John Breitner’s research while affiliated with McGill University and other places

Alzheimer’s disease (AD) is associated with presymptomatic changes in brain morphometry and accumulation of abnormal tau and amyloid-beta pathology. Studying the development of brain changes prior to symptoms onset may lead to early diagnostic biomarkers and a better understanding of AD pathophysiology. AD pathology is thought to arise from a combination of protein accumulation and spreading via neural connections, but how these processes influence brain atrophy progression in the presymptomatic phases remains unclear. Individuals with a family history of AD (FHAD) have an elevated risk of AD, providing an opportunity to study the presymptomatic phase. Here we used structural MRI from three databases (Alzheimer’s Disease Neuroimaging Initiative, Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease and Montreal Adult Lifespan Study) to map atrophy progression in FHAD and AD and assess the constraining effects of structural connectivity on atrophy progression. Cross-sectional and longitudinal data up to four years were used to perform atrophy progression analysis in FHAD and AD compared to controls. Positron emission tomography radiotracers were also used to quantify the distribution of abnormal tau and amyloid-beta protein isoforms at baseline. We first derived cortical atrophy progression maps using deformation-based morphometry from 153 FHAD, 156 AD, and 116 controls with similar age, education, and sex at baseline. We next examined the spatial relationship between atrophy progression and spatial patterns of tau aggregates and amyloid-beta plaques deposition, structural connectivity, and neurotransmitter receptor and transporter distributions. Our results show that there were similar patterns of atrophy progression in FHAD and AD, notably in the cingulate, temporal, and parietal cortices, with more widespread and severe atrophy in AD. Both tau and amyloid-beta pathology tended to accumulate in regions that were structurally connected in FHAD and AD. The pattern of atrophy and its progression also aligned with existing structural connectivity in FHAD. In AD, our findings suggest that atrophy progression results from pathology propagation that occurred earlier, on a previously intact connectome. Moreover, a relationship was found between serotonin receptor spatial distribution and atrophy progression in AD. The current study demonstrates that regions showing atrophy progression in FHAD and AD present with specific connectivity and cellular characteristics, uncovering some of the mechanisms involved in preclinical and clinical neurodegeneration.

Cognitive dysfunction in Alzheimer’s disease (AD) correlates closely with pathology in the neuronal microtubule-associated protein tau. Tau pathology may spread via neural synapses. In a population of cognitively unimpaired elderly at elevated risk of AD, we investigated four cerebrospinal (CSF) markers of synaptic dysfunction and degeneration. Three of these (SYT1, SNAP25, and ADAM23) are derived from pre-synaptic structures, while ADAM22 reflects post-synaptic changes. All four markers correlated strongly with tau protein measures. In statistical models, SYT1 accounted for more than half the total variance in both total- and P(181)-tau levels. Observed correlations with CSF levels of Alzheimer amyloid-β (Aβ42) were somewhat weaker. In longitudinal data, baseline levels of ADAM22 and ADAM23 robustly predicted increase over time in both total- and P-tau. CSF SYT1 levels also correlated with PET image uptake of tau and (at a trend level) Aβ in areas of interest for early AD pathology. CSF SYT1 and SNAP25 levels correlated inversely with a global psychometric score and several of its domain subscales. In quantitative trait loci analyses, all four synaptic markers were associated with at least one AD genetic risk locus. Upon “staging” participants by their evidence of amyloid and tau pathology (A/T/N framework), the CSF synaptic markers were unexpectedly reduced in participants with CSF evidence of amyloid but not tau pathology. They were clearly elevated, however, in the CSF of persons with indications of both tau and amyloid pathology. These observations provide evidence for clear pre-synaptic degeneration in cognitively unimpaired persons with biomarker evidence of early AD pathology.

Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.

Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients. Sections

Background Apolipoproteins and contactin 5 are proteins associated with Alzheimer’s disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment. Objective To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage. Methods Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink’s proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of cognitively unimpaired participants (n = 93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (n = 57) and control subjects (n = 31) and in the hippocampi of mice following entorhinal cortex lesions. Results Contactin 5 positively correlated with apolipoproteins B (p = 5.4×10–8), D (p = 1.86×10–4), E (p = 2.92×10–9), J (p = 2.65×10–9), and with cholesterol (p = 0.0096) in the CSF, and with cholesterol (p = 0.02), HDL (p = 0.0143), and LDL (p = 0.0121) in the plasma. Negative correlations were seen between CNTN5, APOB (p = 0.034) and APOE (p = 0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (p < 0.05), while apob (p = 0.023) and apod (p = 0.006) increased in the deafferentation stage. Conclusions Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage.

