60.1 Dementia: Alzheimer's, Vascular & Lewy Body Disease

Diagnostic Framework: Major Neurocognitive Disorder vs. Mild Cognitive Impairment

Cognitive impairment in older adults represents one of the most common and challenging clinical scenarios encountered in family medicine. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) categorizes progressive cognitive decline under the umbrella of Neurocognitive Disorders (NCD), establishing clear operational distinctions between normal age-related cognitive decline, Mild Neurocognitive Disorder (Mild Cognitive Impairment [MCI]), and Major Neurocognitive Disorder (Dementia).

                     DSM-5 NEUROCOGNITIVE DISORDER CRITERIA

   Diagnostic Category       Cognitive Assessment Findings                Impact on Daily Function (IADLs/ADLs)
   ═════════════════════════════════════════════════════════════════════════════════════════════════════════════
   Age-Associated            Subjective complaints; objective testing     Preserved; independent in all activities;
   Cognitive Decline         within 1 standard deviation of age-matched   no compensatory strategies needed.
                             norms; preserved processing.
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────
   Mild Neurocognitive       Objective impairment (1.0 to 2.0 standard    INDEPENDENCE PRESERVED; complex IADLs
   Disorder (MCI)            deviations below norm) in >= 1 cognitive     maintained, though may require greater effort,
                             domain on formal testing.                    compensatory strategies, or accommodation.
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────
   Major Neurocognitive      Significant cognitive decline (> 2.0         LOSS OF INDEPENDENCE; cognitive deficits
   Disorder (Dementia)       standard deviations below norm) in >= 1      interfere directly with independence in
                             cognitive domain.                            everyday activities (requires assistance with IADLs/ADLs).
   ═════════════════════════════════════════════════════════════════════════════════════════════════════════════

The Six Core Cognitive Domains

Accurate syndromic characterization requires evaluating performance across the six neurocognitive domains delineated by the DSM-5:

1. Complex Attention: Sustained attention, divided attention, selective attention, and processing speed. Manifests clinically as difficulty with multi-step tasks, easy distractibility, or inability to perform mental calculations.
2. Executive Function: Planning, decision-making, working memory, cognitive flexibility, abstract reasoning, and overriding habitual responses. Manifests as inability to manage complex finances, difficulty planning a meal, or struggling to adapt to schedule changes.
3. Learning and Memory: Immediate memory, recent/episodic declarative memory (free recall, cued recall, recognition memory), and long-term semantic memory. Manifests as repeating questions within minutes, losing track of personal possessions, or forgetting recent family events.
4. Language: Expressive language (naming, word finding, fluency, grammar) and receptive language (comprehension). Manifests as word-finding pauses ("tip-of-the-tongue"), circumlocution, paraphasic errors, or difficulty comprehending multi-clause sentences.
5. Perceptual-Motor: Visuoconstructional ability, visual perception, praxis (performing purposeful learned movements), and gnosis (recognizing objects or faces). Manifests as getting lost in familiar neighborhoods, inability to use common household tools (apraxia), or failing to recognize familiar faces (prosopagnosia).
6. Social Cognition: Recognition of emotions, theory of mind (empathy), and behavioral regulation in social contexts. Manifests as social disinhibition, inappropriate remarks, apathy, insensitivity to social cues, or dramatic loss of empathy.

Functional Assessment: IADLs vs. ADLs

The pivotal boundary separating MCI from dementia is the preservation of functional independence:

• Instrumental Activities of Daily Living (IADLs): Complex multi-step activities required to live independently in the community. These are impaired early in dementia: managing medications, handling finances and bills, driving, navigating public transit, meal preparation, shopping, housekeeping, and telephone use.
• Basic Activities of Daily Living (ADLs): Fundamental self-care tasks that are typically preserved until intermediate-to-advanced stages: bathing, dressing, toileting, transferring/ambulation, continence, and feeding.

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Formal Cognitive Screening & Reversible Etiology Workup

Every patient presenting with cognitive concerns requires a structured, multi-modal clinical evaluation to establish objective deficits and systematically rule out potentially reversible or treatable secondary causes.

