Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50–89 years: a cross-sectional study

Abstract

Summary Background As treatment of pre-clinical Alzheimer's disease (AD) becomes a focus of therapeutic intervention, observational research studies should recognize the overlap between imaging abnormalities associated with typical aging vs those associated with AD. Our objective was to characterize how typical aging and pre-clinical AD blend together with advancing age in terms of neurodegeneration and b-amyloidosis. Methods We measured age-specific frequencies of amyloidosis and neurodegeneration in 985 cognitively normal subjects age 50 to 89 from a population-based study of cognitive aging. Potential participants were randomly selected from the Olmsted County, Minnesota population by age- and sex-stratification and invited to participate in cognitive evaluations and undergo multimodality imaging. To be eligible for inclusion, subjects must have been judged clinically to have no cognitive impairment and have undergone amyloid PET, FDG PET and MRI. Imaging studies were obtained from March 2006 to December 2013. Amyloid positive/negative status (A+/A−) was determined by amyloid PET using Pittsburgh Compound B. Neurodegeneration positive/negative status (N+/N−) was determined by an AD-signature FDG PET measure and/or hippocampal volume on MRI. We labeled subjects positive or negative for neurodegeneration (FDG PET or MRI) or amyloidosis by using cutpoints defined such that 90% of 75 clinically diagnosed AD dementia subjects were categorized as abnormal. APOE genotype was assessed using DNA extracted from blood. Every individual was assigned to one of four groups: A−N−, A+N−, A−N+, or A+N+. Age specific frequencies of the 4 A/N groups were determined cross-sectionally using multinomial regression models. Associations with APOE ε4 and sex effects were evaluated by including these covariates in the multinomial models. Findings The population frequency of A−N− was 100% (n=985) at age 50 and declined thereafter. The frequency of A+N− increased to a maximum of 28% (95% CI, 24%-32%) at age 74 then decreased to 17% (95% CI, 11%-25%) by age 89. A−N+ increased from age 60 onward reaching a frequency of 24% (95% CI, 16%-34%) by age 89. A+N+ increased from age 65 onward reaching a frequency of 42% (95% CI, 31%-52%) by age 89. A+N− and A+N+ were more frequent in APOE ε4 carriers. A+N+ was more, and A+N− less frequent in men. Interpretation Accumulation of A/N imaging abnormalities is nearly inevitable by old age yet people are able to remain cognitively normal despite these abnormalities. . The multinomial models suggest the A/N frequency trends by age are modified by APOE ε4 , which increases risk for amyloidosis, and male sex, which increases risk for neurodegeneration. Changing A/N frequencies with age suggest that individuals may follow different pathophysiological sequences. Funding National Institute on Aging; Alexander Family Professorship of Alzheimer's Disease Research.

Isolated, subtle, neurological abnormalities in neurologically and cognitively healthy aging subjects

“…Basal ganglia may shrink by the age per se [49], or because of the disruption of their connections with the cerebral cortex caused by WMH and/or lacunae, or as a consequence of the age-related cortical thinning [50]. Although only speculative, given that a nonnegligible percentage of cognitively unimpaired elderly-old subjects have an increased Ab deposition [5][6][7][8], an additional contribution to subcortical atrophy could be caused by the retrograde transport of Ab along axonal membranes [51] to basal ganglia cell bodies. Interestingly, Ab deposition [52] and atrophy [53] have been described in the striatum of different Alzheimer disease (AD) mutation carriers and sporadic AD [54,55].…”

“…However, certain limitations of our study need to be addressed. Firstly, we acknowledge that four subgroups among cognitively normal subjects aged 50-89 years have been recently identified on the basis of various combination of imaging biomarkers of b-amyloidosis and neurodegeneration and that 43 % only of these subjects had normal AD biomarkers and no evidence of subtle cognitive impairment [8]. The normality of our cohort was ascertained solely on the basis of the medical history and of the cognitive and neurological evaluations, thus we do not know which subgroup our NCH subjects belong to.…”

“…Results from Ab PET studies show that about 20-40 % of cognitively unimpaired subjects aged 60-90 years have high levels of Ab deposition [5,6] and faster rates of cortical atrophy than those with low Ab deposition [7]. Furthermore, 54 % of cognitively normal subjects aged 50-89 years present a various combination of imaging biomarkers of b-amyloidosis and neurodegeneration [8]. Similarly, the frequency of cerebrovascular lesions such as white matter hyperintensities (WMH) [9] and lacunar infarcts [10] increases with age in the general population, and WMH is strongly associated with cortical atrophy [11].…”

Amyloid imaging for dementia in Canada

“…Yet, many people retain normal cogni tive function despite substantial amyloid burden. 8 Hence, the task force does not recommend amy loid imaging in people with normal cognitive function (Box 1). 7 However, some studies have found negative correlations between PiB and episodic memory in this group, whereas other studies found no differences across cognitive measures between PiB positive and PiB nega tive controls.…”

An Emerging Model of Word Retrieval in Preclinical Alzheimer ’s Disease

“…Since until recently it was not possible to study in vivo brain changes associated with Alzheimer's pathology, previous research on word retrieval in normal cognitive aging could not differentiate between CN elderly persons with Alzheimer's pathology from CN elderly without it. Given that Alzheimer's pathology is more frequent in CN elderly persons than previously recognized [14,15], is it possible that previous findings that suggested impaired phonological access in "cognitively normal" aging actually pertain to persons with AD pathology, i.e. to preclinical AD [16]?…”