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Background: Olfactory dysfunction is one of the earliest signs of Alzheimer’s disease (AD), highlighting its potential use as a biomarker for early detection. It has also been linked to progression from mild cognitive impairment (MCI) to dementia. Objective: To study olfactory function and its associations with markers of AD brain pathology in non-demented mutation carriers of an autosomal dominant AD (ADAD) mutation and non-carrier family members. Methods: We analyzed cross-sectional data from 16 non-demented carriers of the Presenilin1 E280A ADAD mutation (mean age [SD]: 40.1 [5.3], and 19 non-carrier family members (mean age [SD]: 36.0 [5.5]) from Colombia, who completed olfactory and cognitive testing and underwent amyloid and tau positron emission tomography (PET) imaging. Results: Worse olfactory identification performance was associated with greater age in mutation carriers (r = –0.52 p = 0.037). In carriers, worse olfactory identification performance was related to worse MMSE scores (r = 0.55, p = 0.024) and CERAD delayed recall (r = 0.63, p = 0.007) and greater cortical amyloid-β (r = –0.53, p = 0.042) and tau pathology burden (entorhinal: r = –0.59, p = 0.016; inferior temporal: r = –0.52, p = 0.038). Conclusion: Worse performance on olfactory identification tasks was associated with greater age, a proxy for disease progression in this genetically vulnerable ADAD cohort. In addition, this is the first study to report olfactory dysfunction in ADAD mutation carriers with diagnosis of MCI and its correlation with abnormal accumulation of tau pathology in the entorhinal region. Taken together, our findings suggest that olfactory dysfunction has promise as an early marker of brain pathology and future risk for dementia.

Background: Cigarette smoking is a known risk factor for Alzheimer’s disease (AD). However, the association between neurodegeneration and other substances has not been fully determined. It is of vital importance to evaluate this relationship in populations at high risk of dementia. Since substance use possibly modifies the progression rate of cognitive decline, we studied this association in a unique and well-phenotyped cohort from the University of Antioquia: carriers of the PSEN1-E280A genetic variant. Objective: To determine the association between substance use and cognitive decline in carriers of the PSEN1-E280A genetic variant. Methods: A retrospective cohort study was conducted with 94 carriers and 69 noncarriers recruited between January 2019 and April 2020. A psychiatrist interviewed the participants using the Consumption of Alcohol, Cigarettes and other Substances questionnaire. The participants were also submitted to cognitive evaluation. The relationship between cognitive decline and substance use was explored through a mixed effects regression model. Results: There was an association between cigarettes and better performance on tasks related to perceptual organization, verbal fluency, and memory in carriers. Alcohol had a positive or negative effect on memory according to the type of alcoholic beverage. Results on marijuana use were no conclusive. Coffee was associated with progressive improvements in executive function and verbal fluency. Conclusion: Cigarette and alcohol were associated with an improvement of some cognitive assessments, possibly by a survival bias. In addition, coffee was related to improvements in executive function and language; therefore, its short-term neuroprotective potential should be studied.

Background: Greater neuroticism has been associated with higher risk for Alzheimer’s disease (AD) dementia. However, the directionality of this association is unclear. We examined whether personality traits differ between cognitively-unimpaired carriers of autosomal-dominant AD (ADAD) and non-carriers, and are associated with in vivo AD pathology. Objective: To determine whether personality traits differ between cognitively unimpaired ADAD mutation carriers and non-carriers, and whether the traits are related to age and AD biomarkers. Methods: A total of 33 cognitively-unimpaired Presenilin-1 E280A mutation carriers and 41 non-carriers (ages 27–46) completed neuropsychological testing and the NEO Five-Factor Personality Inventory. A subsample (n = 46; 20 carriers) also underwent tau and amyloid PET imaging. Results: Carriers reported higher neuroticism relative to non-carriers, although this difference was not significant after controlling for sex. Neuroticism was positively correlated with entorhinal tau levels only in carriers, but not with amyloid levels. Conclusion: The finding of higher neuroticism in carriers and the association of this trait with tau pathology in preclinical stages of AD highlights the importance of including personality measures in the evaluation of individuals at increased risk for cognitive impairment and dementia. Further research is needed to characterize the mechanisms of these relationships.

