and 2.58 for women)³³.

Many in-depth investigations on the prevalence of dementia have been carried out since the forecasts made by the Delphi research. There exist notable variations in the frequency of dementia in underdeveloped countries. These variations may be ascribed to variations in demography, genetics, and lifestyle, in addition to obstacles in standardizing dementia examinations and lower rates of surviving after diagnosis. According to recent data, the average age-adjusted prevalence level of dementia within those age of 65 and older developing countries is 5.3%. In order to perform this computation, the original sample sizes and dementia cases among people 65 and older in various studies per nation were analyzed. Yang's methodology was then followed in recalculating mean estimates using SPSS 15.0 software³⁴.

Researchers utilized race-specific data on AD incidence, mortality rates after illness onset, and all-cause mortality to estimate prevalence in US for African Americans (AAs), Caucasian Americans (CCs), and the combined population. In this analysis, hypothetical cohorts of AA and CC people between the ages of 65 and 90 were created in accordance with the technique described by Brookmeyer et al. Age-specific all-cause mortality rates for CCs in 2013 were multiplied by the population at risk to determine the annual death toll for the CC cohort. AD incidence rates from five population-based studies were used, with rates weighted by case numbers and averaged across studies, to predict the number of new AD cases that the CC cohort will see year.³⁵

The age-adjusted prevalence of Alzheimer's disease (AD) for African Americans (AAs) and Caucasians (CCs) was projected using 2013 US census data, considering populations aged 65 to 90. This analysis revealed that clinically diagnosed AD dementia is common and expected to become more prevalent as the population ages.

Various studies estimate that 3-4% of individuals in their late career or early retirement years have AD dementia. These estimates may vary due to regional differences or methodological variations, such as differing age ranges of study participants or diagnostic criteria for AD dementia. A meta-analysis provided further insight, finding that 7.13% (95% CI: 6.56-7.72) of women and 3.31% (95% CI: 2.85-3.80) of men were affected by AD dementia. Additionally, a systematic review noted that all five studies examining gender differences consistently reported a higher prevalence in women. Corroborating these findings, a study conducted in China found that women were more than twice as likely as men to have AD dementia after adjusting for age, study period, and location (rural vs. urban). The prevalence ratio was 2.37 (95% CI: 1.90-2.96, p<0.0001), further supporting the gender disparity in AD prevalence³⁶.

Globally, dementia is very common in the elderly, and as the population ages, it is expected to become more common. Research from both industrialised and developing nations has shown that the age-standardized prevalence of dementia in most places’ ranges from 5% to 7%. Compared to non-Latino Whites, African Americans and Latinos in the US had greater rates of dementia prevalence. A comprehensive analysis conducted in 2010 in China found that the prevalence of dementia increased with age, from 0.2% in people 55–59 to 48.2% in people 95–99. Furthermore, studies demonstrating greater incidence rates in women than in males suggest that dementia affects more women than men³⁷.

Pathophysiology:

The exact cause of Alzheimer’s disease (AD) is not fully understood, but it is believed to result from a combination of genetic predispositions and environmental influences, making it a multifactorial condition. AD is typically diagnosed based on the presence of specific symptoms and by ruling out other potential causes of dementia using criteria like the DSM-IV. Definitive diagnosis can only be confirmed postmortem through an examination of brain tissue. Key changes commonly observed in the brains of individuals with AD include neurofibrillary tangles, neuritic plaques, and senile plaques, which disrupt neuron communication and lead to cell death³⁸. The aggregation of tau-proteins closely connects with cognitive decrease and brain releated atrophy, involving in the hippocampus³⁹.

Neurofibrillary tangles are filamentous structures found within neurons, composed of the tau protein. Normally, tau's primary role is to stabilize microtubules, which are critical for intracellular transport in axons. However, in Alzheimer's disease, tau becomes hyperphosphorylated due to the aggregation of extracellular beta-amyloid. This abnormal modification leads to the formation of tau aggregates, which twist into neurofibrillary tangles. These tangles initially develop in the hippocampus and later spread throughout the cortex.

