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Higher Levels of Education Buffer Against Autosomal Dominant Alzheimer's Disease

Key findings

  • This study evaluated relationships between apolipoprotein E (APOE) genotype and cognitive function in a kindred with autosomal dominant Alzheimer's disease and whether education influenced those relationships
  • Among 141 carriers of the E280A mutation in the presenilin 1 gene who were also APOE e4+, the onset of age-related cognitive decline was accelerated compared with 534 carriers who were APOE e4-
  • The onset of age-related cognitive decline was delayed in mutation carriers who were APOE e2+ compared with those who were APOE e2-
  • Higher educational attainment was associated with higher cognition scores in mutation carriers and mitigated the cognitive impairment associated with APOE e4
  • Programs that increase years of education may be important aspects of the effort to prevent Alzheimer's disease and minimize the length of time people suffer symptoms of familial forms of the disease

It's well established that the epsilon 4 allele of the apolipoprotein E gene (APOE e4) increases the risk of sporadic Alzheimer's disease.

Now, Massachusetts General Hospital researchers have demonstrated the same is true in autosomal dominant Alzheimer's disease (ADAD), the early-onset, genetically determined form of the disease. Moreover, APOE e2 was protective in ADAD mutation carriers—and regardless of APOE genotype, their number of years of formal education influenced their risk of cognitive decline.

Stephanie Langella, PhD, a research fellow in the Multicultural Alzheimer's Prevention Program (MAPP) at Mass General, Yakeel T. Quiroz, PhD, director of MAPP and the Familial Dementia Neuroimaging Laboratory in the Department of Psychiatry and Department of Neurology, and colleagues published the findings in Nature Communications.


For years Mass General researchers and colleagues in Colombia have been studying an extended Colombian family of more than 6,000 individuals, the largest known kindred with ADAD due to a single mutation. All registry members know they have a parent with the E280A mutation on the presenilin 1 (PSEN1) gene but are blind to their own genetic status.

Carriers of the mutation have a median age of onset of mild cognitive impairment at age 44 and dementia at age 49. However, individual variability in disease onset and progression suggests other genetic and environmental factors influence age-related cognitive decline.

This cross-sectional study involved 675 PSEN1 E280A mutation carriers and 594 noncarriers. 141 mutation carriers were APOE e4+ and 534 were APOE e4−. At the University of Antioquia in Colombia, all participants completed a clinical interview and the Mini Mental State Examination (MMSE), administered in Spanish.

APOE e4 Genotype

Declines in MMSE total score significantly differentiated mutation carriers from non-carriers beginning at age 31.5 years. However, APOE e4 genotype influenced this result:

  • Among carriers of the PSEN1 E280A mutation—The age-related cognitive trajectories of APOE e4+ and e4− individuals diverged at age 44.3, with APOE e4+ individuals showing accelerated decline in MMSE scores
  • Among noncarriers—The cognitive trajectories of APOE e4+ and e4− individuals did not diverge

The APOE e4 and PSEN1 mutations both influence the accumulation of β-amyloid in the brain, and the genetic combination may result in earlier or higher pathological burden.

Level of Education

Greater educational attainment was a protective factor:

  • Regardless of APOE genotype, higher educational attainment was associated with higher MMSE scores (β, 0.41; P<0.001)
  • The negative effect of APOE e4+ was significantly attenuated (β, 0.32; P=0.005) as years of educational attainment increased

APOE e2 Genotype

Previous research published in Molecular Psychiatry linked the presence of the APOE e2 allele to delayed clinical onset of ADAD in the Colombian kindred. That effect was confirmed in this study. Furthermore, higher educational attainment attenuated the negative effect of the APOE e2− genotype in mutation carriers (β, 0.24; P=0.046).

A Modifiable Risk Factor

This cohort represented a broad range of educational attainment, and low levels of educational attainment were shown to confer a particularly greater risk of cognitive decline.

The Lancet Commission on Dementia includes education in its list of 12 modifiable risk factors for dementia and recommends primary and secondary education for all children.

Learn more about the Multicultural Alzheimer's Prevention Program

Learn more about research in the Department of Psychiatry


Massachusetts General Hospital researchers found an MRI measure of locus coeruleus (LC) integrity starts declining about 12 years before symptom onset in autosomal dominant Alzheimer's disease. This and related findings suggest LC integrity is a promising prognostic indicator in the preclinical stage of the disease.


In not-yet-demented carriers of a mutation that inevitably causes Alzheimer's disease (AD), Massachusetts General Hospital researchers found a significant link between "clustering" on a category fluency test and brain levels of amyloid and tau, suggesting cognitive testing might someday detect early or preclinical AD.