Alzheimer's Disease Overview

Alzheimer's Disease (AD) Overview

• AD affects roughly 7.5 million Americans.
• AD is a progressive condition that lacks a known cause.
• AD is characterized by a decline in cognitive and physical abilities.
• Behavior abnormalities are common with AD.

Pathophysiology of AD

• Genetic susceptibility to late-onset AD is primarily linked to the apolipoprotein E (APOE) genotype, though genetic × environmental interactions could be responsible.
• Early onset AD appears in <1% of cases.
• Dominantly inherited forms are linked to chromosomal alterations affecting amyloid precursor protein processing.
• Risk factors include: age, decreased brain reserve, head injury, Down syndrome, depression, mild cognitive impairment, hypertension, elevated homocysteine, elevated low/high density lipoprotein cholesterol, obesity, metabolic syndrome, and diabetes.
• Signature lesions include: intracellular neurofibrillary tangles (NFTs), extracellular plaques, degeneration of neurons/synapses, and cortical atrophy.
• Individuals affected with AD have a higher burden of plaques and NFTs in their younger years.
• Proposed mechanisms include: β-amyloid protein aggregation (plaques), hyperphosphorylation of tau protein (NFTs), synaptic failure, depletion of neurotrophin/neurotransmitters, mitochondrial dysfunction, and oxidative stress.
• Amyloid cascade hypothesis: Imbalance of β-amyloid production/clearance is responsible, resulting in aggregation/accumulation.
• It's unknown if the amyloid cascade hypothesis is the primary pathology in most AD forms.
• Loss of cholinergic activity is the most prominent neurotransmitter deficit correlating with AD severity.
• Cholinergic cell loss is likely a consequence of AD pathology, not the cause.
• Other neurotransmitters involved: Loss of serotonergic neurons of the raphe nuclei and noradrenergic cells of the locus ceruleus, increased monoamine oxidase type B activity, abnormal glutamate pathways, and neurotoxic excitatory neurotransmitters (glutamate).

Clinical Presentation of AD

• Early symptoms: changes in learning/memory, planning, organization, and mood.
• As the disease progresses: further declines in those domains as well as changes in personality, judgment, speech, and spatial orientation arise.
• Late-stage symptoms: functional decline (gait, swallowing, incontinence), and behavioral changes.
• Patients become increasingly unable to care for themselves.

Stages of Alzheimer's Disease using Folstein Mini-Mental State Examination (MMSE)

• Mild (MMSE score 26–21): difficulty remembering recent events, decline in managing finances and performing household activities, getting lost while driving, withdrawing from tasks/hobbies, and denying memory problems.
• Moderate (MMSE score 20–10): requires assistance with daily living activities, disorientation to time, severely impaired recent events recall, forgetting details of past life events/names, fluctuating functioning, denial of problems, suspiciousness, tearfulness, loss of driving ability, agitation, paranoia and delusions.
• Severe (MMSE score 9–0): loss of ability to speak, walk, and feed self, incontinence, and requires 24-hour care.

Diagnosis of AD

• AD is a spectrum starting with an asymptomatic preclinical phase before progressing into a symptomatic preclinical phase and dementia.
• AD diagnosis is clinical and relies on identified symptoms and difficulty with activities of daily living as revealed by interviews with the patient and their caregivers.
• Suspected AD patients should undergo a history and physical examination with labs (ie, serum B12, folate, thyroid panel, blood cell counts, serum electrolytes, and liver function tests).
• Structural imaging (non-contrast enhanced CT or MRI) can identify structural abnormalities consistent with AD or other pathology (brain atrophy, vascular damage, tumors).
• Cerebrospinal fluid analysis or an electroencephalogram can be justified to exclude other diagnoses.
• APOE genetic testing is not recommended.
• Information on medication & substance use; family medical history; and history of trauma, depression, or head injury should be collected.
• Medications (anticholinergics, sedatives, hypnotics, opioids, antipsychotics, anticonvulsants, digoxin, nonsteroidal anti-inflammatory drugs [NSAIDs], histamine 2 [H2] receptor antagonists, amiodarone, antihypertensives, and corticosteroids) should be ruled out as contributors to dementia or delirium.
• Folstein Mini Mental State Examination (MMSE) can establish a history of deficits in two or more areas of cognition at baseline to evaluate changes in severity.
• The average expected decline in an untreated patient is 2–4 points per year.
• Improved brain imaging and validated biomarkers will enable sophisticated diagnosis with identified cognitive strengths/weaknesses and neuroanatomic localization of deficits in the future.