The Braak and Braak staging system categorizes Alzheimer's progression into six stages, based on the distribution of neurofibrillary tangles. This system is essential for the neuropathological diagnosis of Alzheimer's disease, aligning with the National Institute on Aging and the Reagan Institute's criteria. Neurofibrillary tangles are considered a stronger correlate of Alzheimer's disease than amyloid plaques. Additionally, amyloid angiopathy contributes to hippocampal pyramidal cell degeneration, a condition called granulovacuolar degeneration. Cognitive decline in Alzheimer's is also associated with a loss of presynaptic neurons, particularly in laminae III and IV pyramidal neurons, and the degeneration of the nucleus basalis of Meynert, which reduces acetylcholine levels ⁴⁰.

The entorhinal cortex, amygdala, hippocampus, and cortical association regions of the frontal, temporal, and parietal cortices are among the areas most affected by neuronal loss. Affected subcortical regions include the cholinergic basal nucleus, noradrenergic locus coeruleus, and serotonergic dorsal raphe. Tangles originate in the trans-entorhinal cortex and develop in a particular order, impacting cortex, and other areas. This results in a major impact on the lobes. Other important number of plaques is the relationship between the location and amount of tangle formation and the severity of dementia⁴¹.

Amyloid Β Theory and Hyperphosphorylated Tau-Protein:

A key Alzheimer's disease (AD) feature is senile plaque (SP) formation, resulting from amyloid beta (Aβ) deposition. Aβ, typically soluble peptides derived from amyloid precursor protein (APP) cleavage, form toxic oligomers such as protofibrils, fibrils, and plaques because of a mismatch between clearance and production. The factors influencing Aβ formation include its sequence, concentration, and stability conditions, yet the exact reason remains unclear⁴².

Oxidative Stress Hypothesis:

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated in various typical and atypical biological processes. They serve a dual role, both supporting beneficial cellular signaling and contributing to toxic effects that damage cellular components. Due to its high oxygen consumption—20% more than other tissues involved in mitochondrial respiration—the brain is particularly vulnerable to oxidative stress. Neurons, the functional units of the brain, are rich in polyunsaturated fatty acids, which are prone to reactions with ROS, leading to lipid peroxidation and cell apoptosis. Furthermore, low levels of glutathione in neurons exacerbate oxidative stress and increase the risk of neuronal damage⁴².

Metal-ion hypothesis

Metal dyshomeostasis, implicated in diseases like neurodegeneration and cancer, is influenced by ionophores and metal chelators, some under clinical investigation. Progressing levels of trace metals, copper, iron are evident in neuro-degenerative disorder⁴³.

The APOE genotype's impact on acetyl-cholinesterase inhibitor (AChEI) efficacy in Alzheimer's treatment is discussed, considering the "Cholinergic Hypothesis." Binding of the Cholinergic receptor reduces specifically in brain parts, tied to neuropsychiatric symptoms, suggest potential treatment targets linked to aging and Alzheimer's⁴⁴. Clinical decline in Alzheimer's disease stems from substantial loss of cholinergic neurons in forebrain nuclei, leading to reduced acetylcholine-mediated neurotransmission. Cholinesterase inhibitors (ChEIs) like donepezil, regulating acetylcholine levels, have been the cornerstone of symptomatic therapy for over two decades⁴⁵. Amyloid-beta plaques, neuro-fibrillary tangles, neuroinflammation, altered insulin resistance, oxidative stress, and changes in the cerebrovascular system are the causes of Alzheimer's disease. Cholinergic deficits, particularly in basal forebrain nuclei, are associated with neurofibrillary degeneration and amyloid-beta pathology. Animal studies suggest cholinergic depletion contributes to cognitive decline, while nicotinic receptor stimulation shows potential neuroprotective effects against amyloid-beta-induced toxicity. Muscarinic agonists, especially M1, may downregulate amyloidogenic and tau-generating pathways, potentially influencing Alzheimer's disease processes⁴⁶.

