Which of the following is a risk factor for Alzheimer’s disease?

Correct Answer: A. Apo E4

Apolipoprotein E4 (ApoE4) is the most significant genetic risk factor for late-onset Alzheimer's disease (LOAD), which accounts for >95% of AD cases in the Indian population. The ApoE gene exists in three allelic forms (ε2, ε3, ε4), and inheritance of the ε4 allele dramatically increases AD risk in a dose-dependent manner: heterozygotes (ε3/ε4) have 3–4× increased risk, while homozygotes (ε4/ε4) have 8–10× increased risk compared to ε3/ε3 carriers. The pathophysiological mechanism involves ApoE4's impaired ability to clear amyloid-β (Aβ) from the brain and promote tau pathology. ApoE4 is also associated with increased neuroinflammation and reduced synaptic plasticity. Unlike early-onset familial AD (caused by mutations in APP, PSEN1, PSEN2), ApoE4 is not deterministic—it is a susceptibility gene, meaning carriers may never develop clinical dementia. However, among all modifiable and non-modifiable risk factors for AD in Indian populations (age, family history, hypertension, diabetes, cognitive reserve), ApoE4 genotype remains the strongest genetic predictor. This is why ApoE4 screening is increasingly recommended in memory clinics across India for risk stratification and counseling.

Why the other options are wrong

B. Apo E1 — ApoE1 does not exist as a natural allelic variant. The ApoE gene has only three functional alleles (ε2, ε3, ε4) defined by two SNPs at codons 112 and 158. This is a distractor designed to test whether students know the actual genetic nomenclature of ApoE variants. Inventing a non-existent allele is a classic NBE trap. C. Apo E3 — ApoE3 is the most common allele (frequency ~60% globally) and is considered the 'wild-type' or neutral reference. It confers neither increased nor decreased risk for Alzheimer's disease. Homozygotes (ε3/ε3) have baseline population risk. Students may confuse 'most common' with 'most protective,' leading to this error. D. Apo E2 — ApoE2 is actually protective against Alzheimer's disease, with ε2 carriers showing reduced AD risk compared to ε3/ε3 individuals. This is the opposite of ApoE4. The ε2 allele is associated with better Aβ clearance and lower neuroinflammation. Selecting this option reflects confusion about the protective vs. risk alleles.

High-Yield Facts

Mnemonics

ApoE Risk Ladder ε2 (Protected) < ε3 (Neutral) < ε4 (Risk). Remember: 2 is too good, 3 is just right, 4 is a fright. Use when comparing ApoE allele effects on AD risk. ApoE4 Pathology: BRAIN Bad Aβ clearance, Reduced synaptic plasticity, Amplified neuroinflammation, Increased tau pathology, Neurodegeneration. Recall the mechanism of ApoE4-mediated AD risk.

NBE Trap

NBE pairs ApoE4 with "risk factor" to lure students who confuse it with the protective ε2 allele or who think the most common allele (ε3) must be the most important. The inclusion of a non-existent "ApoE1" option tests whether students know the actual genetic nomenclature of ApoE variants.

Clinical Pearl

In Indian memory clinics, ApoE4 genotyping is increasingly used for risk stratification in cognitively normal older adults and those with mild cognitive impairment. A positive ApoE4 status prompts aggressive management of modifiable risk factors (hypertension, diabetes, cognitive engagement) and counseling about lifestyle interventions—critical in resource-limited Indian settings where disease-modifying therapies remain expensive and inaccessible.

_Reference: Robbins and Cotran Pathologic Basis of Disease, Ch. 28 (Central Nervous System); Harrison's Principles of Internal Medicine, Ch. 442 (Alzheimer's Disease and Other Dementias)_