Dementia & AD- Miller

What is dementia?

defines the loss of cognitive functioning (thinking, remembering, reasoning) and behavioral abilities that interfere with a person’s daily life and activities

Does mild cognitive impairment (MCI) warrant a dementia diagnosis?

no! not everyone with MCI will develop dementia (about 15% do)

What is vascular dementia (VaD)?

• how to reduce risk?

• treatment?

• refers to any dementia that is primarily caused by cerebrovascular disease or impaired cerebral blood flow

• reduce risk—> antihypertensives, antithrombotic therapy

• treatment—> cholinesterase inhibitors, memantine

What is frontal lobe dementia?

• any current cure?

• neuropathologically and clinically heterogeneous disorder characterized by focal degeneration of the frontal and/or temporal lobes

• no current “cure”—> tx aimed at s/sx relief

What is the most common pathology of dementia and is defined as a gradual progressive dementia?

Alzheimer’s Disease

Early Onset Alzheimer Disease (EOAD) is age < ____.

Late Onset Alzheimer Disease (LOAD) is age ≥____.

EOAD is age <65

LOAD is age ≥65

What is the exact etiology of AD?

• exact is not known!!! several genetic/environmental factors and hypothesizes

Which genes are most strongly associated with Alzheimer's disease risk, and what biological processes do they influence?

• APOE and ABCA7—> most substantial heritable contributor to genetic risk

  • role: lipid metabolism

• TREM2, CLU, and PICALM

  • role: implicated in amyloid plaque formation, tau pathology, neuroinflammation

What are the key genetic mutations associated with dominantly inherited Early-Onset Alzheimer's Disease (EOAD) and Late-Onset Alzheimer’s Disease (LOAD)

• EOAD

  • dom inherited alterations in chromosomes 1,14, 21 that impact amyloid precursor protein (APP)

• LOAD

  • APOE*4 allele (one copy/heterozygous less risk then two copies/homozygous)

What is Apolipoprotein E (APOE)?

• fxn?

• binds to what?

• APOE*4 allele is associated with what?

• Difference between APOE*4, APOE*3, APOE*2?

• APOE—> a fat-soluble transporter

• responsible for transporting cholesterol in the blood/brain and interacts with b-amyloid binds to NFTs

• APOE*4 allele associated with modified clearance and increased deposition of Ab in AD

  • APOE*4- risk factor for EOAD and LOAD

  • APOE*2- lower risk of AD

  • APOE*3- protective effect from AD development

What is one gene that actually reduces the risk of AD/ EOAD development?

A673T (a rare APP mutation)

PRACTICE:
Genetic susceptibility to late-onset AD is primarily linked to which of the following?

a. apolipoprotein E4 genotype

b. presenilin gene mutations

c. amyloid precursor protein mutations

d. apolipoprotein E2 genotype

a.

T/F: the exact pathophysiologic mechanisms of AD are unknown.

true—> there are signature lesions made of amyloid plaques and NFTs in the brain’s cortical areas and medial temporal lobe structures tho

What is the amyloid cascade hypothesis of AD?

• imbalance of what?

• results in?

• what’s unknown about it?

• imbalance between the production and clearance of b-amyloid peptides

  • results in accumulation/aggregation—> plaque formation—> AD development

• unknown if presence of ab is the primary pathology or changes are a marker of an alternate pathology

What are tau proteins?

What are NFTs?

How are NFTs correlated with dementia?

• tau proteins provide structural support (to microtubules)

• NFTs are composed of abnormally hyperphosphorylated tau proteins (microtubules now can’t fxn properly)

• NFT density tends to correlate with severity of dementia

what is one of the most prominent neurotransmitter defects in AD?

cholinergic abnormalities (aka loss of acetyl choline)

What is the cholinergic hypothesis in AD?

BASICALLY—> a theory that loss of cholinergic neurons and neurotransmitter dysfunction (e.g., acetylcholine) contributes to cognitive/memory impairments in AD

What are the main limitations/flaws of the Cholinergic Hypothesis?

• Cholinergic neurons are just one of many pathways damaged in AD.

• cholinergic cell loss is a secondary consequence of AD pathology

What do cholinergic therapies do in AD?

minimize/ improve symptoms

Explain what the inflammatory mediator hypothesis for AD is.

• BASICALLY—>proposes that chronic brain inflammation plays a key role in Alzheimer’s disease

  • β-amyloid has direct neurotoxicity AND triggers an immune response that indirectly damages neurons.

  • Inflammation represents a failed attempt to clear amyloid.

In addition to acetyl choline, what neurotransmitter abnormalities have been seen in AD?

• glutamate

• serotonin

There is a causal association between what disease and incidence of AD?

