Oriental College of Pharmacy Bhopal.
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Alzheimer's disease (AD) is a condition that results in the degradation of brain cells and is the primary cause of dementia, which is defined by a loss of mental capacity and independence in everyday tasks. The cholinergic and amyloid theories were put up as two key causes of AD, and AD is thought to be a complex illness. Additionally, the condition is influenced by several risk factors, including advancing age, hereditary variables, head traumas, vascular disorders, infections, and environmental factors (Breijyeh & Karaman, 2020). It is one of the main factors that older person experiences impairment and a decline in their quality of life (Cipriani, G. et al). To understand AD pathophysiology, research is concentrating on several pathways, including aberrant tau protein metabolism, amyloid, inflammatory response, and cholinergic and free radical damage to create effective therapies that can halt or alter AD's progression 1 (). The most typical clinical form of sporadic AD (i.e., typical AD dementia) is a slowly progressing amnestic illness that reflects the early predominance of neurofibrillary tangle pathology in medial temporal-lobe structures and progresses to multi-domain dementia that is amnestic-predominant. However, early, predominant impairments in the visual, linguistic, executive, behavioral, and motor domains are used to describe non-amnestic symptoms (Graff-Radford et al., n.d.). The only method now used to treat people with clinically confirmed AD is pharmaceutical regulation of glutamatergic and cholinergic neurotransmission. The FDA has only authorized five medications for AD The N-methyl-D-aspartate (NMDA) receptor partial antagonist memantine, the cholinesterase inhibitors donepezil, rivastigmine, and galantamine, as well as a fixed-dose combination of donepezil and memantine, have all received approval from the United States Food and Drug Administration (FDA) (Alzheimer's Association, 2020). However, none of these medications are particularly successful, and they neither stop the progression of the illness nor significantly alleviate cognitive impairment. Instead, they just temporarily postpone the worsening of AD symptoms (Stoiljkovic et al., 2021).
Alzheimer’s Disease Diagnostic Criteria
(1)probable Alzheimer’s disease, which can be diagnosed by dementia that is confirmed by neuropsychological tests, progressive memory loss, impaired daily-life activity, and other symptoms like aphasia (impairment of a language), apraxia (a motor skills disorder), and agnosia (a loss of perception). All of these symptoms can start from age 40–90, with the absence of any systemic or brain diseases, (Graff-Radford et al., n.d.) possible Alzheimer’s disease can be applied in the absence of neurologic, and psychiatric disorders, and the presence of another illness like systemic or brain disorder, but they are not the primary cause of dementia, and (Mayeux & Stern, 2012) definite Alzheimer’s disease, that is confirmed by histopathologic confirmation obtained from a biopsy or autopsy [. Skoog , and Luchsinger JA et al, ]. (a) markers of brain amyloid such as positron emission tomography (PET) and cerebrospinal fluid (CSF), and (b) markers of neuronal injury like cerebrospinal fluid tau, fluorodeoxyglucose (FDG) for metabolic activity, and magnetic resonance imaging (MRI) for atrophy measurement.( Szekely CA and Leon J, Cheng et al). (1)(Breijyeh & Karaman, 2020)
Senile Plaques (SP)
The senile plaques are extracellular deposits of beta-amyloid protein (A?) with different morphological forms, including neuritic, diffuse, dense-cored, or classic and compact type plaques. Proteolytic cleavage enzymes such as ?-secretase and ?-secretase are responsible for the biosynthesis of A? deposits from the transmembrane amyloid precursor protein (APP) ( Coleman P, Cataldo AM, et al). These enzymes cleave APP into several amino acid fragments: 43, 45, 46, 48, 49, and 51 amino acids, which reach the final forms A?40 and A?42. There are several types of A? monomers, including large and insoluble amyloid fibrils which can accumulate to form amyloid plaques, and soluble oligomers that can spread throughout the brain. A? plays a major role in neurotoxicity and neural function, therefore, accumulation of denser plaques in the hippocampus, amygdala, and cerebral cortex can cause stimulation of astrocytes and microglia, damage to axons, dendrites, and loss of synapses, in addition to cognitive impairments( Cataldo AM and, Doody Reset al)
Neurofibrillary Tangles (NFTs)