Epidemiological studies show that modifiable risk factors account for about 40% of the population variability in risk of developing dementia, including sporadic Alzheimer's disease (sAD). Recent findings suggest that these factors might also modify disease trajectories of people with autosomal dominant Alzheimer's disease (ADAD). With positron emission tomography (PET) imaging it is now possible to study the disease many years before its clinical onset. Such studies can provide key knowledge regarding pathways for either the prevention of pathology or the postponement of its clinical expression. The former "resistance pathway" suggests that modifiable risk factors could affect amyloid and tau burden decades before the appearance of cognitive impairment. Alternatively, the "resilience pathway" suggests that modifiable risk factors might mitigate the symptomatic expression of AD pathology on cognition. These pathways are not mutually exclusive and might appear at different disease stages. Here, in a narrative review, we present neuroimaging evidence that supports both pathways in sAD and ADAD. We then propose mechanisms for their protective effect. Among possible mechanisms, we examine neural and vascular mechanisms for the resistance pathway. We also describe brain maintenance and functional compensation as bases for the resilience pathway. Improved mechanistic understanding of both pathways may suggest new interventions.

National Institute on Aging‐Alzheimer’s Association workgroups have proposed biological research criteria to identify individuals with preclinical Alzheimer’s disease (AD). It remains unclear whether cognitively unimpaired individuals with abnormality in both amyloid (A) and tau (T) biomarkers will go on to develop a clinical AD syndrome. In two independent cohorts, we investigated whether elevated tau‐PET signal in persons with elevated amyloid‐PET predicts near‐term conversion to mild cognitive impairment (MCI). We also tested whether neurodegeneration (N), a non‐specific marker typical of later‐stage AD, improved such prediction. We studied 128 cognitively unimpaired participants from the parental history‐positive PREVENT‐AD cohort and 153 individuals from the Harvard Aging Brain Study. Participants had >1 year of clinical evaluation following tau‐PET scanning (PREVENT‐AD median follow‐up time = 3.21 years [1.51‐4.50]; HABS median=1.94 years [1.13‐5.42]). At the time of PET, participants were stratified as abnormal (+) or normal (‐) on global amyloid‐PET (A), a temporal tau‐PET meta‐ROI (T), and hippocampal volume (N). Tau‐PET scans were also visually inspected for significant neocortical binding. Within the A+T+ groups, 61.5% (8/13; PREVENT‐AD) and 45.5% (5/11; HABS) of participants converted to MCI during follow‐up, compared with <13% of participants in all other PET‐biomarker groups (Figures 1 & 2). In Cox regression models, hazard ratios for conversion to MCI in the A+T+ group vs. the other biomarker groups were all >5 (Figure 3). Importantly, the majority of the A+T+ “non‐converters” still showed longitudinal cognitive decline (80% in PREVENT‐AD and 50% in HABS), suggesting likely future clinical progression (Figures 4 and 5). By contrast, cognitive trajectories in the A+T‐, A‐T+, and A‐T‐ groups remained predominantly stable. Evidence of neurodegeneration increased MCI conversion rates in the A+T+ group to 75%, though ∼33% of A+T+N‐ individuals also progressed (Figure 6). Among two cohorts of cognitively unimpaired older individuals, abnormality in both amyloid‐ and tau‐PET biomarkers was associated a dramatic increase in MCI progression within a short period of time as compared against individuals having only amyloid pathology or no pathology. These findings support the clinical prognostic relevance of a biological definition of AD in individuals without cognitive impairment.

Modifiable factors may influence risk for Alzheimer’s disease (AD) via two distinct, though not mutually exclusive, pathways: resistance and resilience to pathology. Whereas cognitive ‘resilience’ is defined as the maintenance of better‐than‐expected cognitive performance in the face of Aβ and tau pathology, ‘resistance’ refers to an absence or delaying of the pathology itself. We explored the potential influence of psychological factors on resistance and resilience to tau pathology in older adults at risk of AD dementia, and whether grey matter volume mediates these relationships. Measures of psychological factors (including mindfulness, optimism, purpose in life, Big‐5 personality traits, and affective symptoms), longitudinal cognitive assessments, and structural MRI scans were collected in 259 nondemented older adults, along with Aβ‐ and tau‐ positron emission tomography (PET) scans in a subset of 156 individuals. Relationships between psychological factors and entorhinal tau pathology, and between psychological factors and cognitive resilience to entorhinal tau pathology (quantified using the residuals method), were explored, controlling for age, sex, and global Aβ burden. Principal components analysis was then performed to reduce the psychological factors that were associated with resistance/resilience down to their underlying components. Relationships between the psychological components and grey matter volume were explored using voxel‐based morphometry analyses. Finally, the potentially mediating effect of grey matter volume on the relationships between the psychological components and resistance/resilience to pathology were examined. One principal component was associated with resistance to pathology, comprising mindful acting with awareness, perseverative thinking, conscientiousness, neuroticism, depression, purpose in life, and optimism. Two principal components were associated with resilience to pathology, the first comprising mindful nonjudgment, anxiety, and stress, and the second comprising extraversion and openness. These three principal components were associated with partially distinct patterns of grey matter volume, which overlapped in medial prefrontal and posterior cingulate cortices (Figure 1). Grey matter volume partially mediated the relationship between psychological factors and resistance, but not resilience, to pathology. Psychological functioning may influence resistance and resilience to AD pathology in cognitively unimpaired older adults. Increased grey matter associated with different combinations of protective psychological factors may assist in the delaying or prevention of AD pathology.

