Study defines major genetic form of Alzheimer’s disease

Researchers have identified a significant genetic form of Alzheimer’s disease linked to the APOE4 gene variant. This finding, published in Nature Medicine, provides new insights into the early-onset and progression of Alzheimer’s in individuals with specific genetic predispositions.

While most cases of Alzheimer’s disease occur later in life and are influenced by various factors, a small percentage are genetically determined. Early-onset autosomal dominant Alzheimer’s and Alzheimer’s associated with Down syndrome are well-known examples.

However, the study led by Drs. Juan Fortea and Victor Montal at the Sant Pau Research Institute in Barcelona shed light on another genetically influenced form of the disease related to the APOE4 gene variant.

The study analyzed data from the NIH-funded National Alzheimer’s Coordinating Center, involving postmortem brain pathology from over 3,200 individuals of predominantly European descent. This was supplemented by clinical, pathological, and biomarker data from five clinical studies involving more than 10,000 participants. The research was partially funded by the NIH.

Key findings include:

• Prevalence and Onset: Nearly all individuals with two copies of the APOE4 gene (APOE4 homozygotes) displayed Alzheimer’s brain pathology from age 55, compared to about half of those without the gene variant. Symptoms in APOE4 homozygotes typically began around age 65, with mild cognitive impairment diagnosed by age 72, dementia by age 74, and death around age 77. This progression occurred 7 to 10 years earlier than in those without the gene variant.
• Biomarkers: APOE4 homozygotes exhibited high levels of Alzheimer’s biomarkers starting at age 55. By age 65, nearly all had abnormal levels of beta-amyloid in their cerebrospinal fluid, and three-quarters had detectable amyloid on brain imaging.
• Predictability: The age of symptom onset in APOE4 homozygotes was less variable and more predictable compared to those without the gene variant. The sequence of biomarker changes with age in these individuals was consistent and similar to other genetically determined forms of Alzheimer’s.

The findings suggest that Alzheimer’s in APOE4 homozygotes shares significant characteristics with other genetic forms of the disease, leading researchers to propose that this form of Alzheimer’s could also be considered genetically determined.

“These data represent a reconceptualization of the disease or what it means to be homozygous for the APOE4 gene,” Dr. Fortea stated.

The study underscores the necessity for future research focusing on diagnosis and treatment strategies specific to APOE4 homozygotes. NIH currently funds studies exploring potential treatments for those carrying two copies of the APOE4 gene. Moreover, there is a pressing need to study APOE4 homozygote risk in non-European populations, and NIH is actively working to enhance diversity in Alzheimer’s research.

This research received support from various NIH grants, including those from the National Institute on Aging (NIA) and other NIH institutes.