Background: Growing evidence suggests that there may be a sex-specific biological risk for Alzheimer’s disease (AD). Individuals with autosomal dominant AD due to a mutation (E280A) in Presenilin-1 (PSEN1) are genetically determined to develop early-onset dementia and thus, have few age-related risk factors for AD that are known to vary by sex (i.e., cardiovascular disease, menopause, life expectancy). Objective: Investigate sex differences in markers of cognition and neurodegeneration in autosomal dominant AD. Methods: We conducted a retrospective study in 19 cognitively-unimpaired PSEN1 mutation carriers (age range 20–44; 11 females), 11 symptomatic carriers (age range 42–56; 8 females), and 23 matched non-carriers family members (age range 20–50; 13 females). We examined hippocampal volume ratio, CERAD Total Score, and CERAD Word List (i.e., Learning, Delayed Recall, and Recognition). Mann-Whitney U tests, Spearman correlations and regression models were conducted. Results: There were no differential associations between age, CERAD Total Score, CERAD Word List–Learning, Delayed Recall, Recognition, and hippocampal volume ratio in male and female carriers and non-carriers. Cognitively-unimpaired female carriers showed better CERAD Total scores and CERAD Word List-Learning than cognitively-unimpaired male carriers, despite having similar hippocampal volume ratios. The interaction of sex and hippocampal volume ratio did not predict cognitive performance across groups. Conclusion: Our preliminary findings suggest that cognitively-unimpaired female carriers showed a verbal memory reserve, and as disease progresses, female carriers did not exhibit a cognitive susceptibility to AD-related neurodegeneration. Future studies with larger samples of autosomal dominant AD are warranted to further understand sex differences in AD-related clinical and pathological markers.

Background There is a need to find cognitive markers that can help identify individuals at risk for Alzheimer's disease (AD), and that can be used to reliably measure cognitive decline. Objective We tested whether a theoretically driven three-factor structure would characterize cognitive functioning in individuals who are genetically-determined to develop AD due to a mutation in Presenilin-1 (PSEN1) gene. We also examined whether these factors could distinguish cognitively unimpaired PSEN1 mutation carriers from age-matched non-carrier family members. Methods 1,395 cognitively unimpaired members of a Colombian kindred with the PSEN1 E280A mutation were included in the study. A confirmatory factor analysis examined the fit of the three-factor model comprising episodic memory (MMSE memory recall, CERAD-COL Word list recall, and Constructional praxis recall), executive function (Phonemic fluency and WCST perseverative errors), and psychomotor processing speed (TMT-A and WAIS-III Digit Symbol). Results The three-factor model provided an excellent fit for all participants (p = 0.24; RMSEA = 0.01). Further, the episodic memory (p = 0.0004, d = 0.25) and executive functioning (p = 0.001, d = 0.18) factors distinguished cognitively unimpaired carriers from non-carriers. The episodic memory factor provided the earliest indication of preclinical cognitive decline at 35 years of age, nine years before individuals' estimated age of clinical onset. Conclusions The three theoretically derived cognitive factors provide a reliable measure of cognition and may be useful for the early detection of AD, as well as for measuring disease progression. However, longitudinal studies are needed to confirm that these factors can be used to track the progression of cognitive decline in preclinical AD.

Background Presenilin-1 (PSEN1) mutations are the most common cause of familial early onset Alzheimer's disease (AD). The PSEN1 E280A (E280A) mutation has an autosomal dominant inheritance and is involved in the production of amyloid-β. The largest family group of carriers with E280A mutation is found in Antioquia, Colombia. The study of mutation carriers provides a unique opportunity to identify brain changes in stages previous to AD. Electroencephalography (EEG) is a low cost and minimally invasiveness technique that enables the following of brain changes in AD. Objective To examine how previous reported differences in EEG for Theta and Alpha-2 rhythms in E280A subjects are related to specific regions in cortex and could be tracked across different ages. Methods EEG signals were acquired during resting state from non-carriers and carriers, asymptomatic and symptomatic subjects from E280A kindred from Antioquia, Colombia. Independent component analysis (ICA) and inverse solution methods were used to locate brain regions related to differences in Theta and Alpha-2 bands. Results ICA identified two components, mainly related to the Precuneus, where the differences in Theta and Alpha-2 exist simultaneously at asymptomatic and symptomatic stages. When the ratio between Theta and Alpha-2 is used, significant correlations exist with age and a composite cognitive scale. Conclusion Theta and Alpha-2 rhythms are altered in E280A subjects. The alterations are possible to track at Precuneus regions using EEG, ICA, and inverse solution methods.

BACKGROUND Brain regions critical to episodic memory are altered during the preclinical stages of Alzheimer's disease (AD). However, reliable means of identifying cognitively-normal individuals at higher risk to develop AD have not been established. OBJECTIVE To examine whether functional MRI can detect early functional changes associated with scene encoding in a group of presymptomatic presenilin-1 (PSEN1) E280A mutation carriers. METHODS Participants were 39 young, cognitively-normal individuals from an autosomal dominant early-onset AD kindred, located in Antioquia, Colombia. Participants performed a functional MRI scene encoding task and a post-scan subsequent memory test. RESULTS PSEN1 mutation carriers exhibited hyperactivation within medial temporal lobe regions (hippocampus,parahippocampal formation) during successful scene encoding compared to age-matched non-carriers. CONCLUSION Hyperactivation in medial temporal lobe regions during scene encoding is seen in individuals genetically-determined to develop AD years before their clinical onset. Our findings will guide future research with the ultimate goal of using functional neuroimaging in the early detection of preclinical AD.

