Alzheimer’s Disease Neuropathological Comorbidities are Common in the Younger-Old

Abstract

Background: Clinicopathological studies have demonstrated that Alzheimer’s disease dementia (ADD) is often accompanied by clinically undetectable comorbid neurodegenerative and cerebrovascular disease that alter the rate of cognitive decline. Aside from causing increased variability in clinical response, it is possible that the major ADD comorbidities may not respond to ADD-specific molecular therapeutics. Objective: As most reports have focused on comorbidity in the oldest-old, its extent in younger age groups that are more likely to be involved in clinical trials is largely unknown; our objective is to provide this information. Methods: We conducted a survey of neuropathological comorbidities in sporadic ADD using data from the US National Alzheimer’s Coordinating Center. Subject data was restricted to those with dementia and meeting National Institute on Aging-Alzheimer’s Association intermediate or high AD Neuropathological Change levels, excluding those with known autosomal dominant AD-related mutations. Results: Highly prevalent ADD comorbidities are not restricted to the oldest-old but are common even in early-onset ADD. The percentage of cases with ADD as the sole major neuropathological diagnosis is highest in the under-60 group, where “pure” ADD cases are still in the minority at 44%. After this AD as a sole major pathology in ADD declines to roughly 20%in the 70s and beyond. Lewy body disease is the most common comorbidity at younger ages but actually is less common at later ages, while for most others, their prevalence increases with age. Conclusion: Alzheimer’s disease neuropathological comorbidities are highly prevalent even in the younger-old.

Performance of αSynuclein RT-QuIC in relation to neuropathological staging of Lewy body disease

“…The presence of more than one pathology is prevalent in neurodegenerative disorders [ 10 , 41 , 59 ] and Aβ and tau pathologies may act synergistically with αSyn pathology influencing the clinical presentation and prognosis in LBD [ 43 ]. Further, misfolded αSyn might potentiate aggregation of tau [ 6 , 56 ].…”

Changes in glial cell phenotypes precede overt neurofibrillary tangle formation, correlate with markers of cortical cell damage, and predict cognitive status of individuals at Braak III-IV stages

“…Trying to understand the relationship between plaques, tangles and cognition can be confounded by a wide range of variables, including individual differences in the regional burden of lesions [ 38 ], genetic risk and protective factors [ 61 ], presence of distinct tau strains with different propensity to induce tau aggregation [ 22 ], as well as life style factors including educational attainment [ 8 ] and cognitive activity across the life span [ 99 ], that likely contribute to interindividual variation. Moreover, there is the complicating impact of other concomitant neurodegenerative processes (including those marked by inclusions containing alpha-synuclein and TAR DNA-binding protein 43 (TDP-43)) and vascular brain lesions (including small vessel disease such as arteriolar sclerosis and cerebral amyloid angiopathy (CAA), as well as stroke) whose prevalence also increases with age [ 6 , 25 , 46 ]. Clinical-pathological correlation analyses demonstrate that the burden of these lesions lower the threshold for the clinical diagnosis of dementia in the face of low levels of classic AD neuropathological changes [ 45 , 74 ], yet a recent study showed that over one third of cases with clinically manifest AD cannot be attributable to all these age-related neuropathologic indices (AD pathology and comorbidities) combined [ 12 ].…”

Performance of Αsynuclein Rt-Quic in Relation to Neuropathological Staging of Lewy Body Disease

“…The presence of more than one pathology is prevalent in neurodegenerative disorders [10, 36, 53] and Aβ and tau pathologies may act synergistically with α-syn pathology influencing the clinical presentation and prognosis in LBD [38]. Further, misfolded α-syn might potentiate aggregation of tau [6, 50].…”