Annalisa Davin

Identifying older adults at increased dementia risk is a public health priority. Existing scores often emphasize midlife factors or variables of limited utility in late life. We developed a late-life dementia risk score using data from the InveCe.Ab cohort, including 1100 dementia-free individuals aged 70–74 and followed for 12 years. Candidate risk and protective factors were selected based on systematic reviews and expert consensus. Stepwise Cox models were used to construct a weighted score with and without adjustment for non-modifiable factors. External validation was performed in the TRELONG cohort. The selected modifiable factors were diabetes, alcohol consumption, hypercholesterolemia, social participation, and cognitive activity, with strong predictive accuracy for dementia incidence (HR = 1.23; 95% CI 1.14–1.33; p < 0.026), also after adjustment for non-modifiable factors. In the TRELONG cohort, the score remained significant (HR = 1.19; 95% CI 1.05–1.10; p = 0.008), though its predictive value decreased when adjusting for non-modifiable factors. The LateDem-Risk score offers a practical tool for risk stratification in adults aged ≥ 70 years. Further studies are needed to evaluate its predictive performance in different settings and populations.

Alzheimer’s disease (AD), the leading cause of dementia, is expected to markedly increase in prevalence in the coming decades. Beyond amyloid and tau pathologies, accumulating evidence suggests that mitochondrial dysfunction and impaired protein homeostasis play crucial roles in AD onset and progression. Building on our previous identification of molecular signatures associated with disease progression, this study investigated whether epigenetic alterations of mitochondrial DNA (mtDNA) contribute to cognitive decline. Specifically, we analyzed the methylation status of the mtDNA regulatory D-loop region and mtDNA copy number in blood-derived DNA samples from 75 participants who we followed longitudinally over eight years. Subjects were classified into four groups according to clinical progression from healthy cognition to mild cognitive impairment (MCI) and AD. Using a linear mixed-effects model, we observed significant differences in methylation dynamics and mtDNA copy number across groups and time points. Healthy controls showed a progressive increase in D-loop methylation, whereas individuals converting to AD exhibited a marked decrease in its level. An opposite trend was evidenced for mtDNA copy number. These findings suggest that reduced D-loop methylation and increased mtDNA are associated with mitochondrial dysfunction and disease progression, whereas increased methylation may represent a possible protective mechanism.

Neuropathological examination of the brain and its biochemical analyses are fundamental to neuroscience studies and public health decisions, but are dependent on the effectiveness of regulations and operational protocols. The article discusses opportunities and limits of Italian regulation on body donation in relation to the specific requirements of neuropathology and brain sciences, in comparison with the regulations of other countries. Some crucial issues emerge, widely shared in the various regulatory contexts. The main aspect is the willingness to donate, consciously expressed by the subject by signing an informed consent or through the formulation of advanced directives. The donation of a single organ, the brain in particular, does not necessarily imply the donation of the entire body, which should be considered separately. In the specific case of the brain, particular attention is given to reducing the post-mortem interval, in order to obtain tissues suitable for research. Consequently, the centres that deal with the brain and brain banking must have experience and expertise in handling nervous tissue, and do not necessarily have to deal with the management of the entire body. These aspects, still little addressed in Italy, are the basis to develop an effective brain banking activity, which can only develop by integrating post-mortem body donation with specific rules for brain banking without which Italian neuroscience will be penalised in the coming years.

The relationship between aging, mitochondrial dysfunction, neurodegeneration, and the onset of Alzheimer’s disease (AD) is a complex area of study. Aging is the primary risk factor for AD, and it is associated with a decline in mitochondrial function. This mitochondrial dysfunction is believed to contribute to the neurodegenerative processes observed in AD. Neurodegeneration in AD is characterized by the progressive loss of synapses and neurons, particularly in regions of the brain involved in memory and cognition. It is hypothesized that mitochondrial dysfunction plays a pivotal role by disrupting cellular energy metabolism and increasing the production of reactive oxygen species (ROS), which can damage cellular components and exacerbate neuronal loss. Despite extensive research, the precise molecular pathways linking mitochondrial dysfunction to AD pathology are not fully understood. Various hypotheses have been proposed, including the mitochondrial cascade hypothesis, which suggests that mitochondrial dysfunction is an early event in AD pathogenesis that triggers a cascade of cellular events leading to neurodegeneration. With this narrative review, we aim to summarize some specific issues in the literature on mitochondria and their involvement in AD onset, with a focus on the development of therapeutical strategies targeting the mitochondria environment and their potential application for the treatment of AD itself.