NFT are abnormal filaments of the hyperphosphorylated tau protein that in some stages can be twisted around each other to form paired helical filament (PHF) and accumulate in neuralperikaryal cytoplasm, axons, and dendrites, which cause a loss of cytoskeletal microtubules and tubulin-associated proteins. The hyperphosphorylated tau protein is the major constituent of NFTs in the brains of AD patients, and its evolution can reflect NFTs morphological stages, which include: (1) pre-tangle phase, one type of NFT, where phosphorylated tau proteins are accumulated in the somatodendritic compartment without the formation of PHF, (2) mature NFTs, which are characterized by filament aggregation of tau protein with the displacement of the nucleus to the periphery part of the soma, and (3) the extracellular tangles, or the ghost NFTs stage, that results from a neuronal loss due to large amounts of filamentous tau protein with partial resistance to proteolysis (Kihara Tand Although a definitive diagnosis of AD can currently be made only by histopathologic examination of brain tissue after the patient’s death, the classification of dementia disorders by neuropathology is not straightforward.11 Only 50% to 60% of individuals fulfilling the neuropathologic diagnosis of AD have dementia or significant cognitive decline during life. Moreover, no neuroimaging or laboratory markers now exist for the reliable presymptomatic diagnosis of AD.25 Therefore, we are forced to wait until individuals become symptomatic. The diagnosis of AD is primarily one of inclusion, not exclusion, and usually can be made using standardized clinical criteria.26 Potentially reversible causes of dementia should be investigated (table
2).27 AD can be accurately diagnosed even in very mildly impaired individuals.28 Unfortunately, only 60% of patients with AD are correctly diagnosed and only approximately 50% of those people are treated.29 This is consistent for all stages of AD. Using standardized and easy-to-use scales to assess cognition (such as the MMSE) and ADL [such as the Functional Activities Questionnaire (FAQ)30] in older. adults experiencing cognitive deficits may help clinicians make early, accurate diagnoses.31 Input from collateral sources is also recommended for early diagnosis because those are accurate in reporting the cognitive capabilities of individuals with AD, even in the very mild stage.32 In a typical case, the onset of AD is slow. Some individuals with incipient AD are aware of their declining abilities, but most patients with evolving AD never acknowledge that they have memory dysfunction.33 Eventually, recognition may occur because of an apparent crisis, such as getting lost, an accidental fall, or discovery by neighbors or relatives of an unsafe, messy home environment, acute confusion (delirium) during illness, after surgery or hospitalization, or environmental stress. Careful questioning will usually reveal that cognitive impairment and dysfunction have been present for several years before the acute crisis. A decline in calculation abilities is one of the hallmark cognitive features of AD.34(2)
Antecedent Risk Factors That
Increase The Risk of Alzheimer Disease
A large number of factors have been associated with an increased risk of AD, but among those, cerebrovascular disease and its antecedents are the most consistently reported (Table 1).
Figure 1. The annual incidence rate (per 100 person-years) for Alzheimer’s disease. This graph is an estimate of the data collected in 24 published studies.
Cerebrovascular Disease
While it is clear that cerebrovascular disease may present with manifestations resembling dementia,purelyvasculardementiaisuncommon. More often cerebrovascular disease co-exists with AD, so evidence of both vascular disease and prototypical AD manifestations is present (Schneider and Bennett 2010). Pendlebury and Rothwell (2009) analyzed data from several hospitals- and population-based cohorts (7511 patients) and estimated the frequency of new-onset dementia to be approximately 7% following first-stroke. Interestingly, the two-fold increased risk of dementia after an incident stroke was independent of the level or the rate of change of pre-stroke cognitive function, suggesting that pre-stroke cognitive function is not a major determinant of the effect of stroke on the risk of poststroke dementia (Reitz et al. 2008). The proposed mechanisms by which stroke could lead to cognitive impairment include destruction of brain parenchyma with atrophy (Fein et al. 2000; Jellinger 2002), damage in strategic locations that leads to amnestic syndromes, such as thalamic strokes, an increase in Ab deposition and a combination of vascular and Alzheimer-type pathology (Blennow et al. 2006). As one possible mechanism for an increase in Ab, there is evidence from rodent models of ischemia and hypoxia owing to hypoperfusion that a resulting overexpression of p25 and cdk5 increases levels of BACE1, which in turn increases amyloid precursor protein (APP) processing (Wen et al. 2007, 2008). White matter hyperintensities are frequently observed by MRI in patients with dementia, but the mechanisms by which white matter changes contribute to cognitive decline are unclear. Moreover, because hypertension, diabetes, and microvascular disease are each associated with these changes, there is no clear process to explain the effect on cognition or their role in Alzheimer’s disease. Thalamic vascular disease can lead to lower performance on cognitive tasks, particularly those associated with frontal and temporal lobe function, including memory storage and retrieval (Swartz et al. 2008; Wright et al. 2008).
