Table 1 Comparison between CHIP and described genetic variants associated with AD protection

Genetic loci

24 identified loci and at least 57 independently associated variants. Some of the frequently affected genes include: DNMT3A, TET2, ASXL1, TP53³⁰.

19q13.32 locus³¹.

APOE ε3 variant (R136S)³²

RELN (H3447R) variant (7q22.1)³.

Protective association to AD

OR = 0.64 (p = 3.8 × 10⁻⁵). Supported by Mendelian randomization analyses⁵.

ε2 allele is associated to AD protection, ε3 is neutral to AD development, and ε4 is associated to increased risk for AD³³.

Protection depends on zygosity, with homozygote ε2/ε2 having the highest protection.

Homozygote ε2/ε2 compared to homozygote ε3/ε3 (most common variant): OR 0.13 (CI = 0.05–0.36)

Heterozygote ε2/ε3 compared to ε3/ε3: OR 0.39 (CI = 0.30–0.50)⁴.

Amongst carriers of the PSEN1^E280A genetic variant (highly penetrant autosomal dominant presentation of AD) heterozygous APOE3^Ch patients had a median age of onset of cognitive impairment of 52 years compared to 47 years in patients without the APOE3^Ch allele³².

A case report identified an individual with PSEN1^E280A mutation and APOE3^Ch homozygosity with onset of cognitive impairment in her seventies².

Case report of a man with PSEN1^E280A mutation who remained cognitively intact until age 67³.

Risk associations

Malignancies, cardiovascular disease, infection, all-cause mortality³⁰.

2024 cohort study found an increased risk of vascular neurodegenerative diseases and amyotrophic lateral sclerosis³⁴.

ε2/ε2: peripheral vascular disease, thromboembolism, arterial aneurysm, peptic ulcer, cervical disorders, hallux valgus.

ε3ε4 and ε4ε4: AD, hypercholesterolaemia, ischemic heart disease³⁵.

Familial dysbetalipoproteinemia which is associated with early onset atherosclerosis and heart disease³⁶.

Potential risks of the RELN-COLBOS variant are not fully understood and require further research.

Prevalence

10–30% in individuals over age 50^10,11. Prevalence increases with age³⁷.

ε2 is the rarest APOE allele with a prevalence of 8–10%, followed by ε4 with 15–20% and ε3 with 70%³⁸.

The ε2/ε2 genotype is the rarest in the general population with an estimated prevalence of under 2%^39,40.

Rare variant with a frequency of 0.000013 in the gnomAD variant database³⁶.

Frequency of 0.0001333 in admixed Americans³⁶.

Biological and molecular mechanisms associated to protection

Enrichment of microglia (myeloid lineage) with CHIP-associated variants⁵.

Apparent migration and influx of peripheral myeloid cells into the brain parenchyma which compensates for age-associated microglial dysfunction⁵.

APOE2 is less effective at binding to low-density lipoprotein receptors, which may enhance amyloid-beta clearance and reduce neurodegeneration linked to lipid accumulation⁴¹.

This isoform of APOE also enhances the rate of phagocytosis of synapses by astrocytes compared to the ε4 isoform⁴².

Reduction in plaque-associated tau pathology, decreased amyloid response, enhanced microglial response around plaques, reduced neuroinflammation⁴³.

Gain of function mutation that enhances the activation of its target (Dab1) and reduces Tau phosphorylation⁴⁴.