                  COMPARATIVE ANALYSIS OF COGNITIVE SCREENING TOOLS

   Screening Tool       Scale    Threshold   Administration Time   Strengths & High-Yield ABFM Pearls
   ═════════════════════════════════════════════════════════════════════════════════════════════════════════════
   Montreal Cognitive   0-30     < 26 / 30   10 - 12 minutes       • HIGH SENSITIVITY (90%) for MCI and early dementia.
   Assessment (MoCA)                                               • Rigorous testing of executive function (trail making,
                                                                     phonemic fluency) and visuospatial processing.
                                                                   • Superior tool for Vascular Dementia and Parkinson's.
                                                                   • Add +1 point for individuals with <= 12 years education.
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────
   Mini-Mental State    0-30     < 24 / 30   8 - 10 minutes        • Heavily weighted toward language and orientation.
   Examination (MMSE)                                              • POOR SENSITIVITY for MCI and executive dysfunction.
                                                                   • High false-negative rate in highly educated individuals.
                                                                   • Significant ceiling effect; proprietary copyright fees.
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────
   Mini-Cog             0-5      < 3 / 5     3 - 5 minutes         • Combines 3-word recall (0-3 points) with an unprompted
                                 indicates                           clock drawing test (CDT; 0 or 2 points).
                                 impairment                        • Abnormal clock (wrong numbers/hands) = immediate 0 pts.
                                                                   • Rapid, highly specific, language/education resilient.
   ═════════════════════════════════════════════════════════════════════════════════════════════════════════════

Laboratory Screening for Reversible Causes

Although truly reversible dementias account for <5% of cases, identifying and treating secondary metabolic or endocrine derangements can substantially improve baseline cognition and slow functional decline. The American Academy of Neurology (AAN) and American College of Physicians (ACP) mandate:

• Serum Thyroid-Stimulating Hormone (TSH): Exclude overt or severe subclinical hypothyroidism (elevated TSH, depressed free T4), which causes psychomotor slowing, apathy, depression, and reversible executive dysfunction.
• Serum Vitamin B12 (Cobalamin): Deficiency causes subacute combined degeneration of the spinal cord (posterior and lateral column loss) and megaloblastic madness (neuropsychiatric disturbance, sensory ataxia, memory loss).
  • Clinical Pearl: If serum B12 is borderline (200-400 pg/mL), reflexively check serum methylmalonic acid (MMA) and homocysteine. Elevated MMA confirms true cellular cobalamin deficiency even with a normal peripheral blood count.
• Comprehensive Metabolic Panel (CMP): Evaluates serum sodium (hyponatremia causing lethargy/confusion), serum calcium (hypercalcemia causing delirium and encephalopathy), blood urea nitrogen and creatinine (uremia), and hepatic function tests (hepatic encephalopathy).
• Complete Blood Count (CBC): Identifies occult anemia, leukopenia, or infectious processes.
• Selective Diagnostic Testing: Indicated based on individual clinical risk factors:
  • Rapid Plasma Reagin (RPR) or VDRL: Screen for neurosyphilis in patients with Argyll Robertson pupils, tabetic gait, or unexplained behavioral changes.
  • HIV 1/2 Antigen/Antibody: Recommended in high-risk individuals or patients presenting with rapid subcortical cognitive decline under 60 years of age.
  • Serum Folate: Checked concurrently with B12 in malnourished or alcohol-dependent individuals.
  • Urine Toxicology Screen & Medication Reconciliation: Review for anticholinergic burden (diphenhydramine, tricyclic antidepressants, oxybutynin), benzodiazepines, and sedative-hypnotics.