Hypertension
Cross-sectional and longitudinal studies implicate blood pressure as a possible contributor to late-life dementia. Observational studies of the association between elevated blood pressure during middle age and late-life cognitive impairment suggest that mid-life hypertension increases the risk of late-life dementia (Kilander et al. 2000; Launer et al. 2000; Wu et al. 2003; Yamada et al. 2003; Elias et al. 2004; Whitmer et al. 2005b). When hypertension is assessed in later life, the association is somewhat ambiguous, in that both high and abnormally low blood pressure is associated with dementia (Skoog et al. 1996; Knopman et al. 2001; Morris et al. 2001; Ruitenberg et al. 2001; Tyas et al. 2001; Bohannon et al. 2002; Lindsay et al. 2002; Posner et al. 2002; Elias et al. 2003; Kuller et al. 2003; Piguet et al. 2003; Qiu et al. 2003; Reinprecht et al. 2003; Verghese et al. 2003a; Hebert et al. 2004; Solfrizzi et al. 2004; Tervo et al. 2004; Borenstein et al. 2005; Petitti et al. 2005; Waldstein et al. 2005). With Alzheimer’s disease onset and progression, blood pressure begins to decrease, possibly related to vessel stiffening, weight loss, and changes in the autonomic regulation of blood flow. Hypertension is a treatable medical disorder, but clinical trials of antihypertensive medications in AD patients have been attempted with inconsistent results (Forette et al. 2002; Lithell et al. 2003; Tzourio et al. 2003; Peters et al. 2010).
Type II Diabetes
The presence of type II diabetes is associated with an approximately twofold increased risk of AD (risk ratios vary between 1.5 and 4.0; Luchsinger et al. 2001; Peila et al. 2002; Farris et al. 2003; Luchsinger et al. 2004a). It has been suggested that diabetes directly affects Ab accumulation in the brain because hyperinsulinemia, which accompanies type II diabetes, disrupts brain Ab clearance by competing for the insulin-degrading enzyme (Selkoe 2000; Farris et al. 2003). Receptors for advanced glycation end-products, which also play a role in the pathogenesis of diabetes, are present in cells associated with senile plaques and neurofibrillary tangles be one example of a cell surface receptor for Ab. Excess adipose tissue may also predispose to type II diabetes by producing adipokines critical to metabolism and cytokines important in inflammation. Adiponectin, leptin, resistin, TNF-a, and IL-6 are also produced and correlate with insulin resistance and hyperinsulinemia, which in turn may directly or indirectly affect AD risk (Trujillo and Scherer 2005; Yu and Ginsberg 2005). A meta-analysis of longitudinal studies examining type II diabetes and other disorders of glucose or insulin levels found a pooled effect size for diabetes of 1.54 in increasing AD risk (95% confidence interval, CI, 1.33–1.79; z ¼ 5.7; p, .001; Profenno et al. 2009). Regret al. (2008) showed that the administration of intranasal insulin improved cognitive performance in the early phases of AD and patients with amnestic mild cognitive impairment, as did a 6-month trial of the PPAR-g agonist, rosiglitazone (Watson et al. 2005). Another study (Risner et al. 2006) in patients with AD lacking the APOE-14 allele showed significant although small improvements in cognitive and functional improvement in response to rosiglitazone, whereas in a study by Sato et al. (2009), treatment with 15–30 mg pioglitazone daily for 6 months led to improvements in cognitive function and regional cerebral blood flow in the parietal lobe.
