Unlike the usual late-onset Alzheimer's disease (LOAD), early-onset AD (EOAD), with onset before age 65, includes a high percentage of phenotypic variants. These non-familial, variants (vEOAD) present, not with progressive memory loss, but with language, visuospatial, or other cognitive difficulties. We now understand AD as a disorder that manifests with disturbed cognition reflecting disturbed neural networks. A multivariate analysis of neuropsychological tests, the gold standard for objectively defining neurocognitive impairments, coupled with structural and functional neuroimaging analysis of connectomes, can identify the neurocognitive-neural network profiles of vEOAD patients, compared to those with typical AD. This knowledge can increase our understanding of the heterogeneity of AD and how it causes disease. Objective. This proposal aims to show that vEOAD comprises its own clinical-neurobiological disorder, or type 2 AD, evident by a specific neurocognitive profile on neuropsychological tests and by specific structural and functional neural network involvement on magnetic resonance imaging (MRI). The neurobiology of Type 2 AD, which is composed of overlapping clinical syndromes that cluster together, challenges the prevailing view of initial ?42-amyloid deposition followed by neurofibrillary tangle (NFT) formation in the entorhinal- hippocampal cortex, and suggests involvement and propagation via alternate neural networks. Methods. This study recruits 60 vEOAD patients, 30 typical amnestic EOAD patients, and 30 typical LOAD patients as well as 60 normal, age-matched controls.
In Specific Aim 1, all participants undergo neuropsychological tests and neurological tasks related to potentially affected brain regions. It assesses and corroborates a proposed neuropsychological test profile for the diagnosis and one-year follow-up of Type 2 AD.
In Specific Aim 2, the EOAD participants undergo MRI measures of structural and functional neural networks using connectomic analysis of diffusion tensor imaging and resting-state functional MRI. Anticipated Results. This proposal hopes to show that vEOAD constitutes a Type 2 AD.
Specific Aim 1 defines the neuropsychological components of Type 2 AD.
Specific Aim 2 shows that, compared to typical amnestic EOAD or LOAD, Type 2 AD initially spares entorhinal-hippocampi cortex and the default mode network in favor of alternate frontoparietal networks (e.g., central executive network). Together, these specific aims define the distinct neurocognitive-neural network profile of Type 2 AD compared to typical amnestic AD. Conclusions. By recognizing the underlying neurocognitive-neural network profile of Type 2 AD in relation to typical AD, researchers gain crucial knowledge of the variations in the pathophysiological manifestations and neural propagation of this disease. In addition to information that can help in the diagnosis and management of EOAD, this proposal can stimulate novel research into the reasons for this neurobiological heterogeneity in AD and could potentially lead to interventions based on alternate neurocognitive-neural network profiles.

Public Health Relevance

Through investigating the atypical forms of Alzheimer's disease, we can increase our understanding of its underlying mechanisms and how it leads to dysfunction in the brain. This type of scientific understanding is important for the development of treatments and other interventions for this devastating disorder.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Hsiao, John
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Mendez, Mario F (2018) Manic behavior and asymmetric right frontotemporal dementia from a novel progranulin mutation. Neuropsychiatr Dis Treat 14:657-662
Mendez, Mario F (2018) Non-Neurogenic Language Disorders: A Preliminary Classification. Psychosomatics 59:28-35
Mendez, Mario F; Fong, Sylvia S; Ashla, Mark M et al. (2018) Skin Conduction Levels Differentiate Frontotemporal Dementia From Alzheimer's Disease. J Neuropsychiatry Clin Neurosci 30:208-213
Teng, Edmond; Mendez, Mario F (2018) Accurate Etiological Diagnosis of Dementia Contributes to Better Clinical Care. J Am Geriatr Soc 66:827-829
Mendez, Mario F (2018) Methylphenidate Treatment for Patients With Posterior Cortical Atrophy. J Neuropsychiatry Clin Neurosci :appineuropsych17120356
Granadillo, Elias; Paholpak, Pongsatorn; Mendez, Mario F et al. (2017) Visual Ratings of Medial Temporal Lobe Atrophy Correlate with CSF Tau Indices in Clinical Variants of Early-Onset Alzheimer Disease. Dement Geriatr Cogn Disord 44:45-54
Fong, Sylvia S; Paholpak, Pongsatorn; Daianu, Madelaine et al. (2017) The attribution of animacy and agency in frontotemporal dementia versus Alzheimer's disease. Cortex 92:81-94
Mendez, Mario F (2017) Early-Onset Alzheimer Disease. Neurol Clin 35:263-281
Paholpak, Pongsatorn; Mendez, Mario F (2016) Trichotillomania as a Manifestation of Dementia. Case Rep Psychiatry 2016:9782702