Growing Old Without Alzheimer’s Pathology: What’s the Secret?

It may be possible to grow old without developing Alzheimer’s disease pathology (ADP), although a wide range of very different types of protective factors are involved. A study published in JAMA Neurology looked at the differences in patterns of amyloid deposition and neurodegeneration that comprise ADP and found that, although  challenging, “exceptional aging” without ADP is achievable.1

The main objective of the study, conducted by researchers at the Mayo Clinic in Rochester, Minnesota, was to identify and test the effectiveness of the full range of protective factors across a natural lifespan that prevent the development of amyloid deposits in the brain or neurodegeneration, or both. The investigators assembled a cohort of 942 individuals (519 men, 423 women) enrolled in the Mayo Clinic Study of Aging.

The cohort was divided into 4 groups according to combinations of ADP patterns, using imaging biomarkers: amyloid (A)+/neurodegeneration (N)+, A+/N, A/N+, and A/N. The groups differed significantly by age, necessitating adjustment. Amyloid levels varied by sex and apolipoprotein E (APOE) status, whereas neurodegeneration patterns differed by sex, APOE, midlife obesity, smoking, and a composite value of 7 cardiac and metabolic conditions, including hypertension, hyperlipidemia, cardiac arrhythmia, coronary artery disease, congestive heart failure, diabetes, and stroke.

The most important finding was that, apart from demographics and APOE genotype, no overlap in protective factors between the 2 patterns was apparent. History of dyslipidemia at midlife was the only factor that was significantly associated with amyloid deposits at the age of enrollment decades later (mean age, 79.7 years), whereas increased cardiac and metabolic condition values, smoking and obesity and diabetes, at midlife were all associated with increased risks for neurodegeneration, measured by cortical thickness.

The Mayo investigators then looked at the patterns in a special subgroup of “exceptional agers” aged 85 years or older without ADP (A/N) compared with all others older than 85 years with ADP signs (A+, N+, or A+/N+). The main differentiating factor was the presence of the APOE ε4 allele, which conferred protection across both patterns (as did younger age), and was consistent with previous studies.2-5

The results of the study pointed to evidence of exceptional aging in the normal population, and somewhat quantified the multiple protective factors necessary, which included a range of modifiable risks, particularly at midlife. Ultimately, however, the 2 most significant factors in exceptional aging (carrying the APOE ε4 allele and age) are nonmodifiable.

“[F]uture studies will need to further investigate how the cumulative sum of positive and negative factors across the lifespan may contribute to the risk of amyloidosis and neurodegeneration,” the researchers wrote.

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  1. Vemuri, P, Knopman DS, Lesnick TD, et al. Evaluation of amyloid protective factors and Alzheimer disease neurodegeneration protective factors in elderly individuals. JAMA Neurol. 2017;74:718-726. doi:10.1001/jamaneurol.2017.0244
  2. Jansen WJ, Ossenkoppele R, Knol DL, et al. Amyloid Biomarker Study Group. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015;313:1924-1938. doi:10.1001/jama.2015.4668
  3. Jack CR Jr, Wiste HJ,Weigand SD, et al. Age, sex, and APOE ε4 effects on memory, brain structure, and β-amyloid across the adult life span. JAMA Neurol. 2015;72:511-519. doi:10.1001/jamaneurol.2014.4821
  4. Villemagne VL, Burnham S, Bourgeat P, et al. Australian Imaging Biomarkers and Lifestyle (AIBL) Research Group. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12:357-367. doi:10.1016/S1474-4422(13)70044-9
  5. Sojkova J, Zhou Y, An Y, et al. Longitudinal patterns of β-amyloid deposition in nondemented older adults. Arch Neurol. 2011;68:644-649. doi:10.1001/archneurol.2011.77