Traumatic Brain Injury
Compared with those without a history of trauma, individuals who have suffered a traumatic brain injury have a higher risk of dementia, particularly those who carry the APOE-14 allele (Koponen et al. 2004). Meta-analyses demonstrated that the risk of dementia is higher among men (but not women) with a history of traumatic brain injury (Fleminger et al. 2003). Postmortem and experimental studies do support a link: After human brain injury, both Ab deposition (Hartman et al. 2002; Iwata et al. 2002; Stone et al. 2002) and intraneuronal tau pathology are increased, even in younger patients (Smith et al. 2003). In addition, CSF Ab levels are elevated and APP is overproduced(Mayeux & Stern, 2012)
Treatment of Alzheimer’s among the older population
At this time, AD cannot be cured. The primary objective of AD treatment is creating an Early, accurate clinical diagnosis, early implementation of ChEIs and/or NMDA receptor-targeted therapy, treating medical comorbidities and complications related to dementia, ensuring that the necessary services are offered, addressing the long-term well-being of carers, and treating behavioral and psychological symptoms of AD with appropriate nonpharmacologic and pharmacologic interventions are all important aspects of treating AD (table 3). 47 In terms of cognition, ADL, and behavior, ChEI and memantine offer small but clinically significant symptomatic improvements. Although it hasn't been shown, they could contain inherent disease-modifying properties. 48 A year may pass before behavioral and psychological signs of AD appear if ChEI therapy is initiated early. 49 New research confirms the positive effects of ChEIs in the long-term management of moderate to severe AD. 50,51 Memantine and ChEIs may both be beneficial in the treatment of VaD and DLB, respectively. It has been demonstrated that the combination of donepezil and memantine is more effective than donepezil alone in treating moderate to severe AD, possibly indicating a place for dual therapy in more advanced AD. 52 There is evidence that decisions about palliative care for AD patients are not being made effectively. 53 A disease management strategy for AD has been proposed that includes a diagnostic protocol to find and evaluate individuals who may have dementia as well as care management that involves interventions in areas like patient function, carer support, medical treatment, psychosocial support, nutritional planning, and advance directives. 54 Any type of therapy can help with end-of-life care for persons with AD.
Pharmacology
|
Approved by FDA |
Tacrine 80–160 mg/d; donepezil 5–10 mg/d; rivastigmine 6–12 mg/d; galantamine 16–24 mg/d) and N-methyl-D-aspartate receptor–targeted treatment (memantine 10- 20 mg/d) are cholinesterase inhibitors for mild to moderate AD. |
|
|
|
|
Use supported by controlled clinical trial |
Selegiline hydrochloride (5 mg BID), |
|
Compounds under investigation |
AIT-082 (purine hypoxanthine derivative), beta-sheet blockers, huperzine X (acetylcholinesterase inhibitor), secretase inhibitors, glutamate antagonists, xanomeline |
|
|
patch (m1/m4 muscarinic receptor agonist), anti- inflammatory medications (including aminopyridazines), acetylcholinesterase inhibitors, and xanomeline patch |
|
Benefit not generally accepted |
Chelation therapy (possible |
|
Preventive effect supported by epidemiologic evidence but not confirmed by prospective trials |
NSAIDs, statins, estrogen |
|
Nonpharmacologic |
Caregiver education (regarding safety, exercise, nutrition, recreation, communication, understanding the disease process and stages, advanced directives and end-of-life decisions, financial planning, and community resources), reminiscence therapy, music therapy, aromatherapy, environmental manipulation, reality orientation, pet therapy |
All article references in this table: Grossberg,2005)
should also include palliative care and patient-centered care from the time AD is first diagnosed until its last phases. 55 Treating comorbid diseases in addition to ads, such as depression, hearing or vision loss, congestive heart failure, symptomatic urinary tract infection, or hypothyroidism, may be more beneficial in many AD patients. 33 When evaluating AD patients, it's critical to look for treatable cardiovascular risk factors and CVD since these might have an impact on the expression and clinical symptoms of AD. the illness. 11 All of the following should be taken into account for an AD patient: the patient's capability for making decisions; the changing advantages and burdens of therapeutic procedures; the patient's capacity to follow instructions and report side effects; the accessibility of carers; and methods for compensating for communication and other deficits. Aggressive medical care for patients with terminal AD does not decrease the progression of the disease, increase comfort, or extend survival. 