Alzheimer's disease, an affliction of profound neurological consequence, stands as a progressive disorder primarily characterised by the erosion of cognitive faculties, notably memory, cognition, and comportment.

The development of a disease stage classification for Alzheimer's disease (AD) has been a complex process, and there is no complete consensus on the existing systems in place. The definitive staging of the disease remains a subjective decision made during clinical-pathological discussions involving clinicians, neuropsychologists, and pathologists. A significant limitation of the staging system is its approximate applicability to living subjects, as AD pathology is typically confirmed post-mortem. Therefore, a clinical diagnosis of probable AD is often used. The absence of a diagnostic test for AD during a person's lifetime greatly hinders research into the disease's mechanisms and poses challenges for clinical trials, as it introduces additional variability in the patient population. Testing therapeutics is challenging, particularly if they need to be administered before the disease reaches a specific, unclear stage or if the patient group is poorly defined. [1]

AD diagnosis typically relies on the presence of two hallmark pathologies: the extracellular plaque deposits of the β-amyloid peptide (Aβ) and the neurofibrillary tangles formed by the microtubule binding protein tau. For many years, researchers were perplexed by the weak or non-existent correlation between the amount of neuritic plaque pathology in the human brain and the severity of clinical dementia. There is now substantial evidence indicating that the solubility of Aβ and the quantity of Aβ in different pools may be more closely associated with the disease's progression

Several potential theories regarding the progression of Alzheimer's disease (AD) include chronic neuronal stress, convergence of factors, hypoxia, inflammation, mitochondrial dysfunction, the presence of multiple pathologies, oxidative stress, and nutrient deprivation. These interconnected and complex pathologies contribute to synaptic loss and neuronal death, creating a self-perpetuating feedback loop that cannot be halted.

Amyloid beta peptides are produced through the sequential cleavage of the transmembrane protein APP by β- and γ-secretases, known as the amyloidogenic pathway. γ-secretase is a tetramer composed of PSEN1 or PSEN2, APH-1, nicastrin, and PEN-2. Mutations in PSEN1 and PSEN2 influence the length of Aβ peptides, often resulting in longer Aβ42 peptides, which are abundant in AD senile plaques alongside normal Aβ40 peptides.

Numerous scientific studies have demonstrated that when neuronal cell lines and primary neurons are cultured under hypoxic conditions, they exhibit an overexpression of amyloid precursor protein (APP) and produce significant amounts of Aβ. Hypoxia occurs when cellular oxygen levels drop to around 0.5-5%, leading to insufficient oxygen and acetyl-CoA for mitochondria. This results in the increased generation of reactive oxygen species (ROS) and nitric oxide (NO), causing intracellular stress. Interestingly, heightened mitochondrial ROS production inhibits PreP, impeding the degradation of Aβ and causing its accumulation within the mitochondrial matrix.

Oxidative damage is most prominent in the early stages of the disease and diminishes as the disease progresses, correlating with increased brain Aβ levels. These findings have led to the theory that oxidative stress plays a pivotal role in the pathogenesis of Alzheimer's disease. Additionally, the presence of high levels of Aβ bound to metal ions within mitochondria is associated with elevated ROS levels. Notably, markers of oxidative and nitrosative stress have been detected in blood, cerebrospinal fluid, and urine during both early and late stages of AD, suggesting their constant presence throughout the disease's progression, potentially serving as valuable biomarkers to track the disease's trajectory. [2]

Alzheimer's disease is more prevalent among older individuals, and as the global population continues to age, there will be a higher number of people at risk. By 2050, it is estimated that the number of individuals with Alzheimer's disease may triple, primarily due to the aging population. There has been a growing awareness of Alzheimer's disease in recent years, leading to more people seeking diagnosis and treatment. As a result, more cases are being identified, and the prevalence of the disease is increasing. As the number of people affected by the disease increases, so does the cost of care, including medical treatment, caregiving, and support services.

The disorder has no cure, and its rate of progression is variable. Further, the diagnosis of Alzheimer's disease in the early phase is difficult, and there are no specific laboratory or imaging tests to confirm the diagnosis. Alzheimer's disease is a systemic disorder and creates havoc in the family. These individuals often wander, fall, have significant behavioural problems and loss of memory. The majority of patients end up in geriatric care institutions because they become difficult to manage at home. [3]

Incidence rates per 1000 person–years for AD with CDR 0.5 were 3.24 (95% CI: 1.48–6.14) for those aged 65 years and 1.74 (95% CI: 0.84–3.20) for those aged 55 years. Standardised against the age distribution of the 1990 US Census, the overall incidence rate in those aged 65 years was 4.7 per 1000 person–years. [4]

India is experiencing rapid population ageing, with projections indicating that nearly 20% of its population, or 319 million people, will be aged 60 or older by 2050. This demographic shift reflects increasing life expectancy, which has risen from 42.9 years in 1960 to 70.4 years in 2020. Life expectancy at birth ranges from 64.8 years in Bihar to 75.1 years in Kerala. Expected survival at age 60 is 17.4 years for men and 18.9 years for women. The estimated dementia prevalence among individuals aged 60 and older in India is 7.4% (95% confidence interval [CI], 6.4 to 8.5), and age-standardised dementia prevalence is 8.0% (95% CI, 6.8 to 9.2). [5]