Structural Neuroimaging: Head CT vs. Brain MRI

Guidelines mandate baseline structural neuroimaging with non-contrast Head CT or Brain MRI (without IV contrast) for any newly suspected cognitive impairment to exclude structural lesions:

1. Chronic Subdural Hematoma (SDH): Bridging cortical vein tears in elderly individuals with cerebral atrophy; can present with insidious fluctuating confusion following minor forgotten trauma.
2. Intracranial Neoplasms: Primary brain tumors (e.g., glioblastoma, frontal meningioma) or metastatic lesions.
3. Cerebrovascular Disease: Silent cortical or subcortical lacunar infarctions, territorial infarcts, or strategic thalamic strokes.
4. Normal Pressure Hydrocephalus (NPH): A treatable communicating hydrocephalus characterized by the pathognomonic clinical triad:
   • "Wet": Urinary urgency progressing to urge incontinence due to loss of frontal cortical inhibition of the detrusor.
   • "Wacky": Subcortical cognitive impairment, apathy, psychomotor slowing, and impaired attention.
   • "Wobbly": Prominent magnetic, apraxic, broad-based, shuffling gait (feet appear "glued to the floor", short stride length, en bloc turning, preserved arm swing).
   • Neuroimaging Hallmark: Markedly enlarged lateral and third ventricles out of proportion to cortical sulcal enlargement (Evans Index > 0.30, defined as the maximal width of the frontal horns divided by the maximal internal diameter of the skull).
   • Diagnostic & Therapeutic Intervention: High-volume lumbar puncture (Fisher tap test) removing 30 to 50 mL of CSF; documentation of significant objective gait improvement (speed, stride length) 30-60 minutes post-tap confirms diagnosis and predicts excellent long-term response to ventriculoperitoneal (VP) shunting.

[!IMPORTANT] THE NPH GAIT HALLMARK In Normal Pressure Hydrocephalus, the gait disturbance is almost invariably the earliest, most prominent, and most shunt-responsive symptom. Dementia presenting prior to gait difficulty or urinary incontinence strongly argues against NPH and points to Alzheimer disease or Lewy body dementia with secondary ex vacuo ventriculomegaly (ventricular enlargement purely secondary to underlying parenchymal atrophy).

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Differential Diagnosis of Primary Dementia Syndromes

The vast majority of progressive neurocognitive disorders represent primary neurodegenerative or cerebrovascular conditions. Differentiating these syndromes is critical for disease-specific management, prognostic counseling, and the avoidance of fatal pharmacotherapy errors.

                    PRIMARY DEMENTIA SYNDROMES: CLINICAL & PATHOLOGICAL COMPARISON

   Feature          Alzheimer Disease (AD)        Vascular Dementia (VaD)        Dementia with Lewy Bodies (DLB)  Frontotemporal Dementia (FTD)
   ═════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════
   Epidemiology     Most common (60% - 70%)       Second most common (15% - 20%) Third most common (10% - 15%)    Onset younger (45 - 65y);
                    Prevalence doubles q5y >65y   Associated with HTN, DM, CAD   Male predominance                Strong genetic link (~40%)
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
   Neuropathology   Extracellular Amyloid-Beta    Subcortical arteriolosclerosis Intracellular Lewy bodies        Frontotemporal lobar
                    (Aβ42) neuritic plaques;      lacunar infarcts; ischemic     (alpha-synuclein inclusions)     degeneration (tau inclusions
                    hyperphosphorylated tau       demyelination of white matter  in basal ganglia, limbic, and    or TDP-43 inclusions)
                    neurofibrillary tangles       (leukoaraiosis)                cortical neurons
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
   Clinical Course  Insidious onset, gradual      Stepwise deterioration or      Fluctuating alertness and        Insidious onset, rapid progression;
                    relentless linear decline     fluctuating decline tied to    attention; episodic delirium-like early personality/behavioral
                                                  cerebrovascular events         lucid vs confused intervals      change; memory preserved early
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
   Signature        Early episodic declarative    Early executive dysfunction,   1) Fluctuating cognition         1) Behavioral: disinhibition,
   Features         memory loss, impaired         psychomotor slowing, apathy,   2) Detailed visual hallucinations apathy, hyperorality, loss of empathy
                    delayed free recall, word-    focal motor/sensory deficits,  3) REM Sleep Behavior Disorder   2) Language: primary progressive
                    finding pauses, disorientation pseudobulbar affect            4) Spontaneous parkinsonism      aphasia (PPA)
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
   Neuroimaging     Medial temporal lobe and      Multiple lacunar infarcts,     Generalized cortical atrophy;    Circumscribed frontal and/or
                    bilateral hippocampal         extensive confluent periven-   preservation of medial temporal  anterior temporal lobar atrophy
                    atrophy on coronal T1 MRI     tricular white matter disease  lobes on structural MRI          ("knife-edge" gyral atrophy)
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
   Pharmacotherapy  ChEIs (Donepezil,             Intensive vascular risk-factor Cholinesterase inhibitors;       SSRIs/trazodone for agitation;
                    Rivastigmine), Memantine,     modification (statin, BP,      DO NOT USE TYPICAL               CHOLINESTERASE INHIBITORS
                    anti-amyloid monoclonal Abs   antiplatelet); symptomatic ChEIs ANTIPSYCHOTICS (Lethal!)       ARE INEFFECTIVE/WORSEN BEHAVIOR
   ═════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════