56 Antidepressants are useful for treating severe depression in AD, but there is little information on how to manage lesser depressive syndromes. Recreational activities are beneficial for both serious and mild ailments. depressive classifications. Antipsychotics are also useful and continue to be the most researched drugs for treating severe agitation in AD patients, whether or not it includes psychotic symptoms. 57 A combination of behavioral management strategies and exercise training can help AD patients with their mood and physical health. 58 can significantly lower the long-term risk for depression in people who care for spouses or companions with AD when combined with easily accessible assistance. 59 One study discovered that the beneficial effects of these therapies persisted even after persons with AD passed away or were moved into nursing homes, lasting more than 3 years after the original counseling sessions concluded. The placement of AD patients in long-term care may be delayed by a family intervention. 60 The mutations in presenilin 1, presenilin 2, and amyloid precursor protein provide for proper genetic counseling and support as well as genetic screening in suspected cases of familial AD with early onset. Although families of patients with early-onset familial AD have been offered preimplantation genetic diagnosis (PGD) of the embryos, prenatal diagnosis, preimplantation embryo selection, and presymptomatic testing, complex legal and ethical issues surrounding these interventions must be resolved before these interventions can be routinely advised. therapies that alter disease. The AD medications now on the market offer very limited symptomatic relief and no significant disease-modifying advantages. 61 One that is broadly neurotrophic or neuroprotective, one that focuses on particular features of AD pathology, and one that is based on epidemiologic observation are the three primary groups of disease-modifying techniques that can be identified. The most active area of research right now is anti-amyloid therapy. Early events in AD, occurring before any cytopathology can be diagnosed, include oxidative stress and cell cycle-related anomalies, which combined may promote disease development. 62 Antioxidants are thus an AD preventative strategy that should be researched. Additionally, clinicopathologic and neuroradiologic investigations demonstrate that inflammation caused by microglia activation is a rather early pathogenic event that occurs before the degeneration of neurons in AD. 63 Use of NSAIDs, or nonsteroidal anti-inflammatory drugs, has been linked to a lower incidence of AD. 13 Thus, despite the failure of clinical studies to treat AD with NSAIDs, these and other anti-inflammatory drugs may still play a part in lowering the risk for AD. cardiovascular risk factors may be modified.
CONCLUSION
Although long acknowledged, AD biomarkers and innovative neuropathologic techniques have improved our comprehension of the phenotypic range of atypical AD. Early diagnosis and prompt treatment can be ensured by increasing the use of AD biomarkers in clinical practice and a better understanding of various phenotypes. therapy and the right kind of assistance. A growing amount of attention is being paid to making sure that these people have access to the right services and assistance since atypical AD and young-onset AD overlap. Understanding the processes underpinning clinical-radiologic and neuropathologic diversity, particularly about the relative sparing of memory function and medial temporal areas, requires research on the phenotypic heterogeneity of AD. While atypical AD patients are in many respects perfect for clinical trials, For instance, current AD studies focus on memory, and individuals with atypical AD may not meet admission requirements. They also have fewer co-pathologies. Nearly all atypical AD studies disproportionately include Caucasian participants, much like conventional AD research does. Future studies should characterize these disorders in more representative, varied groups. 96 The Longitudinal Early-onset AD Study (LEADS; www.leads-study.org) is a global initiative to systematically gather and share clinical, imaging, genetic, and fluid biomarker data in young-onset and atypical AD patients to establish suitable clinical and biomarker outcome measures and cohorts that are trial-ready.
REFERENCES
Himanshu Thakur*, Understanding the Concept and Treatment of Alzheimer’s Disease Among the Older Population, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 1, 1411-1422. https://doi.org/10.5281/zenodo.14680107
10.5281/zenodo.14680107
