Cognitive decline in middle age may not result from β-amyloid deposition, according to a study published online ahead of print March 16 in JAMA Neurology. Declines in memory and hippocampal volume occur at earlier ages than abnormal amyloid PET does, which implies that these outcomes “must have some mechanistic independence from β-amyloid accumulation,” said Clifford R. Jack, Jr., MD, Professor of Radiology at Mayo Clinic in Rochester, Minnesota.
Clifford R. Jack, Jr., MD
From age 70 onward, median amyloid PET accumulation is greater in cognitively normal individuals with the APOE ε4 allele, compared with people without the allele. In addition, abnormal amyloid PET may appear at an earlier age among APOE ε4 carriers, compared with noncarriers. The study results also indicate that male gender, but not APOE ε4, is associated with worse memory and adjusted hippocampal volume among cognitively normal individuals.
A Population Between Ages 30 and 95
Dr. Jack and colleagues conducted a cross-sectional observational study from March 2006 to October 2014 to compare the effects of age, sex, and APOE ε4 on memory, brain structure (ie, adjusted hippocampal volume), and amyloid PET in cognitively normal people. The researchers studied 1,246 participants from two cohorts. The first cohort was a random sample of 1,209 participants (ages 50 to 95) who were enrolled in the Mayo Clinic Study of Aging (MCSA). The second group included 37 self-selected volunteers (ages 30 to 49). All participants underwent identical PET, MRI, and memory testing protocols, including the Auditory Verbal Learning Test.
The study population’s median age was 72, and approximately 53% of subjects were male. About 27% of participants had the APOE ε4 allele, and the population’s median hippocampal volume at baseline was 7.5 cm³.
Memory Was Worse Among Men
Median memory performance declined for all patients from age 30 through the 90s. The decline after age 70 was steeper for men with APOE ε4 and for women. Memory was worse among men than among women overall, especially after age 40. APOE ε4 status was not associated with a difference in memory, but APOE ε4 carriers tended to have worse memory after age 80 than noncarriers.
For all participants, adjusted hippocampal volume decreased gradually from age 30 to the mid 60s, and the decrease became more acute after that point. Overall, adjusted hippocampal volume was lower in men than in women, especially after age 60. Within each gender, APOE ε4 was not associated with a difference in adjusted hippocampal volume.
The researchers observed a slight upward trend in median amyloid PET from age 30 through the 90s among APOE ε4 noncarriers. APOE ε4 carriers had a slight upward trend in median amyloid PET until age 70, followed by a steeper increase. The ages at which 10% of the population was amyloid PET positive were 57 for APOE ε4 carriers and 64 for noncarriers. The investigators saw no significant difference in amyloid PET by gender.
Data May Represent Typical Aging
“Overall age-dependent trends in our data are largely consistent with prior studies that show progressive declines in memory and brain volumes with age,” said Dr. Jack. The finding that memory and adjusted hippocampal volume worsen continuously from age 30—before obviously abnormal amyloid PET appears—contradicts the theory that subclinical declines in brain structure and cognitive function in middle age result from underlying β-amyloid deposition. The data instead imply that these declines “are a fundamental characteristic of typical aging,” said Dr. Jack.
“Reasonable candidates for non-Alzheimer’s disease processes associated with structural and functional decline in middle age are cerebrovascular disease and its risk factors, including primary age-related tauopathy, brain aging in the absence of any specific pathophysiologic process, or combinations of these [processes],” he added.
The study’s limitations included the small sample size of people between ages 30 and 49, and the non-population-based nature of this sample. The “obvious inflection points” in plots of memory, adjusted hippocampal volume, and amyloid PET versus age, however, appear well within the age range of 50 to the 90s of the MCSA cohort, not between the younger group and the MCSA cohort, said the authors. Another limitation is that cross-sectional studies tend to confound age effects with birth-cohort effects, but “cohort effects are unavoidable when examining age-dependent trends covering a range of 60 years.”
What Causes Memory Decline?
Dr. Jack and his colleagues “present new information that challenges the notion that amyloid accumulation explains memory performance across the entire age range,” said Charles DeCarli, MD, Director of the Alzheimer’s Disease Center at the University of California, Davis Health System in Sacramento, in an accompanying editorial. “This work does not only address the likely highly significant impact of cerebral amyloid accumulation on dementia risk, but also extends current knowledge relating to the impact of the aging process across the spectrum of ages 30 to 95 to brain structure, amyloid accumulation, and memory performance among cognitively normal individuals.”