1. Alzheimer Disease (AD)

Alzheimer disease represents 60% to 70% of all dementias. The neuropathological hallmarks consist of:

• Amyloid-Beta 42 (Aβ42) Plaques: Extracellular senile plaques composed of insoluble cleaved amyloid precursor protein fragments.
• Neurofibrillary Tangles (NFTs): Intracellular aggregates of hyperphosphorylated tau protein, a microtubule-stabilizing protein. Tau density correlates closely with clinical cognitive decline.
• Clinical Progression: Onset is insidious. The earliest and most prominent deficit is the loss of recent episodic declarative memory (rapid forgetting of recently acquired information, failure to retain delayed recall lists even with cueing), due to initial synaptic destruction in the entorhinal cortex and hippocampi. Remote autobiographical memory and procedural memory remain intact until late stages. As pathology spreads across the association cortices, patients develop anomic aphasia, visuospatial disorientation, executive impairment, and apraxia.
• Neuroimaging: High-resolution coronal T1-weighted Brain MRI demonstrates symmetrical or asymmetrical atrophy of the hippocampi, parahippocampal gyri, and medial temporal lobes, accompanied by compensatory enlargement of the temporal horns.

2. Vascular Dementia (VaD)

Vascular dementia (Vascular Neurocognitive Disorder) arises from ischemic or hemorrhagic brain injury:

• Mechanisms: Large-vessel territorial strokes, multiple small-vessel subcortical lacunar infarctions, or extensive chronic microvascular ischemia causing demyelination of periventricular white matter (Binswanger disease / arteriolosclerotic leukoaraiosis).
• Clinical Profile: The classic trajectory is a stepwise or abrupt decline, where each drop in functional status corresponds to a discrete clinical or subclinical cerebrovascular event. Unlike Alzheimer disease, memory impairment is not necessarily the presenting feature. Instead, patients exhibit early, profound executive dysfunction (inability to sequence, organize, or plan), marked psychomotor slowing, apathy, emotional lability (pseudobulbar affect), and focal neurological signs (unilateral hyperreflexia, asymmetric pronator drift, Babinski sign).
• Management: Aggressive secondary cardiovascular risk reduction—intensive blood pressure control (<130/80 mmHg), high-intensity statin therapy, antiplatelet therapy (aspirin or clopidogrel), and glycemic control. Cholinesterase inhibitors offer modest symptomatic benefit for concurrent subcortical cholinergic deafferentation.

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Dementia with Lewy Bodies & Antipsychotic Hypersensitivity

Dementia with Lewy Bodies (DLB) is the third most common cause of neurodegenerative dementia. Pathologically, it is characterized by the widespread cortical, limbic, and brainstem accumulation of alpha-synuclein cytoplasmic inclusions (Lewy bodies).

Core Clinical Criteria

Under the 2017 DLB Consortium diagnostic criteria, a diagnosis of probable DLB requires dementia plus at least two of the following four core clinical features (or one core feature plus one indicative biomarker):

