Protective genetic variants against Alzheimer's disease

Protective gene variants like APOE3 Christchurch may delay Alzheimer’s onset. What does this mean for clinical practice?

Genetic variants that protect the brain in Alzheimer's disease

Genetic resilience to Alzheimer's refers to genetic variants that can protect against or delay the onset of the disease, even in the presence of genetic or environmental risk factors. These variants act as “natural allies” of the brain, enhancing protective mechanisms and neuronal repair.

While most research has focused on genetic risk factors, recent findings have redirected attention toward protective variants that confer resilience to Alzheimer’s disease (AD). Among them, APOE3 Christchurch (APOE3Ch, R136S) is gaining prominence for its association with delayed symptom onset, even in individuals carrying deterministic PSEN1 mutations. The APOE3 Christchurch variant gets its name from the city of Christchurch in New Zealand, where it was first discovered.

The recent study by Quiroz et al. (NEJM, 2024) followed 1077 carriers of the PSEN1 E280A mutation in a Colombian kindred. Heterozygotes for APOE3Ch (n=27) developed mild cognitive impairment at a median age of 52, compared to 47 in non-carriers, a 5-year delay despite identical PSEN1 background

How the APOE3Ch variant works

The APOE3Ch variant appears to alter several aspects of AD pathology:

  1. Amyloid deposition was not reduced; in fact, carriers showed greater plaque burden, yet tau pathology and neuroinflammation were consistently attenuated, suggesting downstream modulation.
  2. Cerebral glucose metabolism, assessed via FDG-PET, remained relatively intact in APOE3Ch carriers despite significant amyloid accumulation.
  3. Cerebral amyloid angiopathy was less pronounced, particularly in the frontal cortex, with reduced partial vessel wall involvement.

The editorial by Hardy (NEJM, 2024) postulates that APOE3Ch disrupts receptor binding to heparan-sulfate proteoglycans (HSPGs), altering intracellular uptake of tau and amyloid aggregates. This mechanism could represent a pivot in drug development strategies, shifting from plaque clearance to blocking pathological propagation.

Clinical implications: from biomarkers to prevention

These findings open up several clinically relevant considerations. In families affected by autosomal dominant Alzheimer’s disease, particularly those carrying highly penetrant mutations such as PSEN1, it may become valuable to include APOE3-Christchurch screening as part of the genetic workup. Knowing whether a patient carries this variant could refine prognosis and help tailor psychological counseling, especially in cases where expected age at onset strongly influences life planning.

Moreover, the presence of protective alleles might help explain atypical trajectories observed in some sporadic AD cases. Integrating these variants into polygenic risk scores could enhance their predictive accuracy (especially in individuals with early-onset symptoms or uncertain diagnostic profiles) offering clinicians a more nuanced stratification of risk.

Finally, the prospect of mimicking the protective effect of APOE3Ch pharmacologically is already being explored. Several therapeutic programs are investigating agents that modulate APOE-receptor binding, interfere with tau internalization, or influence glial responses. These strategies could eventually translate the biological advantage observed in APOE3Ch carriers into viable interventions for the broader population.

Initial results from the INVOKE-2 trial (AL002, a TREM2 agonist antibody) failed to show clinical benefit despite pharmacodynamic target engagement, highlighting the complexity of translating microglial activation into functional outcomes. However, newer approaches such as VG-3927, an oral TREM2 agonist currently in phase I, may offer a more scalable strategy. These trials underscore the need to target early disease stages, select patients using appropriate biomarkers (e.g., sTREM2, APOE genotype), and explore combination regimens.

Emerging target: NDP52-enhanced autophagy

A recent Italo‑French study published in Cell Death & Disease (2025) identified a protective variant in the NDP52 gene (rs550510, G140E) involved in neuronal autophagy. Among 1,400 subjects, including 434 with Alzheimer’s, carriers of this variant showed reduced tau accumulation and slower neurodegeneration. The effect was confirmed in vitro and in vivo (Drosophila model), suggesting a distinct mechanism of resilience via enhanced clearance of toxic proteins.

These findings introduce a third axis of protection (autophagy) complementing APOE-mediated lipid signaling and TREM2-driven glial responses. NDP52 may represent a novel therapeutic target for boosting endogenous neuronal defenses.

A change of perspective in the treatment of Alzheimer's disease

The demonstration that APOE3Ch heterozygosity delays cognitive decline in autosomal dominant AD confirms that resilience is not just anecdotal, but genetically encoded. Together with emerging evidence on TREM2 and NDP52, these findings reinforce the need to look beyond pathology accumulation and toward modulating the brain’s response to it.

Clinicians should remain attentive to upcoming translational studies targeting these pathways, as they may offer preventive interventions not just for genetically defined subgroups, but for the broader AD population.

Sources
  1. Quiroz YT, Aguillon D, Aguirre-Acevedo DC, Vasquez D, Zuluaga Y, Baena AY, Madrigal L, Hincapié L, Sanchez JS, Langella S, Posada-Duque R, Littau JL, Villalba-Moreno ND, Vila-Castelar C, Ramirez Gomez L, Garcia G, Kaplan E, Rassi Vargas S, Ossa JA, Valderrama-Carmona P, Perez-Corredor P, Krasemann S, Glatzel M, Kosik KS, Johnson K, Sperling RA, Reiman EM, Sepulveda-Falla D, Lopera F, Arboleda-Velasquez JF. APOE3 Christchurch Heterozygosity and Autosomal Dominant Alzheimer's Disease. N Engl J Med. 2024 Jun 20;390(23):2156-2164. doi: 10.1056/NEJMoa2308583. PMID: 38899694.
  2. Hardy J. Protection against Alzheimer's Disease with APOE Christchurch Variant - How? N Engl J Med. 2024 Jun 20;390(23):2212-2213. doi: 10.1056/NEJMe2403712. PMID: 38899700.
  3. Marino C, Malotaux V, Giudicessi A, Aguillon D, Sepulveda-Falla D, Lopera F, Quiroz YT. Protective genetic variants against Alzheimer's disease. Lancet Neurol. 2025 Jun;24(6):524-534. doi: 10.1016/S1474-4422(25)00116-4. PMID: 40409316.
  4. Mattioni A, Carsetti C, Bruqi K, Caputo V, Cianfanelli V, Bacalini MG, Casa M, Gabelli C, Giardina E, Cestra G, Strappazzon F. A variant of the autophagic receptor NDP52 counteracts phospho-TAU accumulation and emerges as a protective factor for Alzheimer's disease. Cell Death Dis. 2025 Apr 15;16(1):300. doi: 10.1038/s41419-025-07611-2. PMID: 40234443; PMCID: PMC12000434.
  5. Alector Inc. (2024). A phase 2 study of AL002 in participants with early Alzheimer’s disease (INVOKE-2). ClinicalTrials.gov Identifier: NCT04592874.
  6. Vigil Neuroscience. (2025). A phase 1 study of VG-3927 in healthy volunteers. ClinicalTrials.gov Identifier: NCT05743356.