There is an urgent need to find effective presymptomatic Alzheimer's disease (AD) treatments that reduce the risk of AD symptoms or prevent them completely. It currently takes too many healthy people, too much money and too many years to evaluate the range of promising presymptomatic treatments using clinical endpoints. We have used brain imaging and other measurements to track some of the earliest changes associated with the predisposition to AD. We have proposed the Alzheimer's Prevention Initiative (API) to evaluate investigational amyloid-modifying treatments in healthy people who, based on their age and genetic background, are at the highest imminent risk of developing symptomatic AD using brain imaging, cerebrospinal fluid (CSF), and cognitive endpoints. In one trial, we propose to study AD-causing presenilin 1 [PS1] mutation carriers from the world's largest early-onset AD kindred in Antioquia, Colombia, close to their estimated average age at clinical onset. In another trial, we propose to study apolipoprotein E (APOE) ε4 homozygotes (and possibly heterozygotes) close to their estimated average age at clinical onset. The API has several goals: 1) to evaluate investigational AD-modifying treatments sooner than otherwise possible; 2) to determine the extent to which the treatment's brain imaging and other biomarker effects predict a clinical benefit-information needed to help qualify biomarker endpoints for use in pivotal prevention trials; 3) to provide a better test of the amyloid hypothesis than clinical trials in symptomatic patients, when these treatments may be too little too late to exert their most profound effect; 4) to establish AD prevention registries needed to support these and other presymptomatic AD trials; and 5) to give those individuals at highest imminent risk of AD symptoms access to the most promising investigational treatments in clinical trials.

Recently, it has been demonstrated that there is no obvious correlation between DNA fragmentation (according to Terminal dUTP Nick-End Labeling technique) and the severity of amyloid-beta (Abeta) deposition and neurofibrillary tangle (NFT) formation in patients bearing mutations in presenilin 1[E280A]. Indeed, it was observed in 10 out of 48 brain sections TUNEL-positive labeling, while none showed classical apoptotic morphology. Based on these findings, we were interested to determine whether cortical cells from temporal and hippocampus post mortem brain sections die either by an apoptotic or necrotic process in FAD-brain sections labeled TUNEL positive compared with normal brain subjects labeled TUNEL-negative using electron microscopy (EM). We found that FAD-brain sections labeled TUNEL positive display the typical morphological characteristics of cell death by necrosis i.e. the nuclear chromatin form flocculent aggregates with poorly defined edges and electron lucent (it does not appears black on EM); the chromatin aggregates are irregularly scattered through the nucleus; mitochondria are swoolen with flocculent matrix densities. No apoptotic bodies were observed in any of the brain areas studied. These results may indicate that necrosis is the most generalized cell death process occurring in terminal PS1E280A brains and the DNA fragmentation of nuclei labeled by TUNEL technique may reflect DNA vulnerability. Thus, cell death by necrosis and the accompanying histopathological observations such as severe deposition of amyloid plaques and NFTs, severe gliosis, cortical depopulation, influx of lymphocytes indicative of a chronic inflammation may have an important impact on future therapeutic strategies in the treatment of PS1E280A patients.

Recent studies have shown that the mis- sense mutation in presenilin-1 (E280A) increases depo- sition of amyloid-β (Aβ(1-42/43)) producing severe cerebellar pathology. Although Aβ has been involved as a neurotoxic peptide, its role in neuronal loss in PS-1 (E280A) patients has not yet been established. This study investigated terminal fluorescein 12-dUTP nick- end labeling (TUNEL)-positive cells (neuron, glia and microglial cells) and thioflavine S-stained Aβ-plaques and neurofibrillary tangles in the frontal, parietal, tem- poral, occipital, hippocampus and cerebellum cortices of 3 normal aging and 8 familial Alzheimer's disease patients with the presenilin-1 (E280A) mutation. Using these approaches, we found no obvious correlation be- tween DNA fragmentation and the severity of amyloid- β deposition (Aβ) and neurofibrillary tangle (NFT) formation. Indeed, we only observed 10 out of 48 FAD brain sections displaying TUNEL (+) labeling, and none with the classical apoptotic morphology. These results may indicate that DNA fragmentation is not a generalized phenomenon in early-onset FAD PS1 (E280A) patients or that neuronal cells are dying by a different mechanism of cell death. Taking together these findings suggest that Aβ and NFTs are not per se a causative factor to damage neuronal cells but their damage could be more related with individual neuronal vulnerability and brain aging.