In Search of Early, Asymptomatic Stages of Alzheimer's Disease

Many signs of age-related disease start as early as the 30s, damage that is asymptomatic and minimal, but nonetheless exactly the same type of dysfunction that will later, when present to a much greater degree, cause age-related disease, frailty, and death. This is true of measures of cognitive decline for example, and here researchers demonstrate that the physical signs of Alzheimer's disease in the brain can start to occur comparatively early in life as well. It is a reminder that rejuvenation treatments based on damage repair, once developed, are not only for the old, but that everyone much over the age of 30 should use them for prevention.

Alzheimer disease has an asymptomatic stage during which people are cognitively intact despite having substantial pathologic changes in the brain. While this asymptomatic stage is common in older people, how early in life it may develop has been unknown. To test the hypothesis that asymptomatic Alzheimer disease lesions may appear before 50 years of age, we microscopically examined the postmortem brains of 154 people aged 30 to 39 years (n=59) and 40 to 50 years (n=95) for specific Alzheimer lesions: beta-amyloid plaques, neurofibrillary tangles, and tau-positive neurites. We genotyped DNA samples for the apolipoprotein E gene (APOE).

We found beta-amyloid lesions in 13 brains, all of them from people aged 40 to 49 with no history of dementia. These plaques were of the diffuse type only and appeared throughout the neocortex. Among these 13 brains, five had very subtle tau lesions in the entorhinal cortex and/or hippocampus. All individuals with beta-amyloid deposits carried one or two APOE4 alleles. Among the individuals aged 40 to 50 with genotype APOE3/4, 10 (36%) had beta-amyloid deposits but 18 (64%) had none. Our study demonstrates that beta-amyloid deposits in the cerebral cortex appear as early as 40 years of age in APOE4 carriers, suggesting that these lesions may constitute a very early stage of Alzheimer disease. Future preventive and therapeutic measures for this disease may have to be stratified by risk factors like APOE genotype and may need to target people in their 40s or even earlier.



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