Demensia Alzheimer

01Pathophysiology

Alzheimer's dementia is a chronic neurodegenerative disease that accounts for 60 to 80% of all dementia cases (PNPK Demensia 2026). It predominantly affects individuals older than 65 years, although early-onset forms (EOAD, onset <65 years) exist and are linked to autosomal dominant mutations in APP (chromosome 21), PSEN1 (chromosome 14, found in 30-70% of familial EOAD), and PSEN2 (chromosome 1, <5% of cases) (PNPK Demensia 2026).

The hallmark pathological features are extracellular neuritic plaques composed of aggregated β-amyloid peptides (Aβ40 and Aβ42) and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein (PNPK Demensia 2026). The "amyloid cascade hypothesis" holds that abnormal cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase generates insoluble Aβ42 fragments, which aggregate into oligomers and then plaques. These plaques provoke a neuroinflammatory response, activate microglia, and drive oxidative stress.

Tau pathology follows a stereotypical regional spread (Braak staging): it begins in the entorhinal cortex and hippocampus (explaining the early episodic memory deficit), then ascends to the temporal, parietal, and frontal neocortex. This spreading correlates more tightly with clinical symptom severity than amyloid burden does. The combined effect of amyloid and tau pathology is progressive synaptic loss, cholinergic neuron degeneration, and cortical atrophy, particularly in the medial temporal lobe.

Understanding why each symptom appears:

Episodic memory loss appears first because the hippocampus and entorhinal cortex, which encode new memories, are the earliest structures damaged. Executive dysfunction and impaired judgment emerge as pathology spreads to the prefrontal cortex. Language difficulties (anomia, word-finding problems) reflect temporal and parietal involvement. Visuospatial deficits arise from parietal lobe damage. Behavioral and psychiatric symptoms (apathy, agitation, depression, psychosis) develop as the disease extends to the frontal cortex and limbic structures. The cholinergic deficit is the pharmacological rationale for acetylcholinesterase inhibitors, while NMDA receptor-mediated excitotoxicity from excess glutamate underpins the use of memantine.

02Classification & Clinical Manifestation

NIA-AA Diagnostic Categories (2011)

NIA-AA Revised Biological Staging (2024)

The 2024 revision redefines AD as a biological continuum rather than purely a clinical syndrome, requiring biomarker confirmation (Aβ + tau via fluid or PET). The PNPK Demensia 2026 incorporates this framework with clinical stages 0 through 6 and parallel fluid/imaging biomarker stages (PNPK Demensia 2026, Table 20-22).

2c. Severity Grading by MMSE

Domain-based Clinical Features (DSM-5 / NIA-AA)

03Diagnostic Workup

Step 1: Clinical assessment. Begin with a thorough history from the patient and a reliable informant. Determine the onset (insidious vs. sudden), trajectory (gradual progressive vs. stepwise), pattern of cognitive domains affected, and presence of behavioral/neuropsychiatric symptoms. Document risk factors as outlined in the PNPK: age, sex, family history, APOE status, education level, vascular risk factors, hearing/vision loss, head trauma, alcohol use, smoking, social isolation, air pollution exposure.

Step 2: Cognitive screening (Best Initial Test). Administer a validated bedside cognitive test. The PNPK Demensia 2026 recommends MoCA-INA (cut-off <24) as superior for detecting Mild Cognitive Impairment, and MMSE (cut-off 23/24) as an accurate screener for established dementia. Both are validated in the Indonesian population. The Clock Drawing Test (CDT) can be added as part of a broader battery. If bedside testing is inconclusive, proceed to full neuropsychological testing (2-3 hours, covering memory, intelligence, psychomotor speed, attention, executive function), which can also differentiate AD from FTD, DLB, VaD, and depression.

Step 3: Exclude reversible causes. Order baseline labs including CBC, electrolytes, glucose, renal/liver function, thyroid function tests, vitamin B12, and folate. The PNPK states these are essential at initial evaluation to identify treatable comorbidities such as hypothyroidism and B12 deficiency that can mimic or worsen dementia. Syphilis testing is not routine unless clinically indicated.

Step 4: Structural neuroimaging. Brain MRI is preferred over CT (Grade C, PNPK Demensia 2026) because of its higher sensitivity for vascular lesions and dementia subtypes. Recommended sequences include volumetric 3D T1 (with coronal reformats for hippocampal volume), FLAIR, T2, SWI, and DWI. Use semi-quantitative scales: the MTA scale for medial temporal atrophy, Fazekas scale for white matter changes, and GCA scale for global cortical atrophy. If only CT is available, order non-contrast with coronal reformats.

