Associations Between Alzheimer Disease Biomarkers, Neurodegeneration, and Cognition in Cognitively Normal Older People

Wirth, Miranka; Villeneuve, Sylvia; Haase, Claudia M.; Madison, Cindee; Oh, Hwamee; Landau, Susan; Rabinovici, Gil D.; Jagust, William J.

doi:10.1001/jamaneurol.2013.4013

Cited by 122 publications

(158 citation statements)

References 34 publications

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“…The lack of a relationship between hippocampal volume and memory performance in healthy older adults has been demonstrated previously, 30 and may be due to a limited range of variability among controls compared to the aMCI or AD dementia group (SD 5 928, 1,146, and 1,019, respectively) or because of the low prevalence in controls of AD-specific mechanisms underlying both hippocampal atrophy and memory deficits. In controls, it is presumed that there is a smaller degree of neurodegeneration and less reliance on reserves to maintain normal performance.…”

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confidence: 68%

Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy

et al. 2016

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Objective: To examine sex differences in the relationship between clinical symptoms related to Alzheimer disease (AD) (verbal memory deficits) and neurodegeneration (hippocampal volume/ intracranial volume ratio [HpVR]) across AD stages. Methods:The sample included 379 healthy participants, 694 participants with amnestic mild cognitive impairment (aMCI), and 235 participants with AD and dementia from the Alzheimer's Disease Neuroimaging Initiative who completed the Rey Auditory Verbal Learning Test (RAVLT). Cross-sectional analyses were conducted using linear regression to examine the interaction between sex and HpVR on RAVLT across and within diagnostic groups adjusting for age, education, and APOE e4 status.Results: Across groups, there were significant sex 3 HpVR interactions for immediate and delayed recall (p , 0.01). Women outperformed men among individuals with moderate to larger HpVR, but not among individuals with smaller HpVR. In diagnosis-stratified analyses, the HpVR 3 sex interaction was significant in the aMCI group, but not in the control or AD dementia groups, for immediate and delayed recall (p , 0.01). Among controls, women outperformed men on both outcomes irrespective of HpVR (p , 0.001). In AD dementia, better RAVLT performance was independently associated with female sex (immediate, p 5 0.04) and larger HpVR (delayed, p 5 0.001). The cognitive reserve theory posits that favorable premorbid factors including higher education and IQ delay the onset of clinical deficits despite Alzheimer disease (AD)-related neurodegeneration because compensatory mechanisms are more readily engaged (e.g., alternate brain networks or cognitive strategies). Conclusion:1-3 The theory predicts that the onset of accelerated cognitive decline is closer in time to AD dementia diagnosis in individuals with greater cognitive reserve; however, after onset, their decline is more rapid because neurodegeneration is more advanced at that point. [4][5][6] Throughout life, women outperform men on verbal memory tasks. [7][8][9] We predict that this female advantage may reflect a sex-specific form of cognitive reserve resulting in a delay in the clinical manifestation of memory impairment until more advanced neurodegeneration overwhelms the female advantage and decline begins. Thereafter, we predict that women decline From the Einstein Aging Study and the

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confidence: 68%

Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy

et al. 2016

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“…[10][11][12] Moreover, recent studies suggested that neurodegenerative pathology could emerge through a nonamyloid-related pathway even within regions usually affected by AD. 13,14 Given the major implications for AD research and treatment, 15 SNAP deserves more in-depth investigation. The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with MCI-SNAP.…”

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confidence: 99%

Mild cognitive impairment with suspected nonamyloid pathology (SNAP)