Alzheimer’s disease (AD) is a neurodegenerative disorder that progressively involves brain regions with an often-predictable pattern. Damage to the brain appears to spread and worsen with time, but the molecular mechanisms underlying the region-specific distribution of AD pathology at different stages of the disease are still under-investigated. In this study, a whole-transcriptome analysis was carried out on brain samples from the hippocampus (HI), temporal and parietal cortices (TC and PC, respectively), cingulate cortex (CG), and substantia nigra (SN) of six subjects with a definite AD diagnosis and three healthy age-matched controls in duplicate. The transcriptomic results showed a greater number of differentially expressed genes (DEGs) in the TC (1571) and CG (1210) and a smaller number of DEGs in the HI (206), PC (109), and SN (60). Furthermore, the GSEA showed a difference between the group of brain areas affected early (HI and TC) and the group of areas that were subsequently involved (PC, CG, and SN). Notably, in the HI and TC, there was a significant downregulation of shared DEGs primarily involved in synaptic transmission, while in the PC, CG, and SN, there was a significant downregulation of genes primarily involved in protein folding and trafficking. The course of AD could follow a definite time- and severity-related pattern that arises from protein misfolding, as observed in the PC, CG, and SN, and leads to synaptic impairment, as observed in the HI and TC. Therefore, a map of the molecular and biological processes involved in AD pathogenesis may be traced. This could aid in the discovery of novel biological targets in order to develop effective and well-timed therapeutic approaches.

Background: Aging is often characterized by a progressive loss of cognitive abilities due to the onset of Alzheimer Disease (AD). In recent years, ‐omic sciences have allowed us to begin to shed light on its molecular pathways in order to speculate about new and attractive hypothesis on AD pathogenesis.Method: In this study, a whole transcriptome analysis and a Gene Set Enrichment Analysis (GSEA) have been carried out on brain samples from hippocampus (HI), temporal and parietal cortex (TC, PC), cingulate cortex (CG), and substantia nigra (SN) from the Abbiategrasso Brain Bank (ABB) of 6 subjects with clinical and neuropathological diagnosis of AD and 3 healthy age‐matched controls in duplicate. Clinical and neuropsychological profile were obtained through serial evaluations, made at the baseline and in the following years. According to the ABB protocol, the neuropathological diagnosis was based on a complete histological characterization, including all the main proteinopathies and vascular scoring.Result: Transcriptomic results showed a greater number of differentially expressed genes (DEGs) in TC (1571) and CG (1210) and a least amount of DEGs in HI (206), PC (109) and SN (60). Furthermore, the GSEA showed a difference between the group of early affected brain areas (HI, TC) and the group of the subsequently involved areas (PC, CG, SN). Notably, in HI and TC there was a significant down‐regulation of shared DEGs primarily involved in the synaptic transmission and in the development of the central nervous system (CDK5R1, KCNC1, KCNC2, BSN), while in PC, CG and SN there was a significant down‐regulation of genes primarily involved in the proper protein folding and trafficking and inflammation (HSPA1B, HSPA1A, DNAJB1, FKBP4, CHORDC1, STIP1).Conclusion: The course of AD could follow a definite time and severity‐related pattern that arises from inflammatory processes and protein misfolding, observed in PC, CG and SN, and leads to synaptic impairment, observed in HI and TC. Therefore, we can relate neurobiological processes to clinical manifestations and outline a clearer picture of AD neuropathology and pathogenesis. This could help to discover novel biological targets in order to develop effective and well‐timed therapeutical approaches.