1. Fluctuating Cognition with Pronounced Variations in Attention and Alertness: Patients experience unpredictable, episodic oscillations between lucid coherence and profound confusion, unresponsiveness, or excessive daytime somnolence (staring off into space for long intervals).
2. Recurrent, Well-Formed, Detailed Visual Hallucinations: Present in up to 80% of patients. Hallucinations are characteristically vivid, realistic, and animate (e.g., fully formed children, small animals, deceased relatives, or figures standing silently in the room). They are often emotionally neutral or curious, rather than threatening early in the disease.
3. REM Sleep Behavior Disorder (RBD): Loss of the normal muscle atonia that accompanies rapid eye movement (REM) sleep. Patients physically act out their dreams (thrashing, punching, kicking, yelling, or leaping from bed), frequently causing physical injury to themselves or their bed partners. RBD often precedes the onset of cognitive or motor signs by 5 to 20 years.
4. Spontaneous Motor Parkinsonism: Bradykinesia, resting tremor, cogwheel rigidity, and postural instability. Unlike idiopathic Parkinson disease, the parkinsonism in DLB is typically symmetrical at onset, has less prominent resting tremor, and features more pronounced early gait instability.

The "One-Year Rule"

The chronological relationship between cognitive decline and motor parkinsonism distinguishes DLB from Parkinson's Disease Dementia (PDD):

• Dementia with Lewy Bodies (DLB): Cognitive impairment precedes, develops concurrently with, or appears within 12 months of the onset of motor parkinsonian symptoms.
• Parkinson's Disease Dementia (PDD): Motor Parkinson's disease is well-established for greater than 1 year (typically many years) before the emergence of significant dementia.

                  THE "1-YEAR RULE" IN ALPHA-SYNUCLEINOPATHIES

   Onset of Parkinsonism                     1 Year Mark                        Clinical Diagnosis
   ─────────────────────────────────────────────────────────────────────────────────────────────
   Dementia occurs BEFORE or WITHIN 1 year of motor parkinsonism ---------> Dementia with Lewy Bodies (DLB)
   
   Motor Parkinsonism established for > 1 year BEFORE dementia develops --> Parkinson's Disease Dementia (PDD)

[!WARNING] CRITICAL PRESCRIBING WARNING: EXTREME ANTIPSYCHOTIC HYPERSENSITIVITY Up to 50% of patients with DLB exhibit catastrophic, potentially lethal antipsychotic hypersensitivity when exposed to D2 dopamine receptor antagonists. Administration of first-generation antipsychotics (e.g., Haloperidol, Fluphenazine) or potent second-generation antipsychotics (e.g., Risperidone, Olanzapine) can trigger acute, severe, irreversible worsening of parkinsonian rigidity, autonomic instability, profound sedation, severe neuroleptic malignant syndrome (NMS), and sudden cardiovascular collapse or death (2- to 3-fold increased mortality).

Safe Prescribing Strategy:

1. Maximize non-pharmacologic calming and validation strategies; do not treat benign, non-distressing hallucinations.
2. Optimize Cholinesterase Inhibitors (Donepezil or Rivastigmine), which frequently reduce visual hallucinations and improve alertness by replenishing cortical acetylcholine.
3. If pharmacotherapy for dangerous or severely distressing psychosis is unavoidable, use lowest-dose Quetiapine (12.5 to 25 mg at bedtime) or Pimavanserin (34 mg daily). Pimavanserin is a selective 5-HT2A inverse agonist / antagonist with ZERO dopamine D2 receptor affinity, providing antipsychotic efficacy without worsening motor parkinsonism.

Frontotemporal Lobar Degeneration (FTD / Pick Disease)

Frontotemporal dementia (FTD) represents a spectrum of non-Alzheimer dementias characterized by progressive neurodegeneration localized to the frontal and anterior temporal lobes. FTD is the leading cause of presenile dementia, with a typical age of onset between 45 and 65 years. Approximately 40% of patients report a positive family history, associated with autosomal dominant mutations in C9orf72 (hexanucleotide repeat expansion, also causing ALS), MAPT (tau), or GRN (progranulin).