A rare subgroup (<1%) of individuals in early causation of Alzheimer carries highly impactful mutations that are autosomal dominant. According to this idea, there is a prolonged period of no symptoms, preceded by widespread neurofibrillary tangles and cognitive deterioration that leads to dementia. Specific Aβ plaque accumulations are seen in the limbic system, frontal lobes, and temporal lobes⁴⁷. Despite promising outcomes in animal models, therapeutics aiming to decrease Aβ aggregates or inhibit γ- or β- secretase has faced challenges in clinical trials, evident in costly Phase-II and –III failures. This has sparked a contentious debate around the validity of the amyloid cascade hypothesis⁴⁸.

The application of PET radiotracers, related to Aβ plaques and NFTs, in combination with magnetic resonance imaging (MRI) has provided crucial insights into the molecular and physical changes that occur as Alzheimer's disease progresses from early to advanced stages⁴⁹. The suggested progression of pathology of Aβ typically adheres to a sequenceof spatiotemporal, initiating neocortex and hence extending to midbrain, basal ganglia, allocortex, and ultimately manifesting in the pons and cerebellum⁵⁰.

Particularly, elevated the graph of phosphorylated and total tau in the cerebrospinal fluid (CSF) show a strong positive correlation with cognitive decline, which is further supported by tau PET imaging⁵¹. As the PET of brain imaging methods for tau and Aβ plaque are still in the Advancement and improvement stages, the most commonly used and informative biomarkers for AD are predominantly identified in CSF and to a lesser degree in blood⁵².

A validated combination of biomarkers in CSF for likely AD diagnosis comprises reduced Aβ1-42 or a decreased Aβ1-42/Aβ1-40 ratio, together with increased levels of total tau and phosphorylated (pThr181) tau. This combination of CSF biomarkers shows enough sensitivity to detect asymptomatic pre-clinical Alzheimer's patients and predict the development of Alzheimer's disease from moderate cognitive impairment (MCI)⁵³. An essential aspect of the pathogenesis of Alzheimer's disease (AD) is the buildup of Aβ. One possible therapeutic target for AD is the impairment of normal endosomal function, which is thought to be a crucial step in the disease's cascade. Comprehending the function of the endosomal system in AD provides opportunities for the creation of tailored drugs that target particular subcellular regions. Small molecule inhibitors could be delivered to endosomal APP processing sites to improve safety and efficacy. This would provide a targeted method of inhibiting Aβ synthesis within endosomes while possibly sparing other substrates of γ-secretase⁵⁴. Nowadays Dementia refers broad range of symptoms characterized by a decline in memory and cognitive functions severe enough to disrupt daily life. Alzheimer's disease (AD) is the leading cause, accounting for 60-80% of all dementia cases. AD leads to significant suffering for patients, manifesting in the gradual loss of functional abilities, increasing dependence on others, emotional distress, and behavioral challenges.⁵⁵

CONCLUSION:

Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder primarily affecting older adults. Despite advances in understanding its pathology, including amyloid-beta accumulation, tau hyperphosphorylation, and cholinergic dysfunction, effective disease-modifying treatments remain elusive. Emerging research highlights the role of the dopaminergic system and vascular factors in AD, suggesting a multifaceted disease process. Global prevalence rates vary, with lower incidence in Asia compared to Western countries, influenced by factors like genetics, lifestyle, and demographic trends. The progression of AD is marked by the accumulation of neurofibrillary tangles and amyloid plaques, detectable through biomarkers in cerebrospinal fluid (CSF) and neuroimaging. The identification of these biomarkers is crucial for early diagnosis and potential therapeutic interventions. Despite significant research, the exact causes and effective treatments for AD are not fully understood, necessitating continued exploration of its complex pathophysiology and potential therapeutic targets. Understanding these mechanisms is essential for developing effective interventions and addressing the growing global burden of AD.

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Received on 18.09.2024 Revised on 11.01.2025

Accepted on 19.04.2025 Published on 14.05.2025

Available online from May 16, 2025

Res.J. Pharmacology and Pharmacodynamics.2025;17(2):121-130.

DOI: 10.52711/2321-5836.2025.00020

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