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Better Memory and Greater Brain Volume in Aging Female Brain

With growing concern over the impending epidemic of cognitive loss and dementia, a new study by Jack et al provides striking information about the biology that underlies memory changes with age. The study comes from the Mayo Clinic Study of Aging, which recruited a population based sample of individuals from 50 to 95 years of age. This sample is an age and sex stratified sample from Olmsted County in Minnesota and as such it provides a unique look at a relatively unbiased sample of an aging cohort. The cohort was tested to confirm the absence of any cognitive deficit and more than 1,200 individuals participated in the study. The study included a small (N=37) younger age group (age 30-49 years) to make observations about the full adult age range, but the fact that they were self-selected and such a small group limits the generalizability. The study included Amyloid PET imaging using Pittsburgh Compound B and quantitative magnetic resonance imaging (MRI) along with memory testing which included the Auditory Verbal Learning Test.

In this cross sectional study of cognitively normal adults, as expected, memory scores worsened with each older age group and hippocampal volume decreased. Of note, is that the females had better memory scores across all age groups and had larger hippocampal volumes. While better performance in females than males should not be surprising as many birth cohort studies have demonstrated similar differences, and societal shifts have also supported this difference, the fact that this advantage in absolute terms continues to exist across the age span is of interest. Equally interesting is the associated larger size of hippocampal volume. While apolipoprotein ε4, an allele of the apolipoprotein ε gene that increases the risk for Alzheimer’s disease, was associated with lower brain volume, the benefit of female over male existed in both the carriers and non carriers. Apolipoprotein ε4 was not associated with worse memory performance.

Memory and brain volume in non-demented elders have been thought to be markers of cognitive age and have been referred to as normal brain aging. However, it is the memory and cognitive loss that are most distressing to aging adults and certainly worthy of greater study. Further, changes in rate of decline in performance may be a prodromal stage to Alzheimer’s disease. This cross-sectional study did not measure change, but future work planned by this group will tell us more.

Other findings in the report suggest that amyloid plaque accumulation, as measured by PET imaging, which is the hallmark of Alzheimer’s disease, increased with age, but was not associated with memory scores. To compare across groups, the authors created a scaled score in which zero was “normal” (i.e., based on participants ages 30-49) and 100 was “abnormal” (described as the 95th percentile for amyloid PET accumulation in those with moderately severe symptomatic Alzheimer’s disease). The scaled score for amyloid accumulation becomes sharply higher around age 65 and occurs at younger ages in those with an apolipoprotein ε4 allele than those without. However there was no difference in accumulation between males and females.

There are several important findings in this work. First, the memory loss of aging seems highly associated with brain volume. Acceleration of this loss may also reflect accelerated loss of hippocampal volume and may precede the appearance of amyloid, though we will need longitudinal data to confirm this. While the female cohort has better memory and greater brain volume, the trajectory of decline is similar. This suggests that if we use a single score to detect poor performance, females may be identified at a later point on the trajectory and potentially significant changes for them would go undetected for a longer time. Another issue raised by this data is the degree to which we could expect that interventions for amyloid accumulation could change memory performance given the lack of association of memory scores in this data. Others have shown that amyloid accumulation is higher in those with accelerated memory decline compared to those with relatively stable memory performance , though these studies were conducted in selected samples not necessarily representative of the general population. On the other hand, both pharmacological and non-pharmacological interventions that focus on mechanisms to minimize brain volume loss may be expected to modify memory deterioration. Finally, these studies highlight the invaluable contribution of research participation and the opportunity of all health care professionals to support the decision of their patients to join research efforts.


Clifford R. Jack CR, Wiste HJ, Weigand SD,etal. Age, Sex, and APOE ε4 Effects on Memory, Brain Structure, and β-Amyloid Across the Adult Life Span. JAMA Neurol. doi:10.1001/jamaneurol.2014.4821

Villemagne VL, Pike KE, Darby D, et al. Aβ deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer’s disease. Neuropsychologia. 2008;46: 1688–1697

Mary Sano, PhD, Icahn School of Medicine at Mount Sinai, New York City, New York, United States; James J. Peters VA Medical Center, Bronx, New York, United States

Excerpted article as reprint from IPA’s newsletter, the IPA Bulletin, Volume 32, Number 2


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