Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study

Summary

Background

We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease.

Methods

Between January and August, 2010, 18–26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ_1–42, total tau and phospho-tau₁₈₁ concentrations, and plasma Aβ_1–42 concentrations and Aβ_1–42:Aβ_1–40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests.

Findings

44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ_1–42 concentrations (p=0·008) and plasma Aβ_1–42 concentrations (p=0·01) than non-carriers.

Interpretation

Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ_1–42 overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease.

Funding

Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.

Introduction

What are the earliest brain changes associated with the predisposition to Alzheimer's disease? According to the amyloid hypothesis of Alzheimer's disease, the pathogenic cascade begins in patients with the accumulation of amyloid-β_1–42 (Aβ_1–42; the major constituent of neuritic plaques) into oligomeric and fibrillar assemblies, leading to neuroinflammatory changes, synaptic dysfunction and loss, accumulation and phosphorylation of the microtubule-associated protein tau (the main constituent of neurofibrillary tangles), and neuronal degeneration.¹ In accordance with the prevailing biomarker model of Alzheimer's disease,² evidence of amyloid plaque deposition can be detected by brain imaging and CSF analysis about 10–15 years before clinical onset (increased fibrillar Aβ as measured by PET and reduced CSF Aβ_1–42 concentrations). There is then biomarker evidence of neuronal dysfunction and synaptic loss (eg, regional reductions in cerebral glucose metabolism on PET and altered patterns of functional connectivity on functional MRI,³ alterations in regional brain activity during memory encoding and novel viewing tasks on functional MRI, and reductions in grey matter and cortical thickness on MRI). Biomarker evidence of neurofibrillary tangles, neuronal degeneration, and neuronal loss is also noted (eg, raised CSF total and phosphorylated tau concentrations and MRI measurements of hippocampal atrophy).2, 4

We have previously characterised functional differences in the brain of young adult carriers of the apolipoprotein E (APOE) e4 allele, the major susceptibility gene for late-onset Alzheimer's disease,⁵ and have shown that those differences occur before neurochemical and histopathological evidence of Aβ accumulation can be detected.⁶ The functional brain differences were apparent almost five decades before the estimated average age of clinical onset of Alzheimer's disease, but did not seem to progress until older ages.⁵ Findings from other studies have shown that young APOE ɛ4 carriers have reduced regional grey matter volumes⁷ and altered functional connectivity compared with demographically matched, young, non-APOE ɛ4 carriers.³

According to the Alzheimer Disease and Frontotemporal Dementia Mutation Database, more than 200 mutations of the presenilin 1 (PSEN1), PSEN2, and amyloid precursor protein (APP) genes cause autosomal dominant Alzheimer's disease with almost certain clinical onset before the age of 65 years. In contrast to late-onset Alzheimer's disease, autosomal dominant Alzheimer's disease has been associated with increased Aβ_1–42 production, as shown by increases in plasma Aβ_1–42 concentrations or increase in plasma Aβ_1–42:Aβ_1–40 ratios, or both.8, 9, 10

The study of mutation carriers provides a unique opportunity to characterise the preclinical changes associated with predisposition to Alzheimer's disease.¹¹ We have begun to use brain imaging and quantification of CSF biomarkers to detect and track changes in presymptomatic PSEN1 E280A (Glu280Ala) mutation carriers from the largest known autosomal dominant Alzheimer's disease kindred. Residing in Antioquia, Colombia, this kindred is estimated to have approximately 5000 living relatives, including about 1500 mutation carriers.¹² Carriers from this kindred have an estimated median age of 44 years (95% CI 43–45) at onset of mild cognitive impairment (MCI) and 49 years (49–50) at onset of dementia.¹³

We previously reported that cognitively normal PSEN1 E280A mutation carriers have functional¹⁴ and structural brain changes¹⁵ in the late preclinical stages of Alzheimer's disease, which are similar to those reported by others in the late preclinical stages of autosomal dominant Alzheimer's disease16, 17 and late-onset Alzheimer's disease.18, 19 In this study, we compared functional and structural MRI, CSF and plasma measurements in a cohort of 18–26 year-old PSEN1 E280A mutation carriers and non-carriers. We sought to test the hypotheses that young adult mutation carriers have raised CSF and plasma Aβ₄₂ concentrations, consistent with Aβ overproduction and the absence of Aβ plaque deposition. We also sought to test the hypothesis that young adult mutation carriers have functional and structural MRI differences, even before biomarker evidence of Aβ plaque deposition.