• CV and vascular disease (ex: high cholesterol, HTN)

  • vascular disease may accelerate amyloid deposition and reduce clearance of amyloid b

With what stage of AD does functioning fluctuate from day to day?

a. mild

b. moderate

c. severe

b.

What are some cognitive symptoms of AD?

• memory loss

• aphasia (impaired communication)

  • circumlocution, anomia

• apraxia (can’t sequence movements)

• agnosia

• disorientation

• impaired executive fxn

What are some functional symptoms of AD?

• inability to care

  • eating, toileting, bathing, dressing

What are some neuropsych symptoms of AD?

• depression

  • hallucinations, delusions

• behavioral disturbances

  • aggression

  • uncooperativeness

  • wander

  • repetitive manners

Screening for AD is done at what age regardless of symptoms?

mini-Cof or MoCA is rec at age 65 regardless of symptoms

What are the 4 screening assessments available for AD?

(idk how imp)

• mini-mental state examination

• montreal cognitive assessment

• mini-cog

• saint louis university mental status exam

What are the 2 categories of biomarkers in AD?

• which is early changing versus late changing?

• what do they help do? diagnose?

FYI: Biomarkers are measurable substances or processes in the body that indicate normal or abnormal conditions

1. Core 1 (early-changing)

   • includes b-amyloid and T1

   • help identify presence of AD

2. Core 2 (later-changing)

   • includes T2 biofluid and tau PET

   • help confirm AD diagnosis

What is the definitive diagnosis for AD?

is a clinical diagnosis!!!! (looks at symptoms, history, cognitive tests, imaging)

What is the goal of pharm therapy in AD?

tx cognitive difficulties symptomatically and preserve pt. function for as long as possible

Current AD treatments ______ seem to prolong life, cure AD, or halt/reverse processes of the disorder.

a. do

b. do not

b.

List all the pharm options for cognitive symptoms of AD:

• just an overview, don’t memorize

• cholinesterase inhibitors

  • Donepezil, Rivastigmine, Galantamine

• NMDA receptor antagonists

  • Memantine

• cholinesterase inhibitor + NMDA receptor antagonist

  • Donepezil + memantine

• anti-amyloid monoclonal antibody (mAb)

  • Donanemab

  • Lecanemab

What is the indication of cholinesterase inhibitors?

1st line for mild-moderate AD

Name the cholinesterase inhibitors:

• donepezil

• rivastigmine

• galantamine

What are the ADRs of cholinesterase inhibitors in general?

• dizzy

• syncope

• bradycardia

• atrial arrhythmias

• sinoatrial and AV block

• MI

• n/v/d

• anorexia

• weight loss

ADRs specific to donepezil?

• peptic ulcer disease

• GI bleeding

• insomnia

• vivid dreams/ nightmares

ADRs and Counseling points with Rivastigmine?

• ADR: allergic dermatitis

• admin: take with food

MOA of each of the following:

• donepezil

• rivastigmine

• galantamine

idk how imp

• donepezil- specifically/reversibly inhibits acetylcholinesterase

• rivastigmine- psuedo-irreversible inhibitor of butyrylcholinesterase and acetylcholinesterase

• galantamine

ADR and counseling points of Galantamine?

• ADR: serious skin reactions

• admin: take with meals

MOA of Memantine:

uncompetitive antagonist of the NMDA glutamate receptor

ADRs and counseling points with Memantine (Namenda)?

• ADRs: HA, confusion, dizzy, hallucinations, constipation

• admin: can take w/ or w/out food, can open capsule and sprinkle contents on applesauce

Combination therapy is done for what kind of AD?

moderate-severe

Namzaric is a combination of what 2 drugs?

donepezil + memantine

What drugs are anti-amyloid monoclonal antibodies used in AD?

• Donanemab

• Lecanemab

What is the main ADRs assoicated with Donanemab and Lecanemab?

• ARIA (amyloid-related imaging abnormalities)

• infusion related rxns

How often is each anti-amyloid mAb dosed?

• Donanemab- q 4 weeks

• Lecanemab- q 2 weeks

Contraindications to taking anti-amyloid mAbs?

homozygous for APOE e4 allele

When is pharm therapy for neuropsychiatric symptoms started?

is tx permanant or temporary?

• when nonpharm has failed!!

• temporary tx

If an antidepressant must be used in AD, what is the DOC? what antidepressant should be AVOIDED?

• SSRIs (sertraline, citalopram) most common used in AD

• AVOID Tricyclic antidepressants (anticholinergic activity)

What is the BBW on antipsychotics?

increased mortality in elderly patients with dementia related psychosis

What antipsychotics can be considered in AD?

• aripriprazole

• risperidone

• olanzapine

• quetiapine

Brexipiprazole is FDA approved for ________________________.

agitation with dementia

Suvorexant is approved in patients with mild-to-moderate AD for what?

insomnia