Cognitive function in very old men does not correlate to biomarkers of Alzheimer’s disease

Velickaite et al. BMC Geriatrics (2017) 17:208 DOI 10.1186/s12877-017-0601-6 RESEARCH ARTICLE Open Access Cognitive function in very old men does not correlate to biomarkers of Alzheimer’s disease V. Velickaite1†, V. Giedraitis2†, K. Ström2, I. Alafuzoff3,4, H. Zetterberg5,6,7, L. Lannfelt2, L. Kilander2, E-M. Larsson1 and M. Ingelsson2* Abstract Background: The Alzheimer’s disease (AD) brain displays atrophy with amyloid-β (Aβ) and tau deposition, whereas decreased Aβ42 and increased tau are measured in cerebrospinal fluid (CSF). The aim of this study was to relate cognitive performance to the degree of brain atrophy, CSF biomarker levels and neuropathology in a cohort of aged men. Methods: Fifty-eight 86–92-year-old men from the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort underwent cognitive testing, brain computed tomography and lumbar puncture. Atrophy was graded with established scales. Concentrations of CSF Aβ42, t-tau and p-tau were measured by ELISA. Thirteen brains were examined post mortem. Results: Forty-six of the individuals were considered non-demented, whereas twelve were diagnosed with dementia, either at baseline (n = 4) or during follow-up (n = 8). When comparing subjects with and without dementia, there were no differences in the degree of atrophy, although the mini mental state examination (MMSE) scoring correlated weakly with the degree of medial temporal atrophy (MTA) (p = 0.04). Moreover, the CSF biomarker levels did not differ significantly between healthy (n = 27) and demented (n = 8) subjects (median values 715 vs 472 pg/ml for Aβ42, 414 vs 427 pg/ml for t-tau and 63 vs 60 pg/ml for p-tau). Similarly, there were no differences in the biomarker levels between individuals with mild (n = 24) and severe (n = 11) MTA (median values 643 vs 715 pg/ml for Aβ42, 441 vs 401 pg/ml for t-tau and 64 vs 53 pg/ml for p-tau). Finally, the neuropathological changes did not correlate with any of the other measures. Conclusion: In this cohort of aged men only a weak correlation could be seen between cognitive performance and MTA, whereas the various neuroradiological, biochemical and neuropathological measures did not correlate with each other. Thus, AD biomarkers seem to be less informative in subjects of an advanced age. Keywords: Brain atrophy, Cognitive performance, CSF biomarkers, Neuropathology, AD biomarkers, Advanced age Background Cognitive disorders increase exponentially with advancing age. At the age of 80, the prevalence of dementia has been estimated to 10–12% whereas approximately 40% of individuals over 90 years are affected [1]. Although better early-life socioeconomic conditions and * Correspondence: † Equal contributors 2 Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden Full list of author information is available at the end of the article treatment of cerebrovascular risk factors may have beneficial effects on brain health, the prevalence of dementia is likely to become even higher in the future due to increasing life expectancy [1]. In Alzheimer’s disease (AD), the most common cause of dementia, amyloid-β (Aβ) plaques and neurofibrillary tangles of tau proteins are found in widespread areas of the post mortem brain [2]. However, clinico-pathological studies have demonstrated a lack of correlation between brain function and pathology in aging individuals. Accordingly, some cognitively intact elderly subjects may © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Velickaite et al. BMC Geriatrics (2017) 17:208 Page 2 of 9 display abundant protein deposition or cerebrovascular lesions at autopsy whereas a subgroup of patients with cognitive dysfunction may show a relatively mild neuropathology [3–8]. Thus, the relationship between pathological brain lesions and the clinical status seems to be attenuated at advanced ages. In a recent study, when the brain was assessed post mortem in almost 300 subjects without neurological impairment, it was demonstrated that approximately half of the subjects (47%) displayed Aβ deposition whereas some degree of tau pathology could be seen in almost all brains (98%) [9]. Thus, the protein deposits may not themselves confer a high degree of toxicity and it has instead been suggested that other pathological alterations, such as soluble prefibrillar species of Aβ and tau, correlate better to the cognitive dysfunction in AD [10]. Similarly, brain imaging of older patients may not be conclusive. The medial temporal lobe atrophy (MTA) or global cortical atrophy (GCA), as visualized by computed tomography (CT) or magnetic resonance imaging (MRI), are changes that indicate AD development [11, 12]. However, such structural changes are commonly seen also in cognitively healthy subjects older than 80 years [13, 14]. The development of cerebrospinal fluid (CSF) biomarkers has been of great importance to identify subjects with mild cognitive impairment that subsequently will convert to AD dementia [15]. However, these markers are not suitable to monitor clinical progression as they remain relatively stable throughout the disease process [16]. Moreover, it has been observed that the predictive and diagnostic value of CSF markers is limited in older populations where a substantial part of apparently cognitively healthy subjects still have an AD CSF profile of decreased Aβ42 together with increased levels of total tau (t-tau) and phospho-tau (p-tau) [17, 18]. In addition, a substantial overlap in the biomarker profile has been demonstrated between AD and non-AD dementia cases [19, 20]. Studies on the relationship between protein pathology, structural abnormalities, CSF biomarkers and cognition in subjects of an advanced age are still scarce. We therefore assessed these aspects on a group of 86–92 year old men from the population-based Uppsala Longitudinal Study of Adult Men (ULSAM) cohort. and official registry data are available in databases, which are being continuously updated (http:// www.pubcare.uu.se/ulsam). Of the 2322 individuals who were initially recruited to the ULSAM study, 354 had been examined at the age of 84–88 (ULSAM-88). Of the ULSAM-88 participants, 198 individuals were considered to be able to visit the hospital. However, 38 subjects were reported to be under Coumadin treatment and were therefore excluded. Thus, a total of 160 remaining ULSAM individuals were invited to the study. Fifty-eigh (...truncated)