Background: Few studies investigate the correlation between the quantitative EEG (QEEG) and the neuropathological picture. The purpose of this study is to explore how QEEG can recognize the type and extent of neuropathological changes.Method: The EEG traces and brains belonging to 14 donors of the Abbiategrasso Brain Bank were analyzed. The subjects suffered from neurocognitive disorders due to AD, LBD or AD/vascular lesions (mixed dementia‐MD), with different stages of clinical and neuropathological severity. Clinical and neuropathological characterization was performed according to our protocol; biochemical measurements to determine the amount of proteinopathies are in runtime on frozen samples. QEEG analysis considered the relative power distribution (RPD) of the frequency bands (β, α, θ, δ) and the peak frequency (PF), i.e. the most represented frequency considering all the leads. The PF was measured every 2 seconds for 200‐400 samples, and then averaged. The Kruskall‐Wallis test was used for the comparison between groups.Result: The clinical diagnosis included: 2 MCI, 4 AD, 6 MD, and 2 LBD. The neuropathological definite diagnosis demonstrated frequent co‐pathologies, and some discrepancies compared to the clinical diagnosis. The neuropathological characterization identified 2 cases with low AD pathology (corresponding to the 2 MCI), 8 cases with intermediate or high AD pathology (4 MD with concomitant cerebrovascular disease), and 4 cases with prevalent LBD pathology. Considering both clinical and neuropathological diagnoses, the comparison between groups revealed no significant differences in QEEG parameters. Nonetheless, a trend emerges towards a lower β‐RPD and a higher θ‐RPD in cases with prevalent LBD pathology. Grouping based on the severity of AD pathology (2 low, 4 intermediate, 4 high) demonstrated significant differences depending upon the neuropathological scoring with a progressive decrease of α‐RPD (p = 0.029) and PF (p = 0.019), and an increase of δ‐RPD (p = 0.020).Conclusion: RPD and PF show low discriminatory capacity on etiology. Nonetheless, the presence of LBD seems to boost the EEG slowing. The PF slowing down parallels the increase of AD pathology, representing an indicator for the degenerative load. PF is a simple QEEG parameter, easily obtainable through standard digital EEG; it can be useful for monitoring neurodegenerative burden and disease evolution.

Alzheimer’s disease (AD) and Lewy body dementia (LBD) are two different forms of dementia, but their pathology may involve the same cortical areas with overlapping cognitive manifestations. Nonetheless, the clinical phenotype is different due to the topography of the lesions driven by the different underlying molecular processes that arise apart from genetics, causing diverse neurodegeneration. Here, we define the commonalities and differences in the pathological processes of dementia in two kindred cases, a mother and a son, who developed classical AD and an aggressive form of AD/LBD, respectively, through a neuropathological, genetic (next-generation sequencing), and transcriptomic (RNA-seq) comparison of four different brain areas. A genetic analysis did not reveal any pathogenic variants in the principal AD/LBD-causative genes. RNA sequencing highlighted high transcriptional dysregulation within the substantia nigra in the AD/LBD case, while the AD case showed lower transcriptional dysregulation, with the parietal lobe being the most involved brain area. The hippocampus (the most degenerated area) and basal ganglia (lacking specific lesions) expressed the lowest level of dysregulation. Our data suggest that there is a link between transcriptional dysregulation and the amount of tissue damage accumulated across time, assessed through neuropathology. Moreover, we highlight that the molecular bases of AD and LBD follow very different pathways, which underlie their neuropathological signatures. Indeed, the transcriptome profiling through RNA sequencing may be an important tool in flanking the neuropathological analysis for a deeper understanding of AD and LBD pathogenesis.

Background: Research on brain tissue is essential to understand the biological mechanisms underlying neurodegenerative diseases and brain aging processes.Brain donation for research is influenced by many factors both in clinical and non‐clinical samples. The aim of the present study is to explore the features associated with the decision to join the brain donation program of the Abbiategrasso Brain Bank (ABB) in the context of a population‐based study on brain aging.Method: The longitudinal cohort study InveCe.Ab enrolled participants aged 70‐75 years and residing in Abbiategrasso (MI). During the second follow‐up of the study (2014), the participants fill a questionnaire to investigate attitudes through brain donation for research purpose (N=1010). We compared socio‐cultural aspects and questionnaire responses between participants who adhere to brain donation (N=163; 16,1%) and those who refuse (N=847) using Student’s t Test and chi‐squared test when appropriate. Variables showing significant differences in the group comparisons were included in a logistic regression model with brain donation status (yes/no) as the dependent variable.Result: The groups were comparable for age and sex, while ABB donors were significantly more educated (donors: 7,74, non‐donors: 6,70; p=0,000), more frequently prone to organ donation (donors: 93,4%; non‐donors: 64,3%, p=0,000) and to cremation (donors: 76,8%; non‐donors: 44,8%; p=0,000). Among those who were favorable for brain donation in the questionnaire, only 43,6% actually signed up for brain donation (p=0,000). Moreover, brain donation was associated with friends relationship satisfaction (donors: 96,5%; non‐donors: 91,4%; p=0,023) and better self‐reported health (donors: 83,3%; non‐donors: 73,4%; p=0,028), despite no difference between groups was found in the number of chronic disease (p=0,49). Finally, in the multivariable model, being prone to organ donation was the main factor associated with actual registration for brain donation. The availability for cremation remained significant only for males.Conclusion: Despite a positive attitude through brain donation in nearly half of the respondents, only a minority of older adults actually engage in a brain donation program. Being prone to organ donation was the main factor associated with brain donation subscription. The donors were more educated, with a positive attitude through their health and their relationships with friends.