Clinical Syndromic Variants

1. Behavioral Variant FTD (bvFTD): The most frequent phenotype, marked by early, dramatic disintegration of personality and interpersonal conduct, while episodic memory and visuospatial orientation remain strikingly intact:
   • Early Disinhibition: Inappropriate sexual comments, shoplifting, public urination, reckless financial spending, or offensive jokes (Witzelsucht).
   • Apathy and Inertia: Loss of initiation, emotional flatness, and withdrawal from hobbies and vocational responsibilities.
   • Loss of Empathy / Sympathy: Complete coldness toward family members, lack of remorse, and inability to read emotional distress in others.
   • Hyperorality & Dietary Changes: Binging on sweets and carbohydrates, cramming excessive food into the mouth, or consuming non-food items.
   • Perseverative / Compulsive Behaviors: Motor stereotypies, pacing, tapping, counting, rigid daily rituals, or hoarding.
   • Loss of Executive Insight: Complete lack of awareness regarding the inappropriate nature of their behavior (anosodiaphoria).
2. Language Variants (Primary Progressive Aphasia [PPA]):
   • Non-Fluent / Agrammatic Variant: Effortful, halting speech, telegraphic syntax, and sound errors, with preserved single-word comprehension.
   • Semantic Variant: Fluent, empty speech with profound loss of word meaning (semantic memory loss) and associative object agnosia (e.g., patient asks, "What is an apple?").

Diagnostic Hallmarks & Medication Contraindications

• Neuroimaging: Brain MRI or CT shows dramatic, circumscribed frontal and anterior temporal lobar atrophy, classically producing a paper-thin, "knife-edge" appearance of the gyri with enlarged frontal horn subarachnoid spaces.
• Medication Warning: Cholinesterase inhibitors (Donepezil, Rivastigmine) and Memantine are ineffective in FTD and frequently exacerbate agitation, disinhibition, and behavioral dysregulation. Pharmacotherapy relies on SSRIs (e.g., Sertraline, Citalopram) or Trazodone to modulate compulsions and irritability.

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Evidence-Based Pharmacotherapy for Dementia

While current pharmacotherapies do not reverse existing neuronal destruction, disease-modifying and symptomatic medications can decelerate functional decline and stabilize cognitive performance.

                  EVIDENCE-BASED PHARMACOTHERAPY FOR ALZHEIMER DISEASE

   Drug Class & Agent        Approved Stages           Target Dosages & Titration         Adverse Effects & Clinical Pearls
   ═════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════
   Cholinesterase Inhibitor  Mild, Moderate,           Start 5 mg daily PO at bedtime;    • Cholinergic: nausea, vomiting, diarrhea,
   • Donepezil (Aricept)     and Severe AD             titrate to 10 mg daily after         anorexia, weight loss, vivid dreams (shift to AM).
                                                       4 to 6 weeks.                      • CARDIOVASCULAR: Bradycardia, QT prolongation,
                                                                                            syncope, heart block; check baseline ECG!
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
   Cholinesterase Inhibitor  Mild to Moderate AD       Capsule: 1.5 mg BID, titrate       • Higher oral GI toxicity than donepezil.
   • Rivastigmine (Exelon)   (Oral); Mild, Moderate,   to max 6 mg BID; Transdermal       • TRANSDERMAL PATCH bypasses first-pass hepatic
                             and Severe AD (Patch)     patch: 4.6 mg/24h, titrate to        metabolism, drastically reducing GI adverse
                                                       9.5 mg/24h and max 13.3 mg/24h.      effects; rotate patch sites daily.
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
   Cholinesterase Inhibitor  Mild to Moderate AD       IR: 4 mg BID up to 12 mg BID;      • GI intolerance; caution with CYP2D6/3A4
   • Galantamine (Razadyne)                            ER: 8 mg daily, titrate to           inhibitors; avoid in severe renal/hepatic failure.
                                                       16 mg and max 24 mg daily.
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
   NMDA Receptor Antagonist  Moderate to Severe AD     Start 5 mg daily PO; titrate by    • Modulates glutamate excitotoxicity;
   • Memantine (Namenda)     (MMSE < 20 or             5 mg weekly to target dose of        preserves physiologic synaptic transmission.
                             MoCA < 15)                10 mg BID (or 28 mg ER daily).     • Well tolerated; dizziness, confusion, headache,
                                                                                            constipation; dose reduce in severe renal disease.
   ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
   Anti-Amyloid Monoclonal   Early AD (MCI due to AD   Lecanemab: 10 mg/kg IV q2 weeks;   • Clears amyloid-beta protofibrils and plaques.
   Antibodies                or Mild AD with positive  Donanemab: 700 mg IV q4w x3 doses, • REQUIRES SERIAL MONITORING FOR ARIA
   • Lecanemab (Leqembi)     amyloid biomarkers)       then 1400 mg IV q4 weeks.            (ARIA-E edema, ARIA-H microhemorrhage).
   • Donanemab (Kisunla)                                                                  • Check APOE ε4 genotype (homozygotes high risk).
   ═════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════════