National Institute on Aging‐Alzheimer’s Association workgroups have proposed biological research criteria to identify individuals with preclinical Alzheimer’s disease (AD). It remains unclear whether cognitively unimpaired individuals with abnormality in both amyloid (A) and tau (T) biomarkers will go on to develop a clinical AD syndrome. In two independent cohorts, we investigated whether elevated tau‐PET signal in persons with elevated amyloid‐PET predicts near‐term conversion to mild cognitive impairment (MCI). We also tested whether neurodegeneration (N), a non‐specific marker typical of later‐stage AD, improved such prediction. We studied 128 cognitively unimpaired participants from the parental history‐positive PREVENT‐AD cohort and 153 individuals from the Harvard Aging Brain Study. Participants had >1 year of clinical evaluation following tau‐PET scanning (PREVENT‐AD median follow‐up time = 3.21 years [1.51‐4.50]; HABS median=1.94 years [1.13‐5.42]). At the time of PET, participants were stratified as abnormal (+) or normal (‐) on global amyloid‐PET (A), a temporal tau‐PET meta‐ROI (T), and hippocampal volume (N). Tau‐PET scans were also visually inspected for significant neocortical binding. Within the A+T+ groups, 61.5% (8/13; PREVENT‐AD) and 45.5% (5/11; HABS) of participants converted to MCI during follow‐up, compared with <13% of participants in all other PET‐biomarker groups (Figures 1 & 2). In Cox regression models, hazard ratios for conversion to MCI in the A+T+ group vs. the other biomarker groups were all >5 (Figure 3). Importantly, the majority of the A+T+ “non‐converters” still showed longitudinal cognitive decline (80% in PREVENT‐AD and 50% in HABS), suggesting likely future clinical progression (Figures 4 and 5). By contrast, cognitive trajectories in the A+T‐, A‐T+, and A‐T‐ groups remained predominantly stable. Evidence of neurodegeneration increased MCI conversion rates in the A+T+ group to 75%, though ∼33% of A+T+N‐ individuals also progressed (Figure 6). Among two cohorts of cognitively unimpaired older individuals, abnormality in both amyloid‐ and tau‐PET biomarkers was associated a dramatic increase in MCI progression within a short period of time as compared against individuals having only amyloid pathology or no pathology. These findings support the clinical prognostic relevance of a biological definition of AD in individuals without cognitive impairment.

Blood‐biomarkers of Alzheimer’s disease (AD) pathology have been investigated cross‐sectionally in heterogenous AD cohorts and have been shown to detect underlying AD pathology, even at preclinical stages. However, longitudinal studies, including serial blood‐biomarker measurements, are needed to better understand whether these markers could help monitor disease progression. We aimed to assess blood‐biomarkers temporal trajectories in cognitively unimpaired older adults at different pathological stages as assessed by positron emission tomography (PET). This may provide insight into dynamic changes of these biomarkers beginning prior to abnormality on PET. We included a subset of 126 cognitively unimpaired older adults from the Prevent‐AD cohort. Blood was drawn from baseline up to four‐year follow‐up visits. We measured Aβ42/Aβ40 ratio, pTau181 and pTau231 using novel single molecular array (Simoa). All participants completed Aβ (18F‐NAV4694) and tau (18F‐flortaucipir) PET scans, which were mostly performed at the latest blood collection timepoint. Aβ positivity was defined by global neocortical Aβ‐PET retention (SUVR cut‐off = 1.29), and tau‐PET positivity by entorhinal cortex flortaucipir binding (SUVR cut‐off = 1.23). Using these thresholds, 82 subjects were classified as A‐T‐, 29 as A+T‐, and 15 as A+T+. Linear mixed effects models were used to assess differences in the longitudinal rate of change in plasma biomarkers between the groups. Amyloid‐PET‐positive individuals showed elevated levels of pTau181, and pTau231 and lower levels of Aβ42/40 when compared with amyloid‐PET‐negative participants. Plasma pTau181 levels showed a greater increase over time in the A+T+ group when compared with the A‐T‐ group (p = 0.01; Figure 1). Overall, the A+T‐ and A+T+ groups had lower levels of plasma Aβ42/40 compared with the A‐T‐ group (p = 0.05, p = 0.0189; Figure 2), and the A+T‐ group had higher pTau231 compared with A‐T‐ participants (p = 0.0006; Figure 3). Longitudinal rate of change in Aβ42/40 and pTau231 did not differ between the groups. We observed increased pTau181 levels and rate of change in those with both amyloid and tau pathology on PET. The slopes between PET groups did not differ across time when using pTau231 and Aβ biomarkers despite group differences in the overall level of pathology.