Goals of AD Treatment

• Primary goal: To maintain cognitive functioning and activities of daily living as long as possible.
• Secondary goal: To treat psychiatric and behavioral symptoms.

Non-Pharmacologic Therapy for AD

• Identify causative factors for cognitive/noncognitive symptoms and adapt the environment.
• Manage sleep disturbances, wandering, incontinence, agitation, and aggression with behavioral and environmental interventions through redirection and removing stressors/triggers.
• Educate patients and caregivers on the illness trajectory, available treatments, legal decisions, and lifestyle changes that will become necessary.
• Primary prevention includes the cessation of smoking, increased physical activity, and the reduction of midlife obesity, hypertension, and diabetes.
• Adherence to the Mediterranean or DASH diet may reduce the risk of cognitive impairment/decline.

Pharmacologic Therapy of Cognitive Symptoms for AD

• Consider aducanumab (anti-amyloid monoclonal antibody) for mild cognitive impairment (MCI).
• Titrate it to the recommended maintenance dose as tolerated.
• For mild to moderate AD, consider a cholinesterase inhibitor (donepezil, rivastigmine, or galantamine) or aducanumab, titrating to recommended maintenance dose as tolerated.
• For moderate to severe AD, consider adding memantine (anti-glutamatergic agent), titrating to recommended maintenance dose, or using memantine/cholinesterase inhibitor therapy independently.
• A reasonable response may be a slowed decline in abilities and delayed long-term care placement.
• Simplify dosing regimens, considering patient/caregiver preferences.
• Treatment gaps may result in a loss of benefits when medication is stopped, but it is controversial.
• Behavioral symptoms may need additional pharmacologic approaches.

Cholinesterase Inhibitors for AD

• Donepezil, rivastigmine, and galantamine are indicated for mild to moderate AD.
• Donepezil is also indicated for severe AD.
• No trials have assessed agent effectiveness over another.
• Successful treatment with cholinesterase inhibitors results in an MMSE score decline of less than 2 points per year, with benefits lasting 3–24 months.
• If rivastigmine or galantamine are interrupted for several days, re-titrate starting at the lowest dose.
• Gradual dose titration improves tolerability.
• A washout period is recommended with switching.
• Abrupt discontinuation may worsen cognition and behavior.

Adverse Effects and Monitoring of Cholinesterase Inhibitors and Memantine

• Galantamine: Monitor appearance of skin rash, serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis). Discontinue at the first sign of skin rash unless clearly not related; consider alternative treatment and do not rechallenge with suggestive signs/symptoms
• Rivastigmine: Monitor reaction spread beyond patch size, evidence of a more intense local reaction, persistence of symptoms >48 hours after patch removal for allergic dermatitis. Discontinue if disseminated allergic dermatitis appears; patients sensitized by patch exposure may not be able to take rivastigmine by mouth; allergy testing and close medical supervision recommended.
• Cholinesterase inhibitors: Monitor report of dizziness/falls, pulse, blood pressure, and postural blood pressure change for dizziness, syncope, bradycardia, atrial arrhythmias, sinoatrial/atrioventricular block, and myocardial infarction; Weight and GI complaints for nausea, vomiting, diarrhea, anorexia, weight loss; signs/symptoms of active/occult GI bleeding for peptic ulcer disease/GI bleeding.
• Memantine: Monitor report of dizziness/falls, hallucinations for headache, confusion, dizziness, hallucinations Monitor GI complaints for Constipation.
• Routine pulse checks are recommended at baseline, monthly during titration, and every six months during treatment with cholinesterase inhibitors.
• Confusion may be observed during dose titration and is typically transient.
• Take with food to reduce GI upset, and GI effects less prominent with transdermal vs. oral rivastigmine.