et al. 2015

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Objectives: The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non-Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI). Methods:We measured markers of amyloid pathology (CSF b-amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [18 F]-fluorodeoxyglucose-PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A1/A2 and N1/N2 based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A2N1 cases.Results: The proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71%(60/85) in A2N2, A1N2, SNAP, and A1N1, respectively; the proportion of APOE e4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A1N2 and A1N1 groups (p # 0.005). Hypometabolism in SNAP patients was comparable to A1N1 patients (p 5 0.154), while hippocampal atrophy was more severe in SNAP patients (p 5 0.002). Compared with A2N2, SNAP and A1N1 patients had significant risk of progressive cognitive deterioration (hazard ratio 5 2.7 and 3.8, p 5 0.016 and p , 0.001), while A1N2 patients did not (hazard ratio 5 1.13, p 5 0.771). In A1N2 and A1N1 groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r 5 0.42, p 5 0.073). The amyloid cascade hypothesis 1,2 has so far dominated the Alzheimer disease (AD) field. Jack et al. Conclusions:3,4 proposed a dynamic model that relates disease stage to the best established biomarkers of AD pathology. Based on this, a National Institute on Aging-Alzheimer's Association task force developed recommendations for the diagnosis of preclinical AD based on biomarkers of amyloidosis and neuronal injury.5 Soon afterward, these criteria were operationalized and a

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“…10 However, CN subjects can have neurodegeneration without amyloid deposition, 11,12 and 48% of normal subjects who progressed from normal to MCI or dementia had low PiB retention levels. 13 Furthermore, white matter lesions (WMLs), as markers of small vessel disease, are also risk factors for MCI 14 and incident dementia.…”

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Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old

et al. 2014

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Objective: To examine the association between brain structural changes and b-amyloid deposition, and incident dementia in 183 elderly subjects without dementia (mean age 85.5 years) 2 years later.Methods: Subjects had a brain structural MRI scan and a PET scan with 11 C-labeled Pittsburgh compound B (PiB) in 2009, and were evaluated clinically in 2011.Results: At baseline evaluation, of the 183 participants (146 cognitively normal [CN]); 37 mild cognitive impairment [MCI]), 139 (76%) were PiB1, had small hippocampal volume (,25th percentile), or had high white matter lesion (WML) volume (.75th percentile). Two years later, 111 (61%) were classified as CN, 51 (28%) as MCI, and 21 (11%) as dementia. At baseline, 51% of the CN participants and 67.5% of the MCI cases were PiB1. Thirty percent of the CN and 51% of the MCI cases had small hippocampi, and 24% of the CN and 40.5% of the MCI cases had abnormal WMLs. Of the 21 participants who progressed to dementia, 20 (95%) had at least one imaging abnormality. Only 3 (14%) were only PiB1, 1 (5%) had only small hippocampi, 1 (5%) had only WMLs, 1 (5%) was biomarker negative, and the other 16 had various pairs of imaging abnormalities. Continuous variables of PiB retention, left and right hippocampal volume, and WML volume were independent predictors of dementia in a logistic regression analysis controlling for age, sex, education level, and Mini-Mental State Examination scores. Conclusions:The prevalence of b-amyloid deposition, neurodegeneration (i.e., hippocampal atrophy), and small vessel disease (WMLs) is high in CN older individuals and in MCI. A combination of 2 or 3 of these factors is a powerful predictor of short-term incidence of dementia. Studies of cognition and neurodegeneration in the oldest-old are important because these individuals are at the highest risk of developing dementia, especially Alzheimer disease (AD). 1 Furthermore, the neurodegenerative process that causes AD begins years before the clinical expression of the syndrome.2-4 The proportion of subjects without dementia who have amyloid deposition detected in vivo is approximately 20% to 30%, 4 with rates up to 65% in those aged 80 years or older. 4,5 Amyloid deposition detected with Pittsburgh compound B (PiB) is associated with the development of AD from mild cognitive impairment (MCI), 6,7 and to MCI or AD from normal cognition. 8 Similarly, low hippocampal volume, as a marker of neurodegeneration, is associated with progression to AD in cognitively normal (CN) subjects and in those with MCI.9 It has been hypothesized that AD pathology starts with amyloid deposition, followed by neuronal loss closer

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Associations Between Alzheimer Disease Biomarkers, Neurodegeneration, and Cognition in Cognitively Normal Older People

Cited by 122 publications

References 34 publications

Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy

Better verbal memory in women than men in MCI despite similar levels of hippocampal atrophy

Mild cognitive impairment with suspected nonamyloid pathology (SNAP)

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old

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