Cholinesterase Inhibitors (ChEIs)

• Mechanism: Reversibly inhibit acetylcholinesterase, increasing synaptic acetylcholine availability in the neocortex and hippocampus.
• Indications: Donepezil is approved across all stages (mild, moderate, severe AD). Rivastigmine patch is approved for all stages of AD and mild-to-moderate Parkinson's disease dementia.
• Cardiovascular Red Flag: Increased vagal tone induces sinus bradycardia, sinoatrial block, and atrioventricular block. Any patient taking a ChEI who presents with dizziness, lightheadedness, falls, or syncope must be evaluated for medication-induced bradycardia and conduction blocks; discontinue ChEI immediately.

NMDA Receptor Antagonist (Memantine)

• Mechanism: Uncompetitive, low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist. Pathologic chronic glutamate hyperactivation triggers sustained calcium influx into postsynaptic neurons, leading to excitotoxic cell death. Memantine blocks this tonic pathological noise while allowing normal physiological bursts of glutamate transmission required for learning.
• Clinical Combination: Indicated for moderate-to-severe AD. When added to a cholinesterase inhibitor (e.g., Donepezil + Memantine), it provides synergistic slowing of clinical decline and behavioral stabilization compared to ChEI monotherapy.

Anti-Amyloid Monoclonal Antibodies (Lecanemab & Donanemab)

• Indications: FDA-approved for confirmed Early Alzheimer Disease (Mild Cognitive Impairment due to AD or Mild Alzheimer Dementia) with documented brain amyloid pathology (positive amyloid PET scan or CSF biomarkers showing low Aβ42 and elevated phosphorylated tau).
• Amyloid-Related Imaging Abnormalities (ARIA):
  • ARIA-E (Edema): Vasogenic edema and sulcal effusions resulting from increased vascular permeability during amyloid plaque clearance from cerebral blood vessel walls.
  • ARIA-H (Hemorrhage): Cerebral microhemorrhages, cortical superficial siderosis, and macrohemorrhages.
  • Safety Protocol: Strict pre-treatment APOE genotyping is required; patients carrying two APOE ε4 alleles (homozygotes) carry an exponentially higher risk of ARIA and intracerebral hemorrhage. Serial brain MRIs are legally mandated before initiating therapy and prior to the 5th, 7th, and 14th infusions. If moderate-to-severe ARIA-E or significant ARIA-H occurs, dosing must be suspended or discontinued.

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Advance Care Planning, Driving Safety & Caregiver Support

Driving Safety Assessment

Driving is a complex instrumental activity of daily living requiring divided attention, rapid visual processing, executive reaction speed, and visuospatial judgment:

• Patients with moderate-to-severe dementia must not drive under any circumstances.
• Patients with mild dementia or MCI warrant structured evaluation: query family regarding minor collisions, new vehicle dents, getting lost while driving familiar routes, or traffic citations.
• Cognitive Benchmarks: A MoCA score <18/30 correlates strongly with driving impairment and failure on road evaluations. Formal, objective, behind-the-wheel testing through a certified driver rehabilitation specialist represents the gold standard for borderline cases.
• Primary care clinicians must know their specific state reporting statutes (mandatory reporting vs. discretionary reporting with immunity).

Advance Care Planning

Discussions regarding durable power of attorney for healthcare (DPOA), living wills, financial power of attorney, and preferred goals of care (POLST/MOLST) must be initiated early in the disease course while the patient retains legal decision-making capacity.

Caregiver Burnout & Respite Care

Caregivers of individuals with dementia experience elevated rates of major depression, anxiety, physical morbidity, and premature mortality. Clinicians should routinely screen caregivers using validated instruments such as the Zarit Burden Interview (ZBI), actively recommend local Alzheimer's Association support groups, and connect families with adult day health programs and temporary respite care.