N-methyl-d-aspartate (NMDA) receptor antagonist

• Memantine is used as monotherapy or with a cholinesterase inhibitor for moderate to severe AD.
• It is not metabolized, but requires dosing adjustments for patients with renal impairment and is well-tolerated.
• Combination therapy of cholinesterase inhibitors and memantine slow cognitive and functional decline with some GI effects.

Anti amyloid Monoclonal Antibody

• Four humanized, immunoglobulin G1 mAbs have been designated as AD breakthrough therapies by the FDA (ie, aducanumab, lecanemab, donanemab, and gantenerumab).
• Aducanumab was controversially approved for use in MCI due to AD and mild AD.
• The degree and duration of clinical benefit is unclear.
• Dosing for aducanumab, outlined in Tables 53.2 and 53.3, discusses its adverse effect monitoring.
• Aducanumab: MRI at baseline, prior to 7th and 12th infusions, or if symptoms suggest ARIA, to identify brain edema, microhemorrhage, superficial siderosis. Symptoms of headache, confusion, dizziness, visual disturbances, and nausea, angioedema and urticaria.

Other medications for AD

• Estrogen, NSAIDs, prednisone, statins, or Ginkgo biloba not recommended .
• Do not use Ginkgo biloba with anticoagulants/antiplatelets.
• Use Ginkgo biloba cautiously when taking NSAIDs.
• Vitamin E is under investigation for AD prevention.
• There is insufficient evidence to recommend omega-3 fatty acids or medical foods.

Pharmacologic Therapy of Neuropsychiatric Symptoms for AD

• No medications are FDA approved for AD behavioral and psychological symptoms of dementia (BPSD) that are: psychotic, hyperactive, affective, or apathy.
• Reserve medications for when nonpharmacologic interventions have failed.
• Start with reduced doses and titrate slowly with close monitoring.
• Attempt to taper and discontinue medication with careful documentation
• Cholinesterase inhibitors and memantine may benefit BPSD but do not reduce acute agitation.
• Avoid anticholinergic medications.

Antidepressants for AD

• May help manage anxiety, apathy, agitation, and aggression.
• SSRIs (sertraline and citalopram) for depression.
• Tricyclic antidepressants are usually avoided.

Antipsychotics for AD

• Use with caution because the risks and benefits must be weighed.
• Second-generation antipsychotics (aripiprazole, risperidone, olanzapine, and quetiapine) are more effective than placebo, but their higher risks of adverse effects and mortality offset any potential benefit.
• Restrict for patients with severe symptoms not responding to other measures.
• Taper treatment as early as possible and rarely use beyond 12 weeks.
• Common adverse medication reactions: somnolence, extrapyramidal symptoms, abnormal gait, worsening cognition, cerebrovascular events, and increased death risk (black box warning).

Miscellaneous Therapies for AD

• Evidence for benzodiazepine use is lacking and is not advised.
• Antiseizure medications (carbamazepine, lamotrigine, pregabalin, and gabapentin), may be alternatives for agitation, but its evidence is conflicting.
• Valproic acid is not recommended due to severe adverse effects.

Evaluation of Therapeutic Outcomes for AD

• Identify target symptoms during the initial assessment with the patient and caregiver.
• Define therapeutic goals and document cognitive status, physical status, functional performance, mood, thought processes, and behavior.
• Use a validated scale to assess cognition, activities of daily living, and behavioral disturbances to quantify changes.
• Monitor medication efficacy, dosage adjustments, adherence, potential adverse reactions, method, and monitoring frequency.
• Medication changes and adjustments should occur at 2–4 and 8–12 weeks after initiation with assessments every 3–6 months thereafter.
• It could require months to a year of treatment to determine whether medications for cognition are beneficial.
• When to stop treatment due to lack of efficacy is controversial.
• Medication deprescribing for people with AD may be aided by the availability of depot therapy.