Step 5: Biomarker confirmation (Most Accurate/Confirmatory Tests). These are reserved for diagnostic uncertainty, early-onset cases (<65 years), or atypical presentations. CSF analysis demonstrates decreased Aβ42, increased total tau and p-tau, with p-tau181/Aβ42 ratio around 0.03 as the optimal cut-off (AUC ~0.9). FDG-PET and amyloid/tau PET are not recommended for routine diagnosis but are invaluable in ambiguous cases and are required before initiating disease-modifying therapy (e.g., lecanemab).

The test-writer expects you to know: MoCA is better than MMSE for detecting MCI, while both are accurate for detecting established dementia. MRI is preferred over CT. CSF biomarkers and PET are not routine but are the most accurate. The "best initial test" is cognitive screening + MRI; the "most accurate test" is CSF Aβ/tau or amyloid PET combined with clinical criteria.

04Management & Treatment

Acute stabilization: The "acute" scenario in AD is not the disease itself but rather its behavioral complications. When a patient with AD presents with severe agitation, psychosis, or aggression (BPSD), the first-line approach is always non-pharmacological (environmental modification, redirecting, caregiver education). If BPSD persists and non-pharmacological methods fail, brexipiprazole (0.25-0.5 mg/day, titrated to 1-2 mg/day) is the recommended pharmacological option for agitation in AD (PNPK Demensia 2026). Avoid antipsychotics in DLB due to severe neuroleptic sensitivity.

Cognitive therapy, mild-moderate AD: Start with an AChE inhibitor. The PNPK states there is insufficient evidence to prefer one AChEI over another in terms of clinical efficacy (Grade B, Level 1). In practice, donepezil is the most commonly started because of its once-daily dosing and established evidence (ADAS-Cog improvement confirmed across 12 RCTs). If the patient develops GI intolerance (nausea, vomiting, diarrhea), switch to rivastigmine transdermal patch, which causes two-thirds fewer GI side effects. Galantamine is the third alternative. Reassess with psychometric testing at least once every 6 months (PNPK Demensia 2026, Grade C).

Cognitive therapy, moderate-severe AD: Add or switch to memantine 20 mg/day. The PNPK supports donepezil + memantine combination for moderate-severe AD (Grade A, Level 1++). Memantine alone provides modest benefit on the SIB, CIBIC-Plus, and ADL scales but is not recommended for mild AD in isolation.

Disease-modifying therapy: Lecanemab, a monoclonal antibody targeting aggregated β-amyloid, is approved for early AD (MCI or mild dementia) with confirmed amyloid positivity on PET or CSF. APOE genotyping is required before initiation because APOE ε4 homozygotes carry a higher risk of amyloid-related imaging abnormalities (ARIA). Treatment requires access to MRI for monitoring, ICU capability, and specialist expertise in neurology/radiology (PNPK Demensia 2026).

When to discontinue AChEIs: Consider stopping if there is clinically meaningful deterioration over 6 months without other contributing factors, no observable benefit since starting, end-stage dementia, intolerable side effects, or poor adherence (PNPK Demensia 2026). Do not stop AChEIs in patients with active BPSD (agitation, psychosis, aggression) until those symptoms are stabilized.

Non-pharmacological measures: Cognitive stimulation therapy (CST), physical activity (150 minutes/week moderate-intensity aerobic exercise), caregiver education, and control of modifiable vascular risk factors (hypertension, diabetes, dyslipidemia, obesity) are all strongly recommended.

05Differential Diagnosis & Distractors

06Traps & High-Yield Pearls

Trap 1: Confusing AD with depression. The vignette may describe an elderly patient with "memory loss and withdrawal." Students pick depression because mood changes are mentioned. The key is to look for progressive, insidious course with objective cognitive deficit on testing and poor insight. A depressed patient is more likely to say "I can't remember anything" (preserved insight, exaggerated complaints), while an AD patient may deny the problem or minimize it.

Trap 2: Forgetting reversible causes. Before diagnosing AD, the exam expects you to order or acknowledge baseline labs (TSH, B12, metabolic panel) and structural imaging. Jumping directly to "probable AD" without ruling out hypothyroidism or B12 deficiency is a setup wrong answer.

Trap 3: Over-ordering biomarkers. CSF Aβ/tau, amyloid PET, and genetic testing are not routine. APOE genotyping is not recommended routinely for diagnosis (PNPK Demensia 2026, Grade B). It is recommended only before DMT initiation (lecanemab) for safety. The exam penalizes ordering PET or CSF when the clinical picture and MRI already establish the diagnosis.

Trap 4: Not knowing which drug goes with which stage. AChEIs are for mild-moderate. Memantine is for moderate-severe (or as an alternative when AChEI is contraindicated in mild-moderate). Lecanemab is for early AD only (MCI or mild, amyloid-confirmed). Brexipiprazole is only for AD-associated agitation and should not be used in DLB, VaD, or FTD.

Trap 5: Misinterpreting the "1-year rule." If the vignette gives a patient with parkinsonism who develops dementia within a year, that is DLB, not PDD. PDD requires at least one year of established PD before the cognitive decline begins.