News in the management of Alzheimer's disease

Neurodegenerative processes have been increased by the increase in human longevity, which leads to emphasis on early diagnosis and new treatments. Alzheimer's disease remains the most common type of dementia; With 80%, the main risk factor is age, but from 65 to 76 years of age the risk is 0.4%, and 8% from 80 years of age. 

The differential diagnosis is broad in patients with cognitive impairment, but there are treatable causes of dementia such as: hypothyroidism and thyrotoxicosis, hypoglycemia or hyperglycemia, hypo/hypernatremia or alcohol withdrawal, delirium due to sepsis, depression and dysthymia.

Regarding drugs for chronic and prolonged use, there are benzodiazepines, antihistamines and cholinergics. There is also the group of neurodegenerative dementias (not treatable); Alzheimer's being the most common cause with 65%: Vascular dementias and Multi-infarct dementia

Neuroinfectionon: Creutzfeldt-Jakob disease, dementia associated with HIV and neurosyphilis, Lewy body dementia, dementia associated with Parkinson's disease, frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy.

Alzheimer's Disease (AD): It is a chronic disease that involves a 10-year process of evolution between normal cognition, asymptomatic pre-mild cognitive impairment (MCI), symptomatic pre-MCI, mild cognitive impairment and declared Alzheimer's disease itself.

There are some protective factors determined in studies such as those that begin in childhood, BMI in the elderly (not obesity but avoiding malnutrition processes in this age group), combined treatment of folic acid, vitamin B6, vitamin B12 and constant participation in activities cognitive.

Established risk factors:

• Diabetes mellitus
• Orthostatic hypotension
• High blood pressure in young adults
• TCE
• Stress
• Depression
• Obesity in young adults
• Coronary bypass surgery

Additional points that we must evaluate and improve as far as possible in our patients: exercise in middle age to reduce the risk and is dose dependent, at 65 years of age exercise reduces the risk of late-onset dementia (hyperhomocysteinemia), be detected and understood as a risk factor as well, also circadian rhythm alterations and obstructive sleep apnea syndrome.

Definitions

Dementia: It is the acquired process where there is impairment of two or more executive functions severe enough to impact the patient's ADL, it may present alterations: behavioral and psychological in the DSM-V it is called major neurocognitive disorder

Mild cognitive impairment: minimal impairment of executive functions where the patient's independence in ADL is not affected

AD profile: amnestic type MCI

Pathophysiology of AD: The peptides known as Beta amyloid are natural products of metabolism, they can be 35-43 amino acids: Aβ40 plus Aβ42 (the one that aggregates), in this disease there is an imbalance between: production, clearance and aggregation which leads to a accumulation of beta amyloid.

There is a pre-clinical phase: cell that generates neuroinflammation, vascular alteration and lymphatic dysfunction. The approach to these patients should include cognitive screening with in-office tests such as MMSE. MOCHA

Rule out affective processes such as Depression.

General laboratory study: vitamin profile (B12), thyroid, kidney, liver, blood count, electrolytes
homocysteine, genetic studies (ApoE4 gene), CSF biomarkers.

Neuroimaging: Brain magnetic resonance imaging (MRI), tomography (CT), brain PET

EEG

Treatment: those approved so far in order to delay progression so that the patient is as independent as possible for longer, but they are not curative.

Acetylcholinesterase inhibitors: donepezil, rivastigmine oral or in skin patches.

NMDA antagonists: memantine.

It is important to detail that the important advance in the treatment of this disease has been made by two drugs: aducanumab, which is a recombinant human monoclonal antibody, type IgG1 against amyloid aggregates and insoluble forms of amyloid β.

FDA approval 7-6-2021 for exclusive use in mild cognitive impairment associated with AD and mild Alzheimer's disease. It has a dose that is calculated per kilo of the patient's weight, and is administered intravenously every month.

Due to the adverse effect profile, a strict protocol is followed with brain MRIs required before certain infusions. Aducanumab demonstrated that it generates a clearance of beta amyloid deposited in the brain, but the results were not as expected on cognitive scales.

The most feared adverse effect is the appearance of Amyloid Related Imaging Abnormalities (ARIA), which consists of areas of cerebral edema or microhemorrhages that can range from mild and resolve without problem to fatal events.

On January 6, 2023, Lecanemab is approved, a recent FDA approval for the treatment of patients with mild Alzheimer's disease.

It is a humanized IgG1 monoclonal antibody with high affinity against soluble protofibrillar beta amyloid (> neuronal toxicity) for the same target group of patients: mild AD and AD-associated MCI.

This medication has a better adverse effect profile; It must also be administered intravenously in an infusion center, but with the disadvantage that its application is every two weeks, it was shown that it not only eliminates beta amyloid deposited in the brain, but also improves bone cognition scales that there is clinical improvement.

In conclusion, there is a window of opportunity to work on the risk factors to be candidates for using some of these medications, but with diagnostic precision (through studies on cerebrospinal fluid obtained in a lumbar puncture).

New medications have adverse effects that can be serious and their administration must be done in an infusion center with strict monitoring from a clinical and imaging point of view (brain magnetic resonance imaging).

The management of patients with dementia is multidomain, because memory clinics are needed to guide the patient and their family in this process, as well as undergraduate, graduate and postgraduate training and education for the population so that we can overcome barriers to early diagnosis.