Magnetic Resonance Imaging (MRI) is a non-invasive medical imaging technique that uses powerful magnetic fields and the behavior of hydrogen nuclei (protons) in the body to create detailed internal images. Protons align with or against the magnetic field. An applied radiofrequency pulse disrupts this alignment, causing a temporary reversal of proton spins known as "excitation," which releases energy. RF signals emitted during relaxation are captured by coils around the body, and computer processing generates precise images, aiding in accurate medical diagnoses. Using MRI technique, it is now possible to distinguish atrophy during the early stage of AD from the atrophy of normal ageing. Discrimination of AD from other forms of dementia, namely, frontotemporal dementia (FTD) and DLB (dementia with Lewy bodies) is also possible based on different atrophy patterns that MRI reveals. MRI does not directly visualise or quantify beta-amyloid plaques, a hallmark of Alzheimer's disease. Detecting these plaques typically requires specialised PET (Positron Emission Tomography) scans with amyloid-specific radiotracers. MRI scans can be uncomfortable and challenging for Alzheimer's patients, especially those prone to anxiety or claustrophobia, as they require lying still in a confined space for an extended period.

Computed Tomography (CT) scan, also known as CAT (Computerised Axial Tomography) scan is a medical imaging technique that uses X-rays and computer processing to create cross-sectional images of the body's internal structures. CT scans are invaluable in diagnosing and monitoring a wide range of medical conditions. CT scanning is based on the principle of X-ray absorption. When X-rays pass through the body, they are absorbed to varying degrees by different tissues, depending on their density. Dense tissues like bones absorb more X-rays and appear white on the CT images, while less dense tissues like organs and fluids appear in various shades of grey, with air appearing black. CT primarily provides detailed images of brain structures but may not reveal early cellular or metabolic changes associated with the disease making them less sensitive. Brain atrophy can be caused by various conditions, not just Alzheimer's disease, making it challenging to differentiate between different neurodegenerative disorders solely based on CT imaging.

Cerebrospinal fluid test - A CSF test for Alzheimer's disease is typically performed using a lumbar puncture. A lumbar puncture is a procedure in which a thin needle is inserted into the lower back to collect a sample of CSF. The procedure is usually performed under local anaesthesia and takes about 30 minutes to complete. Once the CSF sample is collected, it is sent to a laboratory for testing. The laboratory will measure the levels of Aβ1-42, T-tau, and P-tau in the CSF. The results of the CSF test can help doctors to diagnose Alzheimer's disease and to differentiate it from other causes of cognitive impairment. CSF testing can also be used to monitor the progression of Alzheimer's disease and to track the response to treatment. Collecting CSF requires a lumbar puncture (spinal tap), which is an invasive procedure. This can be uncomfortable and carries a small risk of complications, including headaches or infection. Analysing CSF biomarkers for Alzheimer's disease can be complex and requires specialised testing. Interpretation may vary between laboratories, leading to potential inconsistencies in results.

One of the central issues is the lack of awareness and understanding of Alzheimer's disease in India, both among the general population and within the healthcare system. Many people often confuse Alzheimer's symptoms with normal signs of aging, leading to delayed diagnosis and treatment. This lack of awareness also extends to the broader societal understanding of the specific care needs of Alzheimer's patients. As a result, there is a pressing need for public health campaigns and education programs to promote awareness, early detection, and destigmatize the condition.

Moreover, the existing healthcare infrastructure in India is ill-equipped to handle the increasing demand for specialised geriatric care and Alzheimer's treatment. Many healthcare facilities lack trained professionals and resources required for the comprehensive care of Alzheimer's patients. Additionally, there is a shortage of geriatric specialists, and the healthcare system tends to be more focused on acute care rather than long-term and palliative care, which is essential for Alzheimer's patients.

In terms of inclusion, elderly individuals, particularly those with Alzheimer's, often face social isolation and neglect. The lack of community support, stigma surrounding mental health issues, and inadequate social services further exacerbate the problem. Family caregivers, who are usually forced to quit their jobs due to the lack of geriatric health care in India, often face significant physical, emotional, and financial stress due to the lack of support and respite services. This is a growing challenge in the face of urbanisation and nuclear families, and mostly, unfairly, takes more of a toll on the women of the family.

So, early and accessible diagnosis can serve both as an important complement to the goal of raising awareness and also give families and our healthcare infrastructure sufficient time to plan and arrange the care our elderly require.

1. https://www.ncbi.nlm.nih.gov/pmc
/articles/PMC2848584/
2. www.ncbi.nlm.nih.gov/pmc/
articles/PMC2813509/
3. https://www.ncbi.nlm.nih.gov/
books/NBK499922/
4. https://n.neurology.org/content
/57/6/985.short
5. https://alz-journals.onlinelibrary.
wiley.com/doi/10.1002/alz.1292